1Journal Vitae | https://revistas.udea.edu.co/index.php/vitaeVolume 30 | Number 01 | Article 349001
Arsenic Trioxide: Pharmacological Applications
JOURNAL VITAE
School of Pharmaceutical and
Food Sciences
ISSN 0121-4004 | ISSNe 2145-2660
University of Antioquia
Medellin, Colombia
Filliations
1 Instituto de Investigaciones
Farmacéuticas (INIFAR), Faculty of
Pharmacy, Universidad de Costa
Rica, San José, Costa Rica.
2Industrial Pharmacy Department,
Faculty of Pharmacy, Universidad
de Costa Rica, San José, Costa
Rica.
3Pharmacy student, Faculty of Pharmacy,
Universidad de Costa Rica, San
José, Costa Rica.
*Corresponding
German Madrigal Redondo
german.madrigal@ucr.ac.cr
Received: 28 February 2022
Accepted: 21 March 2023
Published: 20 April 2023
Arsenic Trioxide: Pharmacological Applications
Trióxido de Arsénico: Aplicaciones farmacológicas
German Madrigal-Redondo1,2* , Celeste Ortega-Monge 3 , Pamela Ceciliano-
Porras 3 , Mariana Cerdas-Delgado3 , Jeison Montero-Rivera 3 , María Fernanda
Rojas-Salas1,2 , Daniela González-Corrales 1,2 , Rolando Vargas-Zúñiga 1,2
ABSTRACT
Background: Arsenic trioxide is a chemical compound that has been used as a treatment for
various diseases. Despite being potentially toxic, this compound has been used as a therapy
to treat Acute Myeloid Leukemia and is being investigated as a possible treatment for different
types of cancer. Objectives: The present review aims to describe the use and studies reported
in the literature of Arsenic Trioxide as a possible therapeutic agent for Acute Myeloid Leukemia,
Acute Promyelocytic Leukemia, Chronic Myeloid Leukemia, Multiple Myeloma, Myelodysplastic
Syndrome, Hepatocellular Carcinoma, Lung Cancer, Neuroblastoma, Breast Cancer, Aplastic
Hepatitis C, and HIV-1. Methods: A systematic review was conducted using databases (Elsevier,
Google Scholar, PubMed) to compile documents published before December 2023. Results:
Multiple pharmacological applications of arsenic trioxide have been reported to treat acute
and chronic myeloid leukemia. Arsenic trioxide has been shown to inhibit angiogenesis, which
helps treat multiple myeloma. Several studies have shown and suggested the effectiveness
of arsenic trioxide as a treatment of hepatocellular carcinoma, lung cancer, neuroblastoma,
prostate cancer, breast cancer, aplastic anemia, hepatitis C, and HIV-1. Conclusion: Despite
potentially toxic effects, Arsenic compounds are therapeutic agents for multiple diseases,
from syphilis to cancer. In recent years, more efficient ways have been investigated to deliver
and find the specific dose to treat the disease, causing the fewest possible adverse effects.
Keywords: arsenic trioxide, pharmacological alternative, cancer, carcinoma.
REVIEW ARTICLE
Published 20 April 2023
Doi: https://doi.org/10.17533/udea.vitae.v30n1a349001
Arsenic Trioxide: Pharmacological Applications
JOURNAL VITAE
School of Pharmaceutical and
Food Sciences
ISSN 0121-4004 | ISSNe 2145-2660
University of Antioquia
Medellin, Colombia
Filliations
1 Instituto de Investigaciones
Farmacéuticas (INIFAR), Faculty of
Pharmacy, Universidad de Costa
Rica, San José, Costa Rica.
2Industrial Pharmacy Department,
Faculty of Pharmacy, Universidad
de Costa Rica, San José, Costa
Rica.
3Pharmacy student, Faculty of Pharmacy,
Universidad de Costa Rica, San
José, Costa Rica.
*Corresponding
German Madrigal Redondo
german.madrigal@ucr.ac.cr
Received: 28 February 2022
Accepted: 21 March 2023
Published: 20 April 2023
Arsenic Trioxide: Pharmacological Applications
Trióxido de Arsénico: Aplicaciones farmacológicas
German Madrigal-Redondo1,2* , Celeste Ortega-Monge 3 , Pamela Ceciliano-
Porras 3 , Mariana Cerdas-Delgado3 , Jeison Montero-Rivera 3 , María Fernanda
Rojas-Salas1,2 , Daniela González-Corrales 1,2 , Rolando Vargas-Zúñiga 1,2
ABSTRACT
Background: Arsenic trioxide is a chemical compound that has been used as a treatment for
various diseases. Despite being potentially toxic, this compound has been used as a therapy
to treat Acute Myeloid Leukemia and is being investigated as a possible treatment for different
types of cancer. Objectives: The present review aims to describe the use and studies reported
in the literature of Arsenic Trioxide as a possible therapeutic agent for Acute Myeloid Leukemia,
Acute Promyelocytic Leukemia, Chronic Myeloid Leukemia, Multiple Myeloma, Myelodysplastic
Syndrome, Hepatocellular Carcinoma, Lung Cancer, Neuroblastoma, Breast Cancer, Aplastic
Hepatitis C, and HIV-1. Methods: A systematic review was conducted using databases (Elsevier,
Google Scholar, PubMed) to compile documents published before December 2023. Results:
Multiple pharmacological applications of arsenic trioxide have been reported to treat acute
and chronic myeloid leukemia. Arsenic trioxide has been shown to inhibit angiogenesis, which
helps treat multiple myeloma. Several studies have shown and suggested the effectiveness
of arsenic trioxide as a treatment of hepatocellular carcinoma, lung cancer, neuroblastoma,
prostate cancer, breast cancer, aplastic anemia, hepatitis C, and HIV-1. Conclusion: Despite
potentially toxic effects, Arsenic compounds are therapeutic agents for multiple diseases,
from syphilis to cancer. In recent years, more efficient ways have been investigated to deliver
and find the specific dose to treat the disease, causing the fewest possible adverse effects.
Keywords: arsenic trioxide, pharmacological alternative, cancer, carcinoma.
REVIEW ARTICLE
Published 20 April 2023
Doi: https://doi.org/10.17533/udea.vitae.v30n1a349001
2Journal Vitae | https://revistas.udea.edu.co/index.php/vitae Volume 30 | Number 01 | Article 349001G. Madrigal-Redondo, C. Ortega-Monge, P. Ceciliano-Porras, M. Cerdas-Delgado, J. Montero-Rivera, M.F. Rojas-Salas, D. González-Corrales, R. Vargas-Zúñiga
1. INTRODUCTION
Arsenic trioxide (ATO) has been used as a therapeutic
substance since ancient Greece and Rome more than
2,400 years ago [1,2]. Hippocrates and Dioscorides
used this chemical compound to handle ulcers
and control pests, syphilis, and malaria. Since
the nineteenth century, it has been used to treat
hematological diseases. In 1865, a patient with chronic
myeloid leukemia (CML) for the first time achieved
clinical remission when using potassium arsenite, for
which, since that year, it was indicated as a treatment
for CML [1]. In 1878, potassium bicarbonate-based
arsenic trioxide solution decreased cell counts in
patients with leukocythemia. In 1910, Salvarsan,
an organic arsenic-based treatment, was used
to treat trypanosomiasis and syphilis [2]. Also, in
1,997, the efficacy of As 2
O3 was highlighted for the
remission of patients with relapsed promyelocytic
leukemia (PML) [1]. In the 20th century, there was
a significant decrease in the use of arsenic as a
pharmacological agent; however, the U.S Food and
Drug Administration (FDA) conducted several clinical
trials and approved its use for patients with relapsed
or refractory acute promyelocytic leukemia (APL) [2].
Despite having a potentially toxic effect, Arsenic
compounds stand out as therapeutic agents for
multiple diseases ranging from syphilis to cancer.
Arsenic trioxide is a powerful drug for acute
promyelocytic leukemia. It is being investigated as
a possible pharmacological option against various
types of cancer: breast cancer, glioma, liver cancer,
hepatocellular carcinoma, cervical cancer, colorectal
cancer, bladder cancer, and lung cancer. In order to
know the antitumor effects of As 2 O3 , research has
focused on the activation of cell signaling pathways
that can lead to cell death induced by said chemical
compound [3].
2. ARSENIC TRIOXIDE
ATO’s action mechanism is based on a reaction
between the arsenic and thiol groups of proteins.
The effect it has on cellular functions depends
on three factors: cell type, duration of treatment,
and dosage [54]. In APL cells, low concentrations
(<0,5μM/L) induce cellular differentiation. APL cells
express PML-RARα, an oncogenic protein that
blocks genes related to a normal differentiation
process. ATO binds to this protein and degrades
it, stimulating differentiation. On the other hand,
at high concentrations (0,5-2μM/L), ATO can induce
dose-dependent apoptosis in APL cells, other
hematopoietic cells, tumor cells, and non-malignant
cell lines. The activation of the caspases cascade, the
production of reactive oxygen species (ROS), and
the decrease in mitochondrial membrane potential
induced by the production of ROS provoke cellular
apoptosis, which is closely related to the antitumor
effect of ATO [54, 3]. The production of ROS also
inhibits antioxidant enzymes. For example, ATO
inhibits glutathione peroxidase by binding to a thiol
group that is needed for its activation, or intracellular
glutathione titrates arsenic, forming a complex with
ATO. This results in a poor antioxidant capacity,
causing cells to be prone to undergo apoptosis [54].
Fur thermore, ATO has been associated with
inhibiting nuclear factor kappa B (NF-κB) in malignant
cells. NF-κB is a transcriptional factor that promotes
cellular survival. When the inhibitor of nuclear factor
kappa B kinase (IκK) phosphorylates the inhibitory
protein IκB, which releases NF-κB, ATO inhibits IκK;
hence, no NF-κB is released [54]. Additionally, ATO
has been shown to induce autophagy by inhibiting
apoptosis markers in macrophages through the
transcription factor EB (TFEB), which regulates the
autophagy-lysosome pathway. The production of
RESUMEN
Antecedentes: El trióxido de arsénico es un compuesto químico que se ha utilizado como tratamiento de diversas enfermedades.
A pesar de ser potencialmente tóxico, este compuesto se ha utilizado como terapia para tratar la leucemia mieloide aguda y se
está investigando como posible tratamiento para diferentes tipos de cáncer. Objetivos: La presente revisión pretende describir
el uso del trióxido de arsénico como posible agente terapéutico para la leucemia mieloide aguda, la leucemia promielocítica
aguda, la leucemia mieloide crónica, el mieloma múltiple, el síndrome mielodisplásico, el carcinoma hepatocelular, el cáncer de
pulmón, el neuroblastoma, el cáncer de mama, la hepatitis C aplásica y el VIH-1. Métodos: Se realizó una revisión sistemática
utilizando bases de datos (Elsevier, Google Scholar, PubMed) para recopilar documentos publicados antes de diciembre de
2023. Resultados: Se ha informado de múltiples aplicaciones farmacológicas del trióxido de arsénico para tratar la leucemia
mieloide aguda y la leucemia mieloide crónica. Se ha demostrado que el trióxido de arsénico inhibe la angiogénesis, lo que
resulta útil para el tratamiento del mieloma múltiple. Varios estudios han demostrado y sugerido la eficacia del trióxido de
arsénico como tratamiento del carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de próstata, el
cáncer de mama, la anemia aplásica, la hepatitis C y el VIH-1. Conclusión: A pesar de tener un efecto potencialmente tóxico,
los compuestos de arsénico destacan como agentes terapéuticos para múltiples enfermedades, desde la sífilis hasta el cáncer.
