Arsenic Trioxide: Pharmacological Applications / Trióxido de Arsénico: Aplicaciones farmacológicas

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.

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.

Osteonecrosis of the jaw induced by arsenic trioxide therapy in acute promyelocytic leukemia patient: a case report and literature review / 口腔疾病防治

Objective @#To investigate the etiology, clinical manifestations, treatment and prevention of jaw necrosis caused by arsenic trioxide to provide a reference for clinical diagnosis and treatment. @*Methods@#To analyze the clinical data and related literature of patients with jaw necrosis caused by acute promyelocytic leukemia treated with arsenic trioxide@*Results@#We report a case of jaw necrosis caused by the use of arsenic trioxide (10 mg once a day for one month) during the treatment of acute promyelocytic leukemia. About 20 days after treatment, the patient developed right maxillary pain accompanied by gingival redness and swelling and mucosal ulcer, 14-17 teeth had buccal and palatal alveolar bone exposed, gingival mucosa was missing, gingival tissue was damaged to the bottom of vestibular groove, and palatal soft tissue was damaged to 5-8 mm of palatal suture. Due to the unstable condition of acute promyelocytic leukemia, the patient was given conservative treatment such as oral vitamin and Kangfuxin liquid gargle to keep his mouth clean. Drug induced jaw necrosis reported in the literature can be caused by bisphosphonates. Arsenic trioxide can also cause local jaw necrosis. Clinically, it is often manifested as long-term wound nonunion, pus, alveolar bone or jaw bone exposure, dead bone formation, accompanied by pain, loose teeth, facial swelling and other symptoms. Anti inflammation, debridement and surgical removal of dead bone are commonly used treatment methods.@*Conclusion @# In clinical practice, we should be alert to drug-induced jaw necrosis and strengthen prevention.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Comparison of clinical efficacy and treatment costs in different regimens for patients with acute promyelocytic leukemia / 白血病·淋巴瘤

Objective:To explore the clinical efficacy and treatment costs of different regimens for newly diagnosed acute promyelocytic leukemia (APL).Methods:The clinical data of 37 newly diagnosed APL patients admitted to Jingjiang People's Hospital from January 2011 to December 2020 were retrospectively analyzed. They received different induction therapy regimens and consolidation therapy after achieving complete remission (CR). Among them, 11 patients received induction chemo therapy with all-trans retinoic acid (ATRA) combined with anthracycline, which was consolidated with ATRA combined with chemotherapy after CR (ATRA+chemotherapy group); 13 patients were treated with ATRA combined with arsenite acid (ATO) and anthracycline, which was consolidated with ATRA combined with chemotherapy after CR(ATRA+ATO+ chemotherapy group). The other 13 patients received double induction therapy of ATRA combined with ATO, which was consolidated with ATRA combined with ATO after CR (ATRA+ATO double induction group). The clinical efficacy and treatment costs of newly diagnosed APL patients in 3 groups were analyzed.Results:There were 10, 12, 12 patients with newly diagnosed APL achieving CR, respectively in ATRA+chemotherapy group, ATRA+ATO+chemotherapy group, ATRA+ATO double induction group, and the difference was statistically significant ( P > 0.05). The differences of hematological, cardiac, gastrointestinal adverse reactions and infection incidence in the 3 groups were not statistically significant (all P > 0.05). The costs of induction therapy in ATRA+chemotherapy group, ATRA+ATO+chemotherapy group and ATRA+ATO double induction group were (73 755±4 820) yuan, (74 101±5 097) yuan, (52 944±4 099) yuan, respectively; the costs of consolidation treatment were (26 366±2 497) yuan, (25 801±2 528) yuan, (19 674±1 940) yuan, and the treatment time was (41±4) d, (39±4) d, (34±3) d, respectively; and the differences were statistically significant ( F value was 84.77, 31.90, 9.62, all P < 0.001). Conclusion:The chemotherapy-free therapy regimen of induction and consolidation with ATRA and ATO has the advantage of high cost-effectiveness with no significant difference in clinical efficacy.

Caracterización clínica y citogenética de una cohorte de pacientes con leucemia promielocítica aguda atendidos en un Hospital Universitario en Medellín, Colombia / Clinical and cytogenetic characterization of a cohort of patients with acute promyelocytic leukemia treated at a University Hospital in Medellín, Colombia

Introducción. La leucemia promielocítica aguda (LPA) es un subtipo poco frecuente de leucemia mieloide aguda (LMA), que se caracteriza por un comportamiento clínico particularmente agresivo, y en ausencia de tratamiento, su curso generalmente es fatal. El objetivo de este trabajo fue determinar las características clínicas y citogenéticas de una cohorte de pacientes con LPA, con la finalidad de evaluar su relación con las complicaciones, el pronóstico y el desenlace de estos pacientes. Metodología. Se realizó un estudio observacional, descriptivo, retrospectivo de los pacientes mayores de