En los últimos años, se han investigado formas más eficientes de administrar y encontrar la dosis específica para poder tratar
la enfermedad, causando los menores efectos adversos posibles.
Palabras clave: Trióxido de arsénico, alternativa farmacológica, cáncer, carcinoma
1. INTRODUCTION
Arsenic trioxide (ATO) has been used as a therapeutic
substance since ancient Greece and Rome more than
2,400 years ago [1,2]. Hippocrates and Dioscorides
used this chemical compound to handle ulcers
and control pests, syphilis, and malaria. Since
the nineteenth century, it has been used to treat
hematological diseases. In 1865, a patient with chronic
myeloid leukemia (CML) for the first time achieved
clinical remission when using potassium arsenite, for
which, since that year, it was indicated as a treatment
for CML [1]. In 1878, potassium bicarbonate-based
arsenic trioxide solution decreased cell counts in
patients with leukocythemia. In 1910, Salvarsan,
an organic arsenic-based treatment, was used
to treat trypanosomiasis and syphilis [2]. Also, in
1,997, the efficacy of As 2
O3 was highlighted for the
remission of patients with relapsed promyelocytic
leukemia (PML) [1]. In the 20th century, there was
a significant decrease in the use of arsenic as a
pharmacological agent; however, the U.S Food and
Drug Administration (FDA) conducted several clinical
trials and approved its use for patients with relapsed
or refractory acute promyelocytic leukemia (APL) [2].
Despite having a potentially toxic effect, Arsenic
compounds stand out as therapeutic agents for
multiple diseases ranging from syphilis to cancer.
Arsenic trioxide is a powerful drug for acute
promyelocytic leukemia. It is being investigated as
a possible pharmacological option against various
types of cancer: breast cancer, glioma, liver cancer,
hepatocellular carcinoma, cervical cancer, colorectal
cancer, bladder cancer, and lung cancer. In order to
know the antitumor effects of As 2 O3 , research has
focused on the activation of cell signaling pathways
that can lead to cell death induced by said chemical
compound [3].
2. ARSENIC TRIOXIDE
ATO’s action mechanism is based on a reaction
between the arsenic and thiol groups of proteins.
The effect it has on cellular functions depends
on three factors: cell type, duration of treatment,
and dosage [54]. In APL cells, low concentrations
(<0,5μM/L) induce cellular differentiation. APL cells
express PML-RARα, an oncogenic protein that
blocks genes related to a normal differentiation
process. ATO binds to this protein and degrades
it, stimulating differentiation. On the other hand,
at high concentrations (0,5-2μM/L), ATO can induce
dose-dependent apoptosis in APL cells, other
hematopoietic cells, tumor cells, and non-malignant
cell lines. The activation of the caspases cascade, the
production of reactive oxygen species (ROS), and
the decrease in mitochondrial membrane potential
induced by the production of ROS provoke cellular
apoptosis, which is closely related to the antitumor
effect of ATO [54, 3]. The production of ROS also
inhibits antioxidant enzymes. For example, ATO
inhibits glutathione peroxidase by binding to a thiol
group that is needed for its activation, or intracellular
glutathione titrates arsenic, forming a complex with
ATO. This results in a poor antioxidant capacity,
causing cells to be prone to undergo apoptosis [54].
Fur thermore, ATO has been associated with
inhibiting nuclear factor kappa B (NF-κB) in malignant
cells. NF-κB is a transcriptional factor that promotes
cellular survival. When the inhibitor of nuclear factor
kappa B kinase (IκK) phosphorylates the inhibitory
protein IκB, which releases NF-κB, ATO inhibits IκK;
hence, no NF-κB is released [54]. Additionally, ATO
has been shown to induce autophagy by inhibiting
apoptosis markers in macrophages through the
transcription factor EB (TFEB), which regulates the
autophagy-lysosome pathway. The production of
RESUMEN
Antecedentes: El trióxido de arsénico es un compuesto químico que se ha utilizado como tratamiento de diversas enfermedades.
A pesar de ser potencialmente tóxico, este compuesto se ha utilizado como terapia para tratar la leucemia mieloide aguda y se
está investigando como posible tratamiento para diferentes tipos de cáncer. Objetivos: La presente revisión pretende describir
el uso del trióxido de arsénico como posible agente terapéutico para la leucemia mieloide aguda, la leucemia promielocítica
aguda, la leucemia mieloide crónica, el mieloma múltiple, el síndrome mielodisplásico, el carcinoma hepatocelular, el cáncer de
pulmón, el neuroblastoma, el cáncer de mama, la hepatitis C aplásica y el VIH-1. Métodos: Se realizó una revisión sistemática
utilizando bases de datos (Elsevier, Google Scholar, PubMed) para recopilar documentos publicados antes de diciembre de
2023. Resultados: Se ha informado de múltiples aplicaciones farmacológicas del trióxido de arsénico para tratar la leucemia
mieloide aguda y la leucemia mieloide crónica. Se ha demostrado que el trióxido de arsénico inhibe la angiogénesis, lo que
resulta útil para el tratamiento del mieloma múltiple. Varios estudios han demostrado y sugerido la eficacia del trióxido de
arsénico como tratamiento del carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de próstata, el
cáncer de mama, la anemia aplásica, la hepatitis C y el VIH-1. Conclusión: A pesar de tener un efecto potencialmente tóxico,
los compuestos de arsénico destacan como agentes terapéuticos para múltiples enfermedades, desde la sífilis hasta el cáncer.
En los últimos años, se han investigado formas más eficientes de administrar y encontrar la dosis específica para poder tratar
la enfermedad, causando los menores efectos adversos posibles.
Palabras clave: Trióxido de arsénico, alternativa farmacológica, cáncer, carcinoma
3Journal Vitae | https://revistas.udea.edu.co/index.php/vitaeVolume 30 | Number 01 | Article 349001
Arsenic Trioxide: Pharmacological Applications
ROS related to ATO can induce a translocation of
TFEB, promoting autophagosomal and lysosomal
gene expression [55].
ATO has been well tolerated regarding adverse
effects, toxicity, and safety. The most common
adverse effects in APL patients were leukocytosis,
gastrointestinal symptoms (nausea, vomiting,
diarrhea, anorexia, and abdominal discomfort),
fever, headache, cough, dyspnea, fatigue, and
hepatotoxicity [54, 56, 57]. Hepatotoxicity is a
common side effect due to an increased liver
enzymatic activity, usually solved by decreasing
the dose or interrupting treatment [56]. Skin lesions
like xerosis cutis, hyperpigmentation, and erythema
have been observed, but do not represent a severe
or major adverse event [56, 57]. The most serious
adverse events that can occur are APL differentiation
syndrome (APLDS) and electrocardiography (ECG)
abnormalities. APLDS refers to a group of signs
and symptoms related to induction therapy for
remission with ATO. It includes fever, dyspnea,
hypotension, acute renal failure, pleuropericardial
effusion, and lung infiltrate. It is usually treated
with corticosteroids. On the other hand, ECG
abnormalities commonly include prolonged QT
intervals. Complete atrioventricular blockage and
“torsade de pointes” type ventricular arrhythmia
rarely occur. For this reason, it is recommended
to monitor ECG and electrolyte levels before and
during treatment with ATO [54, 56].
3. POSSIBLE PHARMACOLOGICAL
APPLICATIONS OF ARSENIC TRIOXIDE
3.1 Acute Myeloid Leukemia and Acute
Promyelocytic Leukemia
Acute myeloid leukemia (AML) is the most common
in adults, with two incidence peaks, between
25 and 30 years old and 60 and 70 years old [4].
AML is caused by uncontrolled proliferation due
to abnormal progenitor cells that accumulate in
the bone marrow and blood. A block in myeloid
differentiation can also cause it [5]. Arsenic trioxide
has been used as first-line therapy in combination
with low-dose cytarabine to treat AML; however, it
should be used in low-risk patients [6].
Ac u te p ro myelo c y tic leuke mia ( A PL ) is a
subtype of AML due to a translocation between
chromosomes 15 and 17, which is t (15; 17) PML/
RARA. This rearrangement will allow a blockage
in the differentiation of myeloid stem cells in the
promyelocyte stage [4,7].
Arsenic trioxide is an effective therapeutic agent
against newly diagnosed low- or intermediate-risk
APL. It is used with all-trans retinoic acid (ATRA) as
first-line therapy without chemotherapy. It has been
shown that this combination of drugs can cure most
low or intermediate-risk patients with low or normal
white blood cells and registering low toxicity. The
mechanism of action of ATO is based on its effect on
the leukemic promyelocyte, which is not cytotoxic.
Instead, it affects various intracellular signal
transduction pathways, alters the cells’ function,
and induces apoptosis. Among these mechanisms
is the degradation of the fusion protein product of
the PML/RARA gene, which causes the blocking of
genes responsible for myeloid differentiation. On
the other hand, ATO at lower concentrations induces
cell differentiation [4].
ATRA/ATO consolidation after induction of ATRA/
ATO has also been shown to achieve outstanding
results in low or intermediate-risk patients [8,9]. In
addition, ATO is used in patients with APL who do
not respond to previous retinoid treatments or when
the disease returns after other drug options have
been used [10].
Some studies conducted in China and the United
States showed that ATO could induce sustained
molecular remission, being used as monotherapy
in patients who suffer a relapse after treatment
containing ATRA; later, other studies confirmed
these findings. [11]
According to the European Medicines Agency, in the
induction phase, ATO should be administered every
day until it is verified that the drug is working, which
means that the cancer cells have been eliminated
from the bone marrow. The treatment should be
interrupted if it is not achieved before day 50 or 60. It
can also be used for the consolidation phase, where
it should be given once a day for five days, then a
2-day break, which is repeated for 4 to 5 weeks [10].
Some side effects that may arise after the use of
this drug are dyspnea, fever of unknown origin,
unexplained weight gain, hypotension, acute renal
failure, the appearance of pulmonary and pericardial
edema [12], headaches, fatigue, ar thralgia,
myalgia, bone pain, itching, hyperkeratosis,
skin hyperpigmentation, exfoliative dermatitis,
inflammation of the mucous membranes of the
eyes, nose, mouth and digestive tract, abdominal
cramps, diarrhea, hypokalaemia, hypomagnesemia,
elevated transaminases, segment prolongation QT
on the electrocardiogram and sudden deaths [1].
Arsenic Trioxide: Pharmacological Applications
ROS related to ATO can induce a translocation of
TFEB, promoting autophagosomal and lysosomal
gene expression [55].
ATO has been well tolerated regarding adverse
effects, toxicity, and safety. The most common
adverse effects in APL patients were leukocytosis,
gastrointestinal symptoms (nausea, vomiting,
diarrhea, anorexia, and abdominal discomfort),
fever, headache, cough, dyspnea, fatigue, and
hepatotoxicity [54, 56, 57]. Hepatotoxicity is a
common side effect due to an increased liver
enzymatic activity, usually solved by decreasing
the dose or interrupting treatment [56]. Skin lesions
like xerosis cutis, hyperpigmentation, and erythema
have been observed, but do not represent a severe
or major adverse event [56, 57]. The most serious
adverse events that can occur are APL differentiation
syndrome (APLDS) and electrocardiography (ECG)
abnormalities. APLDS refers to a group of signs
and symptoms related to induction therapy for
remission with ATO. It includes fever, dyspnea,
hypotension, acute renal failure, pleuropericardial
effusion, and lung infiltrate. It is usually treated
with corticosteroids. On the other hand, ECG
abnormalities commonly include prolonged QT
intervals. Complete atrioventricular blockage and
“torsade de pointes” type ventricular arrhythmia
rarely occur. For this reason, it is recommended
to monitor ECG and electrolyte levels before and
during treatment with ATO [54, 56].
3. POSSIBLE PHARMACOLOGICAL
APPLICATIONS OF ARSENIC TRIOXIDE
3.1 Acute Myeloid Leukemia and Acute
Promyelocytic Leukemia
Acute myeloid leukemia (AML) is the most common
in adults, with two incidence peaks, between
25 and 30 years old and 60 and 70 years old [4].
AML is caused by uncontrolled proliferation due
to abnormal progenitor cells that accumulate in
the bone marrow and blood. A block in myeloid
differentiation can also cause it [5]. Arsenic trioxide
has been used as first-line therapy in combination
with low-dose cytarabine to treat AML; however, it
should be used in low-risk patients [6].
Ac u te p ro myelo c y tic leuke mia ( A PL ) is a
subtype of AML due to a translocation between
chromosomes 15 and 17, which is t (15; 17) PML/
RARA. This rearrangement will allow a blockage
in the differentiation of myeloid stem cells in the
promyelocyte stage [4,7].
Arsenic trioxide is an effective therapeutic agent
against newly diagnosed low- or intermediate-risk
APL. It is used with all-trans retinoic acid (ATRA) as
first-line therapy without chemotherapy. It has been
shown that this combination of drugs can cure most
low or intermediate-risk patients with low or normal
white blood cells and registering low toxicity. The
mechanism of action of ATO is based on its effect on
the leukemic promyelocyte, which is not cytotoxic.
Instead, it affects various intracellular signal
transduction pathways, alters the cells’ function,
and induces apoptosis. Among these mechanisms
is the degradation of the fusion protein product of
the PML/RARA gene, which causes the blocking of
genes responsible for myeloid differentiation. On
the other hand, ATO at lower concentrations induces
cell differentiation [4].
ATRA/ATO consolidation after induction of ATRA/
ATO has also been shown to achieve outstanding
results in low or intermediate-risk patients [8,9]. In
addition, ATO is used in patients with APL who do
not respond to previous retinoid treatments or when
the disease returns after other drug options have
been used [10].
Some studies conducted in China and the United
States showed that ATO could induce sustained
molecular remission, being used as monotherapy
in patients who suffer a relapse after treatment
containing ATRA; later, other studies confirmed
these findings. [11]
According to the European Medicines Agency, in the
induction phase, ATO should be administered every
day until it is verified that the drug is working, which
means that the cancer cells have been eliminated
from the bone marrow. The treatment should be
interrupted if it is not achieved before day 50 or 60. It
can also be used for the consolidation phase, where
it should be given once a day for five days, then a
2-day break, which is repeated for 4 to 5 weeks [10].
Some side effects that may arise after the use of
this drug are dyspnea, fever of unknown origin,
unexplained weight gain, hypotension, acute renal
failure, the appearance of pulmonary and pericardial
edema [12], headaches, fatigue, ar thralgia,
myalgia, bone pain, itching, hyperkeratosis,
skin hyperpigmentation, exfoliative dermatitis,
inflammation of the mucous membranes of the
eyes, nose, mouth and digestive tract, abdominal
cramps, diarrhea, hypokalaemia, hypomagnesemia,
elevated transaminases, segment prolongation QT
on the electrocardiogram and sudden deaths [1].
4Journal Vitae | https://revistas.udea.edu.co/index.php/vitae Volume 30 | Number 01 | Article 349001G. Madrigal-Redondo, C. Ortega-Monge, P. Ceciliano-Porras, M. Cerdas-Delgado, J. Montero-Rivera, M.F. Rojas-Salas, D. González-Corrales, R. Vargas-Zúñiga
3.2 Chronic Myeloid Leukemia
Another disease that can be treated through
ATO is chronic myeloid leukemia (CML). CML is a
myeloproliferative neoplasm originated from the
acquisition of the BCR-ABL fusion gene associated
with t 9;22) (q34; q11) [13]. Specifically, the main
cause of CML is believed to be a chromosomal
abnormality in a chromosome called Philadelphia
(Ph1), the result of a reciprocal translocation in
a single fusion gene, called BCR-ABL, that is a
mutation formed by the combination of two genes
(the BCR and the ABL). [14,15]
From a pathophysiological point of view, the BCR-
ABL gene is distributed throughout the cytoplasm
and interacts with proliferation, differentiation, and
survival functions [13]. This generates interferences
in the MAPK mechanisms (which causes an
expansion of the tumor clone), in the PI3K pathway
(which suppresses programmed cell death), and
in focal adhesion components, which decreases
cell adhesion, among others [13]. In addition, its
medullary microenvironment is characterized by
factors such as the reduced capacity to support
normal hematopoiesis, protection against apoptosis,
and induction of resistance mediated by cytokines
and cell-cell interactions [13]. Likewise, there is a
vascular endothelial growth factor (VEGF) which
is associated with the growth of cancerous tumors
and contributes to the pathogenesis of chronic
myelogenous leukemia (CML) since it has been
found that the BCR-ABL gene that causes CML also
increases VEGF [16].
For its treatment, molecularly directed therapies
based on tyrosine kinase inhibitors [14] are used,
which block the mechanism of enzymatic action of
the BCR-ABL gene fusion protein and are successful
in most cases. Those therapies that are based on
the use of tyrosine kinase inhibitors such as imatinib
mesylate; however, resistance to this drug tends to
be developed, both due to intrinsic factors (such
as mutations in the same fusion gene or clonal
evolution) and extrinsic factors (lower bioavailability
of the drug) [13]; therefore, the ATO can also be used
for the treatment of CML.
Various investigations [17,18] mention that ATO and
other drugs used to treat CML have side effects
such as thrombocytopenia and bleeding, which in
some cases are the leading cause of death in some
patients with this type of leukemia. For this reason,
more efficient ways have been investigated [18] both
to deliver this drug to patients and to find the specific
dose so that the disease can be treated in this
way. For example, it is known that drug treatments
that have combinations of ATO with imatinib can
eliminate CML-initiating cells. In contrast, the same
treatment without implementing ATO (only with
imatinib) did not show positive results and did not
achieve the goal of curing the disease [19].
Also, ATO can be combined with tretinoin (all-trans-
retinoic acid or ATRA) to give complete remission
results more significant than 90% in the treatment
of CML or with idarubicin for induction therapies
[20]. The ATRA/ATO combination induces the
differentiation of leukemic promyelocytes into
mature granulocytes, and this combination also
reduces relapse rates compared to treatments
with these compounds individually. Furthermore,
ATRA/ATO has lower hematological toxicities and
significantly improves survival in CML patients with
chemotherapy [21].
Another relevant investigation focused on human
serum albumin (HSA) nano-drug labeled with folate
(FA) and loaded with ATO, called FA-HSA-ATO.
This nano-drug could specifically recognize folate-
β-positive receptors (FRβ +) in CML cancer cells
resulting in a higher intermolecular concentration
of ATO, verified by in vitro experiments, which can
increase the efficacy of this drug and decrease its
side effects [17].
3.3 Multiple myeloma
Multiple myeloma (MM) is a malignant neoplasm of
clones of plasma cells. MM is characterized by the
production of monoclonal proteins, kidney diseases,
plasmacytosis in the bone marrow, bone lesions,
anemia, immunodeficiency, and hypercalcemia. The
evolution of MM will depend on genetic changes
in tumor cells and conditions that favor a suitable
microenvironment in the bone marrow for cancer
cells [22].
Arsenic trioxide has been used as a treatment for
MM since it activates procaspase-3, which generates
apoptosis in MM cell lines by degrading the tumor
necrosis factor receptor inactivating protein.
Furthermore, it induces cell cycle suspension by
triggering apoptosis via caspase-3 and inducing the
cyclin-dependent kinase inhibitor protein p21 [23].
Also, ATO has been shown to inhibit angiogenesis,
which is very useful for treating MM. It has been
proposed as a mechanism of action that ATO
interrupts the intrinsic apoptosis pathways since it
generates reactive oxygen species (ROS) and blocks
the redox enzymes of reduced glutathione, thiol
transferase, and glutathione (GSH) peroxidase.
3.2 Chronic Myeloid Leukemia
Another disease that can be treated through
ATO is chronic myeloid leukemia (CML). CML is a
myeloproliferative neoplasm originated from the
acquisition of the BCR-ABL fusion gene associated
with t 9;22) (q34; q11) [13]. Specifically, the main
cause of CML is believed to be a chromosomal
abnormality in a chromosome called Philadelphia
(Ph1), the result of a reciprocal translocation in
a single fusion gene, called BCR-ABL, that is a
mutation formed by the combination of two genes
(the BCR and the ABL). [14,15]
From a pathophysiological point of view, the BCR-
ABL gene is distributed throughout the cytoplasm
and interacts with proliferation, differentiation, and
survival functions [13]. This generates interferences
in the MAPK mechanisms (which causes an
expansion of the tumor clone), in the PI3K pathway
(which suppresses programmed cell death), and
in focal adhesion components, which decreases
cell adhesion, among others [13]. In addition, its
medullary microenvironment is characterized by
factors such as the reduced capacity to support
normal hematopoiesis, protection against apoptosis,
and induction of resistance mediated by cytokines
and cell-cell interactions [13]. Likewise, there is a
vascular endothelial growth factor (VEGF) which
is associated with the growth of cancerous tumors
and contributes to the pathogenesis of chronic
myelogenous leukemia (CML) since it has been
found that the BCR-ABL gene that causes CML also
increases VEGF [16].
For its treatment, molecularly directed therapies
based on tyrosine kinase inhibitors [14] are used,
which block the mechanism of enzymatic action of
the BCR-ABL gene fusion protein and are successful
in most cases. Those therapies that are based on
the use of tyrosine kinase inhibitors such as imatinib
mesylate; however, resistance to this drug tends to
be developed, both due to intrinsic factors (such
as mutations in the same fusion gene or clonal
evolution) and extrinsic factors (lower bioavailability
of the drug) [13]; therefore, the ATO can also be used
for the treatment of CML.
Various investigations [17,18] mention that ATO and
other drugs used to treat CML have side effects
such as thrombocytopenia and bleeding, which in
some cases are the leading cause of death in some
patients with this type of leukemia. For this reason,
more efficient ways have been investigated [18] both
to deliver this drug to patients and to find the specific
dose so that the disease can be treated in this
way. For example, it is known that drug treatments
that have combinations of ATO with imatinib can
eliminate CML-initiating cells. In contrast, the same
treatment without implementing ATO (only with
imatinib) did not show positive results and did not
achieve the goal of curing the disease [19].
Also, ATO can be combined with tretinoin (all-trans-
retinoic acid or ATRA) to give complete remission
results more significant than 90% in the treatment
of CML or with idarubicin for induction therapies
[20]. The ATRA/ATO combination induces the
differentiation of leukemic promyelocytes into
mature granulocytes, and this combination also
reduces relapse rates compared to treatments
with these compounds individually. Furthermore,
ATRA/ATO has lower hematological toxicities and
significantly improves survival in CML patients with
chemotherapy [21].
Another relevant investigation focused on human
serum albumin (HSA) nano-drug labeled with folate
(FA) and loaded with ATO, called FA-HSA-ATO.
This nano-drug could specifically recognize folate-
β-positive receptors (FRβ +) in CML cancer cells
resulting in a higher intermolecular concentration
of ATO, verified by in vitro experiments, which can
increase the efficacy of this drug and decrease its
side effects [17].
3.3 Multiple myeloma
Multiple myeloma (MM) is a malignant neoplasm of
clones of plasma cells. MM is characterized by the
production of monoclonal proteins, kidney diseases,
plasmacytosis in the bone marrow, bone lesions,
anemia, immunodeficiency, and hypercalcemia. The
evolution of MM will depend on genetic changes
in tumor cells and conditions that favor a suitable
microenvironment in the bone marrow for cancer
cells [22].
Arsenic trioxide has been used as a treatment for
MM since it activates procaspase-3, which generates
apoptosis in MM cell lines by degrading the tumor
necrosis factor receptor inactivating protein.
Furthermore, it induces cell cycle suspension by
triggering apoptosis via caspase-3 and inducing the
cyclin-dependent kinase inhibitor protein p21 [23].
Also, ATO has been shown to inhibit angiogenesis,
which is very useful for treating MM. It has been
proposed as a mechanism of action that ATO
interrupts the intrinsic apoptosis pathways since it
generates reactive oxygen species (ROS) and blocks
the redox enzymes of reduced glutathione, thiol
transferase, and glutathione (GSH) peroxidase.
5Journal Vitae | https://revistas.udea.edu.co/index.php/vitaeVolume 30 | Number 01 | Article 349001
Arsenic Trioxide: Pharmacological Applications
In addition, phase I and II clinical trials were
conducted in patients with this disease who are
in a relapsed or refractory stage with intensive
pretreatment. It should be noted that using ATO as
a treatment for multiple myeloma has had limited
success in patients who are in refractory MM since
they achieve more excellent resistance of tumor cells
to ATO due to the changes that this drug causes
in the levels of GSH and other regulators that have
the function of apoptosis [24]. Other studies have
shown that ATO administration in combination with
other anti-MM drugs (bortezomib, DNA methylation
inhibitor 5-azacitidine, and melphalan) causes a
synergistic effect.
3.4 Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most
common primary neoplasm in the liver. This type
of cancer mainly affects people with chronic liver
diseases caused by liver cirrhosis, which is due
to the hepatitis C virus, the hepatitis B virus, or
alcohol. HCC is the most common cause of death
in patients with liver cirrhosis [26,27]. Transcatheter
hepatic arterial chemoembolization (TACE) is
the first-line treatment for patients with primary
hepatic carcinoma since it does not have as many
adverse effects, has a curative effect, and is easy to
establish collateral circulation. However, repeated
treatment can worsen liver damage because it can
cause ischemia and hypoxia, leading to increased
vascular endothelial growth factors in tumor tissues.
For this reason, arsenic trioxide has been used as
an alternative in conjunction with TACE for the
curative treatment of this type of cancer since
they demonstrated an improvement in the clinical
efficacy rate, improving the quality of life of patients,
increasing their one-year survival rate, and reducing
the side effects caused by chemotherapy [28].
Another randomized, single-blind, two-parallel-
group study was conducted in three medical centers
with 139 patients with biopsy-confirmed HCC and
lung metastasis. This study evaluated the safety
and efficacy of transarterial chemoembolization
with arsenic trioxide and intravenous administration
in unresectable HCC with lung metastasis. As a
result, it was obtained that intravenous infusion with
ATO has a better therapeutic effect, the survival
time of the patients was increased, and there were
no serious adverse effects, so it was possible to
conclude that this treatment is safe and effective for
people with HCC with lung metastasis [29]. Another
study with 24 patients with HCC was conducted to
investigate the effects of arsenic trioxide treatment
on ezrin expression and serum alpha-fetoprotein
(AFP) levels in this type of cancer. Ezrin expression
is essential in the invasion of tumor cells, and its
expression level is related to the development,
metastasis, and prognosis of tumor cells. As a result
of this study, it was obtained that the expression
of the ezrin gene was reduced after using arsenic
trioxide as a treatment; it was also possible to show
that it can significantly decrease the levels of AFP
in serum, which is why it is considered a potent
inhibitor of the growth of cancer cells [30].
3.5 Lung cancer
Lung cancer is one of the most severe diseases, with
one of the highest incidences in humans and a high
rate of oncological mortality globally. Furthermore,
it is the leading cause of cancer mortality in men
and the third in women [31]. A study hypothesized
that arsenic trioxide has bioactivity against lung
cancer, and its mechanisms of action are through
cell damage, apoptosis, and changes in proteins
related to stress in tumor cells. The research
indicated that arsenic trioxide causes toxicity in lung
carcinoma cells (A549), and oxidative, apoptotic, and
genotoxic mechanisms can produce these effects.
In addition, it is suggested that arsenic trioxide may
be a potential chemotherapeutic agent for treating
this type of cancer; however, it is necessary to carry
out more in vivo studies with animal models of lung
tumorigenesis to confirm the therapeutic effects of
arsenic trioxide [32].
3.6 Neuroblastoma
Neuroblastoma (NBL) is an extracranial tumor
characterized as an embryonal neoplasm that affects
the development of the paravertebral sympathetic
nodes and the adrenal medulla in children [33,34].
Arsenic trioxide has been used as a possible
treatment for NBL since it stops the cell cycle of
tumor cells in the G2/M phase. A study suggests
combining chemotherapeutic drugs with arsenic
trioxide can improve the effectiveness of cytotoxic
effects against neuroblastoma. It is essential to
mention that the order of application of the drugs
is a fundamental factor since the study showed that
preincubation with arsenic trioxide followed by a
specific agent of the mitosis phase could achieve
a greater effect against cancer compared to the
application single-drug or followed by a phase-
specific non-mitosis agent [35].
Arsenic Trioxide: Pharmacological Applications
In addition, phase I and II clinical trials were
conducted in patients with this disease who are
in a relapsed or refractory stage with intensive
pretreatment. It should be noted that using ATO as
a treatment for multiple myeloma has had limited
success in patients who are in refractory MM since
they achieve more excellent resistance of tumor cells
to ATO due to the changes that this drug causes
in the levels of GSH and other regulators that have
the function of apoptosis [24]. Other studies have
shown that ATO administration in combination with
other anti-MM drugs (bortezomib, DNA methylation
inhibitor 5-azacitidine, and melphalan) causes a
synergistic effect.
3.4 Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most
common primary neoplasm in the liver. This type
of cancer mainly affects people with chronic liver
diseases caused by liver cirrhosis, which is due
to the hepatitis C virus, the hepatitis B virus, or
alcohol. HCC is the most common cause of death
in patients with liver cirrhosis [26,27]. Transcatheter
hepatic arterial chemoembolization (TACE) is
the first-line treatment for patients with primary
hepatic carcinoma since it does not have as many
adverse effects, has a curative effect, and is easy to
establish collateral circulation. However, repeated
treatment can worsen liver damage because it can
cause ischemia and hypoxia, leading to increased
vascular endothelial growth factors in tumor tissues.
For this reason, arsenic trioxide has been used as
an alternative in conjunction with TACE for the
curative treatment of this type of cancer since
they demonstrated an improvement in the clinical
efficacy rate, improving the quality of life of patients,
increasing their one-year survival rate, and reducing
the side effects caused by chemotherapy [28].
Another randomized, single-blind, two-parallel-
group study was conducted in three medical centers
with 139 patients with biopsy-confirmed HCC and
lung metastasis. This study evaluated the safety
and efficacy of transarterial chemoembolization
with arsenic trioxide and intravenous administration
in unresectable HCC with lung metastasis. As a
result, it was obtained that intravenous infusion with
ATO has a better therapeutic effect, the survival
time of the patients was increased, and there were
no serious adverse effects, so it was possible to
conclude that this treatment is safe and effective for
people with HCC with lung metastasis [29]. Another
study with 24 patients with HCC was conducted to
investigate the effects of arsenic trioxide treatment
on ezrin expression and serum alpha-fetoprotein
(AFP) levels in this type of cancer. Ezrin expression
is essential in the invasion of tumor cells, and its
expression level is related to the development,
metastasis, and prognosis of tumor cells. As a result
of this study, it was obtained that the expression
of the ezrin gene was reduced after using arsenic
trioxide as a treatment; it was also possible to show
that it can significantly decrease the levels of AFP
in serum, which is why it is considered a potent
inhibitor of the growth of cancer cells [30].
3.5 Lung cancer
Lung cancer is one of the most severe diseases, with
one of the highest incidences in humans and a high
rate of oncological mortality globally. Furthermore,
it is the leading cause of cancer mortality in men
and the third in women [31]. A study hypothesized
that arsenic trioxide has bioactivity against lung
cancer, and its mechanisms of action are through
cell damage, apoptosis, and changes in proteins
related to stress in tumor cells. The research
indicated that arsenic trioxide causes toxicity in lung
carcinoma cells (A549), and oxidative, apoptotic, and
genotoxic mechanisms can produce these effects.
In addition, it is suggested that arsenic trioxide may
be a potential chemotherapeutic agent for treating
this type of cancer; however, it is necessary to carry
out more in vivo studies with animal models of lung
tumorigenesis to confirm the therapeutic effects of
arsenic trioxide [32].
3.6 Neuroblastoma
Neuroblastoma (NBL) is an extracranial tumor
characterized as an embryonal neoplasm that affects
the development of the paravertebral sympathetic
nodes and the adrenal medulla in children [33,34].
Arsenic trioxide has been used as a possible
treatment for NBL since it stops the cell cycle of
tumor cells in the G2/M phase. A study suggests
combining chemotherapeutic drugs with arsenic
trioxide can improve the effectiveness of cytotoxic
effects against neuroblastoma. It is essential to
mention that the order of application of the drugs
is a fundamental factor since the study showed that
preincubation with arsenic trioxide followed by a
specific agent of the mitosis phase could achieve
a greater effect against cancer compared to the
application single-drug or followed by a phase-
specific non-mitosis agent [35].
6Journal Vitae | https://revistas.udea.edu.co/index.php/vitae Volume 30 | Number 01 | Article 349001G. Madrigal-Redondo, C. Ortega-Monge, P. Ceciliano-Porras, M. Cerdas-Delgado, J. Montero-Rivera, M.F. Rojas-Salas, D. González-Corrales, R. Vargas-Zúñiga
3.7 Prostate cancer
Prostate cancer is a hormone-dependent neoplasm
that is the second leading cause of death in men
worldwide. Its prevalence increases after age 50;
this disease is not so frequent before this age. It
is considered a “silent disease” because ten years
can go by without symptoms as cells grow and
transform. Prostatic carcinoma is a malignant tumor
derived from the acinar and ductal epithelium of the
prostate that can vary considerably in its glandular
differentiation, anaplasia, behavior, metastatic
patterns, and response to treatment [36].
The growth rate of prostate carcinoma tumors
ranges from very slow to moderately rapid. Some
patients may have prolonged survival even after
cancer has metastasized to distant sites such as
bone. Arsenic trioxide kills prostate carcinoma cell
lines in culture and has significant antitumor activity
in an androgen-independent murine model of
prostate cancer. In a phase II trial of arsenic trioxide
in patients with advanced hormone-refractory
prostate cancer, the prostate-specific antigen (PSA)
levels in two of the 15 evaluable patients were
markedly reduced, and the rise in levels was reduced
in another 12 patients. [37].
An in vitro study was conducted in LNCaP cells
(androgen-sensitive human prostate cancer cells) and
PC-3 cells (androgen-independent human prostate
cancer cells) to investigate the anticancer effects of
ionizing radiation combined with Arsenic Trioxide.
The combined treatment induced autophagy
and apoptosis in LNCaP cells and mainly induced
autophagy in PC-3 cells. The results obtained in
vitro were supported by in vivo experiments using
mouse models with PC-3 cell xenograft tumors;
the combined treatment suppressed tumor volume
and weight in nude mice compared to treatment
with Arsenic Trioxide or ionizing radiation alone.
Furthermore, the combination therapy resulted
in a 74% tumor growth inhibition. The cell death
observed in the in vitro study induced by the
combination treatment was primarily the result of the
inhibition of Akt/mTOR signaling pathways. These
findings suggest that the combined treatment of
Arsenic Trioxide and ionizing radiation is a potential
therapeutic strategy for androgen-dependent
prostate cancer and androgen-independent
prostate cancer [38].
3.8 Breast cancer
Breast cancer is the malignant proliferation of
epithelial cells that line the ducts or lobules of the
mammary gland. It is a disease that affects mainly
older women; 75% of cases occur in women over
50. The female: male ratio is 150:1; it is a hormone-
dependent disease [39].
In order to investigate the possible therapeutic
application of As 2 O3 in breast cancer, the effects of
As 2 O3 on the growth of four human breast cancer
cell lines were analyzed: MCF7, MDA-MB-231,
T-47D, and BT-20. The susceptibility to the direct
apoptotic effects of As 2 O3 was analyzed; in addition
to evaluating the signs of cell differentiation, the
expression profile of ICAM-1 (CD54) was evaluated,
and the consequences of treatment with As 2 O3 on
the immunogenicity of tumor cells and the effector
cells of the immune system. This study demonstrated
by standard cytotoxicity assays that As 2 O3 treatment
can increase the lysis of breast cancer cells by
lymphokine-activated killer cells (LAK cells) and
demonstrate an important role for the ICAM-1/LFA-
1 interaction in this process. As 2 O3 induced varying
degrees of differentiation, apoptosis, and lysis in
these model cell lines and may be a promising
adjuvant to current breast cancer treatments by its
apoptotic, differentiating, and immunomodulatory
effects [40].
An in vitro study evaluated the effects of As 2 O3 on
the growth of two ER-positive breast cancer cell
lines: MCF7 and T47D. It was found that at high doses
of As 2 O3 , the survival of the two ER-positive breast
cancer cell lines, MCF7 and T47D, was reduced,
while lower doses of As 2 O3 significantly inhibited
the expression of the estrogen receptor alpha (ER-
alpha), but they did not affect ER-beta expression.
ER-alpha expression is fully restored when As 2 O3
is absent for 24 hours. As 2 O3 strongly repressed
17-beta-estradiol (E2)-stimulated transcriptional
activation. Furthermore, As 2 O 3 abolished E2-
mediated transcriptional induction of the estrogen-
sensitive gene pS2. These results indicated that
As 2 O3 specifically inhibits the ER-alpha signaling
and expression pathway. As 2 O3, in combination with
other methods, could provide a new therapeutic
approach for ER-alpha-positive breast cancer [41].
A study was conducted on breast cancer patients
in which the combined effect of topical As 2 O3 and
radiotherapy on fungal and infiltrating skin lesions
of breast cancer was examined. According to the
results of this investigation, significant systemic
absorption of As 2 O3 was not determined from a
pharmacokinetic study; in addition, a decrease in
wound secretion and an improvement in local tumor
control were observed, as well as other benefits that
3.7 Prostate cancer
Prostate cancer is a hormone-dependent neoplasm
that is the second leading cause of death in men
worldwide. Its prevalence increases after age 50;
this disease is not so frequent before this age. It
is considered a “silent disease” because ten years
can go by without symptoms as cells grow and
transform. Prostatic carcinoma is a malignant tumor
derived from the acinar and ductal epithelium of the
prostate that can vary considerably in its glandular
differentiation, anaplasia, behavior, metastatic
patterns, and response to treatment [36].
The growth rate of prostate carcinoma tumors
ranges from very slow to moderately rapid. Some
patients may have prolonged survival even after
cancer has metastasized to distant sites such as
bone. Arsenic trioxide kills prostate carcinoma cell
lines in culture and has significant antitumor activity
in an androgen-independent murine model of
prostate cancer. In a phase II trial of arsenic trioxide
in patients with advanced hormone-refractory
prostate cancer, the prostate-specific antigen (PSA)
levels in two of the 15 evaluable patients were
markedly reduced, and the rise in levels was reduced
in another 12 patients. [37].
An in vitro study was conducted in LNCaP cells
(androgen-sensitive human prostate cancer cells) and
PC-3 cells (androgen-independent human prostate
cancer cells) to investigate the anticancer effects of
ionizing radiation combined with Arsenic Trioxide.
The combined treatment induced autophagy
and apoptosis in LNCaP cells and mainly induced
autophagy in PC-3 cells. The results obtained in
vitro were supported by in vivo experiments using
mouse models with PC-3 cell xenograft tumors;
the combined treatment suppressed tumor volume
and weight in nude mice compared to treatment
with Arsenic Trioxide or ionizing radiation alone.
Furthermore, the combination therapy resulted
in a 74% tumor growth inhibition. The cell death
observed in the in vitro study induced by the
combination treatment was primarily the result of the
inhibition of Akt/mTOR signaling pathways. These
findings suggest that the combined treatment of
Arsenic Trioxide and ionizing radiation is a potential
therapeutic strategy for androgen-dependent
prostate cancer and androgen-independent
prostate cancer [38].
3.8 Breast cancer
Breast cancer is the malignant proliferation of
epithelial cells that line the ducts or lobules of the
mammary gland. It is a disease that affects mainly
older women; 75% of cases occur in women over
50. The female: male ratio is 150:1; it is a hormone-
dependent disease [39].
In order to investigate the possible therapeutic
application of As 2 O3 in breast cancer, the effects of
As 2 O3 on the growth of four human breast cancer
cell lines were analyzed: MCF7, MDA-MB-231,
T-47D, and BT-20. The susceptibility to the direct
apoptotic effects of As 2 O3 was analyzed; in addition
to evaluating the signs of cell differentiation, the
expression profile of ICAM-1 (CD54) was evaluated,
and the consequences of treatment with As 2 O3 on
the immunogenicity of tumor cells and the effector
cells of the immune system. This study demonstrated
by standard cytotoxicity assays that As 2 O3 treatment
can increase the lysis of breast cancer cells by
lymphokine-activated killer cells (LAK cells) and
demonstrate an important role for the ICAM-1/LFA-
1 interaction in this process. As 2 O3 induced varying
degrees of differentiation, apoptosis, and lysis in
these model cell lines and may be a promising
adjuvant to current breast cancer treatments by its
apoptotic, differentiating, and immunomodulatory
effects [40].
An in vitro study evaluated the effects of As 2 O3 on
the growth of two ER-positive breast cancer cell
lines: MCF7 and T47D. It was found that at high doses
of As 2 O3 , the survival of the two ER-positive breast
cancer cell lines, MCF7 and T47D, was reduced,
while lower doses of As 2 O3 significantly inhibited
the expression of the estrogen receptor alpha (ER-
alpha), but they did not affect ER-beta expression.
ER-alpha expression is fully restored when As 2 O3
is absent for 24 hours. As 2 O3 strongly repressed
17-beta-estradiol (E2)-stimulated transcriptional
activation. Furthermore, As 2 O 3 abolished E2-
mediated transcriptional induction of the estrogen-
sensitive gene pS2. These results indicated that
As 2 O3 specifically inhibits the ER-alpha signaling
and expression pathway. As 2 O3, in combination with
other methods, could provide a new therapeutic
approach for ER-alpha-positive breast cancer [41].
A study was conducted on breast cancer patients
in which the combined effect of topical As 2 O3 and
radiotherapy on fungal and infiltrating skin lesions
of breast cancer was examined. According to the
results of this investigation, significant systemic
absorption of As 2 O3 was not determined from a
pharmacokinetic study; in addition, a decrease in
wound secretion and an improvement in local tumor
control were observed, as well as other benefits that
7Journal Vitae | https://revistas.udea.edu.co/index.php/vitaeVolume 30 | Number 01 | Article 349001
Arsenic Trioxide: Pharmacological Applications
include the drying of skin lesions and reduction of
unpleasant odor. As 2 O3 can stop the cycle of tumor
cells in the G2/M phase, the tumor cells being more
sensitive to radiation at this stage of the cycle can
produce sensitization of tumor cells to radiation [42].
Combining As 2 O3 and radiation therapy offers a
practical, tolerable, and safe treatment modality
for the palliative care of breast cancer patients with
superficial malignant lesions. Although the results
of this pilot study are promising, the limitation of
the small number of patients enrolled and the lack
of a specific comparison with the efficacy of solar
radiation makes necessary further randomized
phase III trials [42].
3.9 Aplastic anemia
Aplastic anemia is a pathology with pancytopenia
and a reduction in hematopoietic stem cells in which
hematopoietic tissue is exchanged for adipose
tissue. This disease is one of the anemias considered
regenerative [43]. Aplastic anemia is caused by an
over-activation of T lymphocytes that target the
bone marrow. Cytotoxic CD8 T cells that are over-
activated attack hematopoietic progenitors and
stem cells, generating excessive apoptosis [44].
Arsenic trioxide favors the expression of the BMP4
gene in stem cells from patients with aplastic
anemia, which decreases differentiation into adipose
cells and increases differentiation into osteoblasts
[45]. In addition, a study was conducted in patients
with severe aplastic anemia where a dose of 0.15
mg/kg was administered intravenously daily for
five days every week for eight weeks. This study
demonstrated that arsenic trioxide helps to improve
hematopoiesis in severe refractory aplastic anemia
since it could regulate adipogenic and osteogenic
differentiation of mesenchymal stem cells (MSCs),
inhibiting adipogenic differentiation and enhance
osteogenic differentiation of MSCs. [46]. Likewise, it
was shown that arsenic trioxide could collaborate in
immune regulation since it regulates the percentage
of Tregs and can decrease the levels of IFN-γ, IL-4,
IL-17, and TGF-β1 in the peripheral blood of patients
with severe aplastic anemia [44].
3.10 Hepatitis C
Hepatitis is an inflammation of the liver, with an
irregular degeneration of parenchymal cells, the
necrosis of liver cells, and a lobar inflammatory
reaction and disruption of the hepatocyte cords.
These alterations cause Kupffer cell hyperplasia,
cellular degeneration, and periportal infiltration by
mononuclear cells. Hepatitis C (HCV) is mild, with a
minimal elevation of liver enzymes. Patients with this
disease usually do not require hospitalization, and
jaundice only occurs in less than 25% of people with
hepatitis C. Yet, many patients may develop cirrhosis
and are at high risk for hepatocellular carcinoma [47].
Multiple antiviral trials demonstrated that arsenic
trioxide in sub-micromolar concentrations could
inhibit the replication of the hepatitis C virus. It
was shown that combining interferon-alpha and
arsenic trioxide can generate synergistic effects
against HCV. Likewise, ATO and IFN-alpha can
synergistically induce a negative regulation of
genes involved with the cell cycle, which causes it
to stop and generate apoptosis of cells. The anti-
HCV activity of arsenic trioxide has been verified
through various assays using Ava5 cells that have
the subgenomic HCV RNA replicon. Furthermore,
it was shown that ATO could completely abolish
the signal of the hepatitis C virus in an alternative
replication system of the virus [48].
3.11 HIV-1
HIV-1 is a retrovirus of the lentivirus family,
composed of two identical copies of single-stranded
RNA molecules. It invades cells containing specific
membrane receptors and incorporates a DNA
copy into the host genome. HIV-1 is acquired
by contacting infected body fluids, particularly
blood, and semen. The most common modes of
transmission are sexual, parenteral (recipients of
blood or blood products, injection drug users, and
occupational exposure to contaminated products),
and vertical transmission (mother to fetus) [49].
One study demonstrated that arsenic trioxide
reactivates latent provirus in CD4+ T cells of HIV-1
patients and simian immunodeficiency virus (SIV)
infected macaques without significant systemic
T cell activation and no inflammatory responses.
Arsenic trioxide combined with antiretroviral therapy
(ART) delays viral rebound after ART termination,
reduces integrated SIV DNA copies on CD4+ T cells,
and restores CD4+ T cell counts in vivo [50,51].
Half of the arsenic trioxide-treated macaques
showed no detectable viral rebound in plasma
for at least 80 days after antiretroviral therapy was
stopped. CD4 receptors and CCR5 coreceptors
on CD4+ T cells are significantly down-regulated
by treatment with arsenic trioxide, which reduces
susceptibility to infection after provirus reactivation.
Fur thermore, increased SIV-specific immune
Arsenic Trioxide: Pharmacological Applications
include the drying of skin lesions and reduction of
unpleasant odor. As 2 O3 can stop the cycle of tumor
cells in the G2/M phase, the tumor cells being more
sensitive to radiation at this stage of the cycle can
produce sensitization of tumor cells to radiation [42].
Combining As 2 O3 and radiation therapy offers a
practical, tolerable, and safe treatment modality
for the palliative care of breast cancer patients with
superficial malignant lesions. Although the results
of this pilot study are promising, the limitation of
the small number of patients enrolled and the lack
of a specific comparison with the efficacy of solar
radiation makes necessary further randomized
phase III trials [42].
3.9 Aplastic anemia
Aplastic anemia is a pathology with pancytopenia
and a reduction in hematopoietic stem cells in which
hematopoietic tissue is exchanged for adipose
tissue. This disease is one of the anemias considered
regenerative [43]. Aplastic anemia is caused by an
over-activation of T lymphocytes that target the
bone marrow. Cytotoxic CD8 T cells that are over-
activated attack hematopoietic progenitors and
stem cells, generating excessive apoptosis [44].
Arsenic trioxide favors the expression of the BMP4
gene in stem cells from patients with aplastic
anemia, which decreases differentiation into adipose
cells and increases differentiation into osteoblasts
[45]. In addition, a study was conducted in patients
with severe aplastic anemia where a dose of 0.15
mg/kg was administered intravenously daily for
five days every week for eight weeks. This study
demonstrated that arsenic trioxide helps to improve
hematopoiesis in severe refractory aplastic anemia
since it could regulate adipogenic and osteogenic
differentiation of mesenchymal stem cells (MSCs),
inhibiting adipogenic differentiation and enhance
osteogenic differentiation of MSCs. [46]. Likewise, it
was shown that arsenic trioxide could collaborate in
immune regulation since it regulates the percentage
of Tregs and can decrease the levels of IFN-γ, IL-4,
IL-17, and TGF-β1 in the peripheral blood of patients
with severe aplastic anemia [44].
3.10 Hepatitis C
Hepatitis is an inflammation of the liver, with an
irregular degeneration of parenchymal cells, the
necrosis of liver cells, and a lobar inflammatory
reaction and disruption of the hepatocyte cords.
These alterations cause Kupffer cell hyperplasia,
cellular degeneration, and periportal infiltration by
mononuclear cells. Hepatitis C (HCV) is mild, with a
minimal elevation of liver enzymes. Patients with this
disease usually do not require hospitalization, and
jaundice only occurs in less than 25% of people with
hepatitis C. Yet, many patients may develop cirrhosis
and are at high risk for hepatocellular carcinoma [47].
Multiple antiviral trials demonstrated that arsenic
trioxide in sub-micromolar concentrations could
inhibit the replication of the hepatitis C virus. It
was shown that combining interferon-alpha and
arsenic trioxide can generate synergistic effects
against HCV. Likewise, ATO and IFN-alpha can
synergistically induce a negative regulation of
genes involved with the cell cycle, which causes it
to stop and generate apoptosis of cells. The anti-
HCV activity of arsenic trioxide has been verified
through various assays using Ava5 cells that have
the subgenomic HCV RNA replicon. Furthermore,
it was shown that ATO could completely abolish
the signal of the hepatitis C virus in an alternative
replication system of the virus [48].
3.11 HIV-1
HIV-1 is a retrovirus of the lentivirus family,
composed of two identical copies of single-stranded
RNA molecules. It invades cells containing specific
membrane receptors and incorporates a DNA
copy into the host genome. HIV-1 is acquired
by contacting infected body fluids, particularly
blood, and semen. The most common modes of
transmission are sexual, parenteral (recipients of
blood or blood products, injection drug users, and
occupational exposure to contaminated products),
and vertical transmission (mother to fetus) [49].
One study demonstrated that arsenic trioxide
reactivates latent provirus in CD4+ T cells of HIV-1
patients and simian immunodeficiency virus (SIV)
infected macaques without significant systemic
T cell activation and no inflammatory responses.
Arsenic trioxide combined with antiretroviral therapy
(ART) delays viral rebound after ART termination,
reduces integrated SIV DNA copies on CD4+ T cells,
and restores CD4+ T cell counts in vivo [50,51].
Half of the arsenic trioxide-treated macaques
showed no detectable viral rebound in plasma
for at least 80 days after antiretroviral therapy was
stopped. CD4 receptors and CCR5 coreceptors
on CD4+ T cells are significantly down-regulated
by treatment with arsenic trioxide, which reduces
susceptibility to infection after provirus reactivation.
Fur thermore, increased SIV-specific immune
8Journal Vitae | https://revistas.udea.edu.co/index.php/vitae Volume 30 | Number 01 | Article 349001G. Madrigal-Redondo, C. Ortega-Monge, P. Ceciliano-Porras, M. Cerdas-Delgado, J. Montero-Rivera, M.F. Rojas-Salas, D. González-Corrales, R. Vargas-Zúñiga
responses after treatment with arsenic trioxide may
suppress viral rebound [51].
3.12 Myelodysplastic syndrome
Myelodysplastic syndrome is a hematologic disease
characterized by a clonal disorder, where dysplasias
are observed in one or more cell lines and ineffective
hematopoiesis, and there is an increased risk of
developing acute myeloid leukemia [52]. Patients’
most common symptoms are related to cytopenias,
including infections, fatigue, and bleeding. Most
patients will need red blood cells or platelet
transfusions during the condition [53].
Some in vitro studies demonstrated apoptosis in
cells with Myelodysplastic syndrome exposed to
As 2 O3 . Cells with Myelodysplastic syndrome are
subjected to more significant oxidative stress,
which leads to the possibility of having sensitivity
to As 2 O3 . In two phase II clinical studies involving
191 patients, As 2 O3 as a single agent was associated
with a hematological improvement in 26–34% of
patients with lower-risk Myelodysplastic syndrome
and 6–17% of those with higher-risk Myelodysplastic
syndrome [54].
In addition, As 2 O3 was investigated together with
thalidomide based on the hypothesis that this
combination would target both the myelodysplastic
s y n d r o m e c l o n e a n d t h e b o n e m a r r o w
microenvironment. This combination was evaluated
in patients with a myelodysplastic syndrome,
where it was observed that patients with high
baseline levels of the EVI1 marker responded to the
combination; later, this observation was supported
by in vitro experiments, which demonstrated greater
sensitivity to As 2 O3 in cells expressing high levels of
EVI1. [54]. A phase II study evaluating the safety and
efficacy of this treatment was also conducted, where
most of the adverse effects observed were mild or
moderate, and there were no treatment-associated
deaths [53].
CONCLUSIONS
Despite having a potentially toxic effect, Arsenic
compounds stand out as therapeutic agents for
multiple diseases ranging from syphilis to cancer.
Arsenic trioxide (ATO) has been used as a therapeutic
substance since ancient Greece and Rome for more
than 2,400 years, but since the 19th century, it has
been used to treat hematological diseases.
Arsenic trioxide is a potent drug for acute
promyelocytic leukemia and is being investigated
as a possible pharmacological option against
various types of cancer: breast, glioma, liver cancer,
hepatocellular carcinoma, cervical cancer, colorectal
cancer, bladder cancer, and lung cancer. In order to
know the antitumor effects of As 2 O3 , research has
focused on the activation of cell signaling pathways
that can lead to cell death induced by said chemical
compound.
Some side effects that may arise after the use
of this medicine are: dyspnea, fever of unknown
origin, unexplained weight gain, hypotension, acute
renal failure, the appearance of pulmonary and
pericardial edema, headaches, fatigue, arthralgia,
myalgia, bone pain, pruritus, hyperkeratosis,
skin hyperpigmentation, exfoliative dermatitis,
inflammation of the mucous membranes of the
eyes, nose, mouth and digestive tract, abdominal
cramps, diarrhea, hypokalaemia, hypomagnesemia,
elevated transaminases, QT segment prolongation
in the electrocardiogram and sudden deaths; Due
to the above, in recent years, more efficient ways
have been investigated both to deliver this drug to
patients, and to find the specific dose so that in this
way the disease can be treated causing the fewest
possible adverse effects.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
[1] Padrón C, Espinosa E, Losada R, Ávila O, Hernández P. Trióxido
de arsénico: una nueva luz en el tratamiento de la leucemia
promielocítica. Rev Cubana Hematol Inmunol Hemoter [Internet].
2008; 24(2): 1-9. Available from: http://scielo.sld.cu/scielo.
php?script=sci_arttext&pid=S0864-02892008000200001
[2] Antman K. Introduction: The History of Arsenic Trioxide in
Cancer Therapy. The Oncologist. 2001; 6(2): 1-2. DOI: https://
doi.org/10.1634/theoncologist.6-suppl_2-1
[3] Hoonjan M, Jadhav V, Bhatt P. Arsenic trioxide: insights into its
evolution to an anticancer agent. JBIC. 2018; 23(3): 313–329.
DOI: https://doi.org/10.1007/s00775-018-1537-9
[4] Suárez C, Noa Y, Rodríguez I, Hernández G, de la Uz Ruesga B.
Tratamiento con trióxido de arsénico en pacientes con leucemia
promielocítica aguda. MEDISAN [Internet]. 2014; 18(1): 25-33.
Available from: https://www.medigraphic.com/cgi-bin/new/
resumen.cgi?IDARTICULO=47402
[5] Mejía J, Núñez J, Fajardo A, Rodríguez M, Martín J, Duarte D,
et al. Epidemiología descriptiva de la leucemia mieloide aguda
(LMA) en niños residentes de la Ciudad de México: reporte del
Grupo Mexicano Interinstitucional para la Identificación de las
Causas de la Leucemia en Niños. Gac Med Mex [Internet]. 2016;
152(S2): 66-77. Available from: https://www.medigraphic.com/
cgi-bin/new/resumen.cgi?IDARTICULO=68755
responses after treatment with arsenic trioxide may
suppress viral rebound [51].
3.12 Myelodysplastic syndrome
Myelodysplastic syndrome is a hematologic disease
characterized by a clonal disorder, where dysplasias
are observed in one or more cell lines and ineffective
hematopoiesis, and there is an increased risk of
developing acute myeloid leukemia [52]. Patients’
most common symptoms are related to cytopenias,
including infections, fatigue, and bleeding. Most
patients will need red blood cells or platelet
transfusions during the condition [53].
Some in vitro studies demonstrated apoptosis in
cells with Myelodysplastic syndrome exposed to
As 2 O3 . Cells with Myelodysplastic syndrome are
subjected to more significant oxidative stress,
which leads to the possibility of having sensitivity
to As 2 O3 . In two phase II clinical studies involving
191 patients, As 2 O3 as a single agent was associated
with a hematological improvement in 26–34% of
patients with lower-risk Myelodysplastic syndrome
and 6–17% of those with higher-risk Myelodysplastic
syndrome [54].
In addition, As 2 O3 was investigated together with
thalidomide based on the hypothesis that this
combination would target both the myelodysplastic
s y n d r o m e c l o n e a n d t h e b o n e m a r r o w
microenvironment. This combination was evaluated
in patients with a myelodysplastic syndrome,
where it was observed that patients with high
baseline levels of the EVI1 marker responded to the
combination; later, this observation was supported
by in vitro experiments, which demonstrated greater
sensitivity to As 2 O3 in cells expressing high levels of
EVI1. [54]. A phase II study evaluating the safety and
efficacy of this treatment was also conducted, where
most of the adverse effects observed were mild or
moderate, and there were no treatment-associated
deaths [53].
CONCLUSIONS
Despite having a potentially toxic effect, Arsenic
compounds stand out as therapeutic agents for
multiple diseases ranging from syphilis to cancer.
Arsenic trioxide (ATO) has been used as a therapeutic
substance since ancient Greece and Rome for more
than 2,400 years, but since the 19th century, it has
been used to treat hematological diseases.
Arsenic trioxide is a potent drug for acute
promyelocytic leukemia and is being investigated
as a possible pharmacological option against
various types of cancer: breast, glioma, liver cancer,
hepatocellular carcinoma, cervical cancer, colorectal
cancer, bladder cancer, and lung cancer. In order to
know the antitumor effects of As 2 O3 , research has
focused on the activation of cell signaling pathways
that can lead to cell death induced by said chemical
compound.
Some side effects that may arise after the use
of this medicine are: dyspnea, fever of unknown
origin, unexplained weight gain, hypotension, acute
renal failure, the appearance of pulmonary and
pericardial edema, headaches, fatigue, arthralgia,
myalgia, bone pain, pruritus, hyperkeratosis,
skin hyperpigmentation, exfoliative dermatitis,
inflammation of the mucous membranes of the
eyes, nose, mouth and digestive tract, abdominal
cramps, diarrhea, hypokalaemia, hypomagnesemia,
elevated transaminases, QT segment prolongation
in the electrocardiogram and sudden deaths; Due
to the above, in recent years, more efficient ways
have been investigated both to deliver this drug to
patients, and to find the specific dose so that in this
way the disease can be treated causing the fewest
possible adverse effects.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
[1] Padrón C, Espinosa E, Losada R, Ávila O, Hernández P. Trióxido
de arsénico: una nueva luz en el tratamiento de la leucemia
promielocítica. Rev Cubana Hematol Inmunol Hemoter [Internet].
2008; 24(2): 1-9. Available from: http://scielo.sld.cu/scielo.
php?script=sci_arttext&pid=S0864-02892008000200001
[2] Antman K. Introduction: The History of Arsenic Trioxide in
Cancer Therapy. The Oncologist. 2001; 6(2): 1-2. DOI: https://
doi.org/10.1634/theoncologist.6-suppl_2-1
[3] Hoonjan M, Jadhav V, Bhatt P. Arsenic trioxide: insights into its
evolution to an anticancer agent. JBIC. 2018; 23(3): 313–329.
DOI: https://doi.org/10.1007/s00775-018-1537-9
[4] Suárez C, Noa Y, Rodríguez I, Hernández G, de la Uz Ruesga B.
Tratamiento con trióxido de arsénico en pacientes con leucemia
promielocítica aguda. MEDISAN [Internet]. 2014; 18(1): 25-33.
Available from: https://www.medigraphic.com/cgi-bin/new/
resumen.cgi?IDARTICULO=47402
[5] Mejía J, Núñez J, Fajardo A, Rodríguez M, Martín J, Duarte D,
et al. Epidemiología descriptiva de la leucemia mieloide aguda
(LMA) en niños residentes de la Ciudad de México: reporte del
Grupo Mexicano Interinstitucional para la Identificación de las
Causas de la Leucemia en Niños. Gac Med Mex [Internet]. 2016;
152(S2): 66-77. Available from: https://www.medigraphic.com/
cgi-bin/new/resumen.cgi?IDARTICULO=68755
9Journal Vitae | https://revistas.udea.edu.co/index.php/vitaeVolume 30 | Number 01 | Article 349001
Arsenic Trioxide: Pharmacological Applications
[6] Sanz M, Fenaux P, Tallman M, Estey, E, Löwenberg B, Naoe T,
Lengfelde, E, Döhener H, Burnett A, Chen Sai-Juan, Mathewa V,
Iland H, Rego E, Kantarjian H, Adés L, Avvisati G, Montesinoes
P, Platzbecker U, Ravandi F, Russell N, Lo-Coco F. Management
of acute promyelocytic leukemia: updated recommendations
from an expert panel of the European LeukemiaNet. Blood.
2019; 133(15): 1630 -1643. DOI: ht tps://doi.org/10.1182/
blood-2019-01-894980
[7] Mejía-Buriticá L, Torres-Hernández JD, Vásquez G de J. Leucemia
promielocítica aguda. Estado del arte. Iatreia. 2020; 34(1): 42-53.
DOI: https://doi.org/10.17533/udea.iatreia.76
[8] Watts J, Tallman M. Acute promyelocytic leukemia: What is the
new standard of care?. Blood Rev. 2014; 28(5): 205-212. DOI:
https://doi.org/10.1016/j.blre.2014.07.001
[9] Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G,
Jabbour E, et al. Long-term outcome of acute promyelocytic
leukemia treated with all-trans-retinoic acid, arsenic trioxide, and
gemtuzumab. Blood. 2017; 129(10): 1275-1283. DOI: https://doi.
org/10.1182/blood-2016-09-736686
[10] European Medicines Agency. Science Medicines Health,
Trisenox. https://www.ema.europa.eu/en/medicines/human/
EPAR/trisenox 2019.
[11] Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM,
Iacobelli S, et al. Retinoic Acid and Arsenic Trioxide for Acute
Promyelocytic Leukemia. N Engl J Med. 2013; 369(2): 111-121.
DOI: https://doi.org/10.1056/nejmoa1300874
[12] Moreno M, Lassaletta A, García A, Sevilla J, Madero L.
Tratamiento con trióxido de arsénico en paciente con recaída
de leucemia promielocítica aguda. Anales de Pediatría. 2010;
73(1): 39-41. DOI: https://doi.org/10.1016/j.anpedi.2010.04.010
[13] Aristizábal J, Chandia M, del Cañizo M.C, Sánchez-Guijo F.
Microambiente medular en la leucemia mieloide crónica: su
relación con la enfermedad y la respuesta al tratamiento.
Rev. méd. Chile. 2014; 142(5): 599-605. DOI: http://dx.doi.
org/10.4067/S0034-98872014000500008
[14] Goldman J, Melo J. Chronic myeloid leukemia - advances in
biology and new approaches to treatment. N Engl J Med.
2003. 349(15): 1451-1464. DOI: http://dx.doi.org/10.1056/
NEJMra020777
[15] El Eit RM, Iskandarani AN, Saliba JL, Jabbour MN, Mahfouz RA,
Bitar NMA, et al. Effective targeting of chronic myeloid leukemia
initiating activity with the combination of arsenic trioxide and
interferon alpha: Arsenic and interferon targets CML initiating
cells activity. Int J Cancer. 2014; 134(4): 988-996. DOI: https://
doi.org/10.1002/ijc.28427
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5956.1000379
Arsenic Trioxide: Pharmacological Applications
[6] Sanz M, Fenaux P, Tallman M, Estey, E, Löwenberg B, Naoe T,
Lengfelde, E, Döhener H, Burnett A, Chen Sai-Juan, Mathewa V,
Iland H, Rego E, Kantarjian H, Adés L, Avvisati G, Montesinoes
P, Platzbecker U, Ravandi F, Russell N, Lo-Coco F. Management
of acute promyelocytic leukemia: updated recommendations
from an expert panel of the European LeukemiaNet. Blood.
2019; 133(15): 1630 -1643. DOI: ht tps://doi.org/10.1182/
blood-2019-01-894980
[7] Mejía-Buriticá L, Torres-Hernández JD, Vásquez G de J. Leucemia
promielocítica aguda. Estado del arte. Iatreia. 2020; 34(1): 42-53.
DOI: https://doi.org/10.17533/udea.iatreia.76
[8] Watts J, Tallman M. Acute promyelocytic leukemia: What is the
new standard of care?. Blood Rev. 2014; 28(5): 205-212. DOI:
https://doi.org/10.1016/j.blre.2014.07.001
[9] Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G,
Jabbour E, et al. Long-term outcome of acute promyelocytic
leukemia treated with all-trans-retinoic acid, arsenic trioxide, and
gemtuzumab. Blood. 2017; 129(10): 1275-1283. DOI: https://doi.
org/10.1182/blood-2016-09-736686
[10] European Medicines Agency. Science Medicines Health,
Trisenox. https://www.ema.europa.eu/en/medicines/human/
EPAR/trisenox 2019.
[11] Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM,
Iacobelli S, et al. Retinoic Acid and Arsenic Trioxide for Acute
Promyelocytic Leukemia. N Engl J Med. 2013; 369(2): 111-121.
DOI: https://doi.org/10.1056/nejmoa1300874
[12] Moreno M, Lassaletta A, García A, Sevilla J, Madero L.
Tratamiento con trióxido de arsénico en paciente con recaída
de leucemia promielocítica aguda. Anales de Pediatría. 2010;
73(1): 39-41. DOI: https://doi.org/10.1016/j.anpedi.2010.04.010
[13] Aristizábal J, Chandia M, del Cañizo M.C, Sánchez-Guijo F.
Microambiente medular en la leucemia mieloide crónica: su
relación con la enfermedad y la respuesta al tratamiento.
Rev. méd. Chile. 2014; 142(5): 599-605. DOI: http://dx.doi.
org/10.4067/S0034-98872014000500008
[14] Goldman J, Melo J. Chronic myeloid leukemia - advances in
biology and new approaches to treatment. N Engl J Med.
2003. 349(15): 1451-1464. DOI: http://dx.doi.org/10.1056/
NEJMra020777
[15] El Eit RM, Iskandarani AN, Saliba JL, Jabbour MN, Mahfouz RA,
Bitar NMA, et al. Effective targeting of chronic myeloid leukemia
initiating activity with the combination of arsenic trioxide and
interferon alpha: Arsenic and interferon targets CML initiating
cells activity. Int J Cancer. 2014; 134(4): 988-996. DOI: https://
doi.org/10.1002/ijc.28427
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10Journal Vitae | https://revistas.udea.edu.co/index.php/vitae Volume 30 | Number 01 | Article 349001G. Madrigal-Redondo, C. Ortega-Monge, P. Ceciliano-Porras, M. Cerdas-Delgado, J. Montero-Rivera, M.F. Rojas-Salas, D. González-Corrales, R. Vargas-Zúñiga
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application of arsenic trioxide may potentiate cytotoxic effects
of vinorelbine/docetaxel on neuroblastoma SK-N-SH cells.
Biomedicine & Pharmacotherapy. 2019; 113: 108665. DOI: https://
doi.org/10.1016/j.biopha.2019.108665
[36] Ruiz A, Pérez J, Cruz Y, González L. Actualización sobre cáncer
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ctrv.2007.05.001
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the Radiation Sensitivit y of Androgen- Dependent and
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7(2): e31579. DOI: https://doi.org/10.1371/journal.pone.0031579
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MG, et al. Arsenic Trioxide and Breast Cancer: Analysis of the
Apoptotic, Differentiative and Immunomodulatory Effects. Breast
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org/10.1023/a:1015272401822
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receptor a by arsenic trioxide in human breast cancer cells.
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et al. Combined effect of topical arsenic trioxide and radiation
therapy on skin-infiltrating lesions of breast cancer a pilot
study. Anticancer Drugs. 2003; 14(10): 825-8. DOI: https://doi.
org/10.1097/00001813-200311000-00008
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Hematología. La sangre y sus enfermedades, 4e. McGraw-Hill;
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the Tregs ratio and the levels of IFN-γ, IL-4, IL-17 and TGF-β1 in
the peripheral blood of severe aplastic anemia patients. Medicine
(Baltimore). 2020; 99(26): e20630. DOI: https://doi.org/10.1097/
MD.0000000000020630
[45] Cheng H, Liu S, Li W, Zhao X, Cheng M, Qiu L et al. Arsenic
trioxide regulates adipogenic and osteogenic differentiation in
bone marrow MSCs of aplastic anemia patients through BMP4
gene, Acta Biochimica et Biophysica Sinica. 2015; 47(9): 673-679.
DOI: https://doi.org/10.1093/abbs/gmv065
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hematopoiesis in refractory severe aplastic anemia. J Hematol
Oncol. 2015; 5:61. DOI: https://doi.org/10.1186/1756-8722-5-61
[47] Riedel S, Hobden JA, Miller S, Morse SA, Mietzner TA, Detrick B,
Mitchell TG, Sakanari JA, Hotez P, Mejia R. Microbiología Médica
[Internet]. 28e. McGraw-Hill; 2020. Available from: https://
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Hepatitis C Virus Replication by Arsenic Trioxide. Antimicrobial
Agents and Chemotherapy. 2004; 48 (8), 2876–2882. DOI: https://
doi.org/10.1128/AAC.48.8.2876-2882.2004
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SYSTEM. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds.
Hurst’s The Heart, 14e New York, NY: McGraw-Hill; 2017. Available
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ac.cr:2048/content.aspx?bookid=2046§ionid=176566883.
[50] Wang Q, Jiang Y, Naranmandura H. Therapeutic Strategy of
Arsenic Trioxide in the Fight Against Cancers and Other Diseases.
Metallomics. 2020; 12(3): 317-462. 10.1039.C9MT00308H–. DOI:
https://doi.org/10.1039/c9mt00308h
[51] Yang Q, Feng F, Li P, Pan E, Wu C, He Y, Zhang F, Zhao J, Li
R, Feng L, Hu F, Li L, Zou H, Cai W, Lehner T, Sun C, Chen L.
Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound
after Termination of ART in Chronically SIV-Infected Macaque.
Advanced Science. 2019; 6(13):1900319. DOI: https://doi.
org/10.1002/advs.201900319
[52] Mora G, Espinosa D, Casas C. Caracterización clínica de los
pacientes con síndrome mielodisplásico. Acta Médica Colomb.
2016; 41(1): 36-41. DOI: https://doi.org/10.36104/amc.2016.538
[53] Vey N, Bosly A, Guerci A, Feremans W, Dombret H, Dreyfus F, et
al. Arsenic Trioxide in Patients with Myelodysplastic Syndromes:
A Phase II Multicenter Study. J Clin Oncol. 2006; 24(16):2465-71.
DOI: https://doi.org/10.1200/JCO.2005.03.9503
[54] Emadi A, Gore SD. Arsenic trioxide — An old drug rediscovered.
Blood Rev. 2010; 24(4-5):191-9. DOI: https://doi.org/10.1016/j.
blre.2010.04.001
[55] Fang S, Wan X, Zou X, Sun S, Hao X, Liang C, et al. Arsenic
trioxide induces macrophage autophagy and atheroprotection
by regulating ROS-dependent TFEB nuclear translocation and
AKT/mTOR pathway. Cell Death Dis. 2021; 12(1):88. DOI: https://
doi.org/10.1038/s41419-020-03357-1
[56] Wang QQ, Hua HY, Naranmandura H, Zhu H-H. Balance between
the toxicity and anticancer activity of arsenic trioxide in treatment
of acute promyelocytic leukemia. Toxicol Appl Pharmacol.
2020;409. DOI: https://doi.org/10.1016/j.taap.2020.115299
[57] Zhang P. On arsenic trioxide in the clinical treatment of acute
promyelocytic leukemia. Leuk Res Reports. 2017; 7:29–32. DOI:
https://doi.org/10.1016/j.lrr.2017.03.001
[33] Dumba, M, Jawad N, McHugh K. Neuroblas toma and
nephroblastoma: a radiological review. Cancer imaging. 2015;
15(1):5. DOI: https://doi.org/10.1186/s40644-015-0040-6
[34] Tsubota S, Kadomatsu K. Origin and initiation mechanisms of
neuroblastoma. Cell Tissue Res. 2018; 372(2): 211-221. DOI:
https://doi.org/10.1007/s00441-018-2796-z
[35] Qi K, Li Y, Huang K, Xiong X, Chuchu F, Zhang C, Weng W. Pre-
application of arsenic trioxide may potentiate cytotoxic effects
of vinorelbine/docetaxel on neuroblastoma SK-N-SH cells.
Biomedicine & Pharmacotherapy. 2019; 113: 108665. DOI: https://
doi.org/10.1016/j.biopha.2019.108665
[36] Ruiz A, Pérez J, Cruz Y, González L. Actualización sobre cáncer
de próstata. Correo Científico Médico [Internet]. 2017; 21(3):
876-887. Available from: https://www.medigraphic.com/cgi-bin/
new/resumen.cgi?IDARTICULO=73979
[37] Dilda P, Hogg P. Arsenical-based cancer drugs. Cancer Treat
Rev. 2007; 33(6), 542–564. DOI: https://doi.org/10.1016/j.
ctrv.2007.05.001
[38] Chiu HW, Chen YA, Ho SY, Wang YJ. Arsenic Trioxide Enhances
the Radiation Sensitivit y of Androgen- Dependent and
-Independent Human Prostate Cancer Cells. PLoS ONE. 2012;
7(2): e31579. DOI: https://doi.org/10.1371/journal.pone.0031579
[39] Hayes DF, Lippman ME. Cáncer de mama. Jameson J, Fauci
AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J(Eds.), Harrison.
Principios de Medicina Interna, 20e. McGraw-Hill; 2018.
[40] Baj G, Arnulfo A, Deaglio S, Mallone R, Vigone A, De Cesaris
MG, et al. Arsenic Trioxide and Breast Cancer: Analysis of the
Apoptotic, Differentiative and Immunomodulatory Effects. Breast
Cancer Res Treat. mayo de 2002;73(1):61-73. DOI: https://doi.
org/10.1023/a:1015272401822
[41] Chen G, Guan L, Hu W, Wang Z. Functional repression of estrogen
receptor a by arsenic trioxide in human breast cancer cells.
Anticancer Res [Internet]. 2002; 22(2A): 633-638. Available from:
https://pubmed.ncbi.nlm.nih.gov/12014631/
[42] Lai Y-L, Chang H-H, Huang M-J, Chang K-H, Su W-H, Chen H-W,
et al. Combined effect of topical arsenic trioxide and radiation
therapy on skin-infiltrating lesions of breast cancer a pilot
study. Anticancer Drugs. 2003; 14(10): 825-8. DOI: https://doi.
org/10.1097/00001813-200311000-00008
[43] Cantú O. Anemia aplásica. In: Pérez J, Almaguer D. eds.
Hematología. La sangre y sus enfermedades, 4e. McGraw-Hill;
2016. Accessed November 02, 2020.
[44] Zhao J, Song Y, Liu L, Yang S, Fang B. Effect of arsenic trioxide on
the Tregs ratio and the levels of IFN-γ, IL-4, IL-17 and TGF-β1 in
the peripheral blood of severe aplastic anemia patients. Medicine
(Baltimore). 2020; 99(26): e20630. DOI: https://doi.org/10.1097/
MD.0000000000020630
[45] Cheng H, Liu S, Li W, Zhao X, Cheng M, Qiu L et al. Arsenic
trioxide regulates adipogenic and osteogenic differentiation in
bone marrow MSCs of aplastic anemia patients through BMP4
gene, Acta Biochimica et Biophysica Sinica. 2015; 47(9): 673-679.
DOI: https://doi.org/10.1093/abbs/gmv065
[46] Li N, Song Y, Zhou J, Fang B. Arsenic trioxide improves
hematopoiesis in refractory severe aplastic anemia. J Hematol
Oncol. 2015; 5:61. DOI: https://doi.org/10.1186/1756-8722-5-61
[47] Riedel S, Hobden JA, Miller S, Morse SA, Mietzner TA, Detrick B,
Mitchell TG, Sakanari JA, Hotez P, Mejia R. Microbiología Médica
[Internet]. 28e. McGraw-Hill; 2020. Available from: https://
accessmedicina-mhmedical-com.ezproxy.sibdi.ucr.ac.cr/content.
aspx?bookid=2955§ionid=250836470
[48] Hwang D, Tsa, Y, Lee J, Huang K, Lin R, Ho C, et al. Inhibition of
Hepatitis C Virus Replication by Arsenic Trioxide. Antimicrobial
Agents and Chemotherapy. 2004; 48 (8), 2876–2882. DOI: https://
doi.org/10.1128/AAC.48.8.2876-2882.2004
[49] Lewis W, Currie PF. HIV/AIDS AND THE CARDIOVASCULAR
SYSTEM. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds.
Hurst’s The Heart, 14e New York, NY: McGraw-Hill; 2017. Available
from: http://accessmedicine.mhmedical.com.ezproxy.sibdi.ucr.
ac.cr:2048/content.aspx?bookid=2046§ionid=176566883.
[50] Wang Q, Jiang Y, Naranmandura H. Therapeutic Strategy of
Arsenic Trioxide in the Fight Against Cancers and Other Diseases.
Metallomics. 2020; 12(3): 317-462. 10.1039.C9MT00308H–. DOI:
https://doi.org/10.1039/c9mt00308h
[51] Yang Q, Feng F, Li P, Pan E, Wu C, He Y, Zhang F, Zhao J, Li
R, Feng L, Hu F, Li L, Zou H, Cai W, Lehner T, Sun C, Chen L.
Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound
after Termination of ART in Chronically SIV-Infected Macaque.
Advanced Science. 2019; 6(13):1900319. DOI: https://doi.
org/10.1002/advs.201900319
[52] Mora G, Espinosa D, Casas C. Caracterización clínica de los
pacientes con síndrome mielodisplásico. Acta Médica Colomb.
2016; 41(1): 36-41. DOI: https://doi.org/10.36104/amc.2016.538
[53] Vey N, Bosly A, Guerci A, Feremans W, Dombret H, Dreyfus F, et
al. Arsenic Trioxide in Patients with Myelodysplastic Syndromes:
A Phase II Multicenter Study. J Clin Oncol. 2006; 24(16):2465-71.
DOI: https://doi.org/10.1200/JCO.2005.03.9503
[54] Emadi A, Gore SD. Arsenic trioxide — An old drug rediscovered.
Blood Rev. 2010; 24(4-5):191-9. DOI: https://doi.org/10.1016/j.
blre.2010.04.001
[55] Fang S, Wan X, Zou X, Sun S, Hao X, Liang C, et al. Arsenic
trioxide induces macrophage autophagy and atheroprotection
by regulating ROS-dependent TFEB nuclear translocation and
AKT/mTOR pathway. Cell Death Dis. 2021; 12(1):88. DOI: https://
doi.org/10.1038/s41419-020-03357-1
[56] Wang QQ, Hua HY, Naranmandura H, Zhu H-H. Balance between
the toxicity and anticancer activity of arsenic trioxide in treatment
of acute promyelocytic leukemia. Toxicol Appl Pharmacol.
2020;409. DOI: https://doi.org/10.1016/j.taap.2020.115299
[57] Zhang P. On arsenic trioxide in the clinical treatment of acute
promyelocytic leukemia. Leuk Res Reports. 2017; 7:29–32. DOI:
https://doi.org/10.1016/j.lrr.2017.03.001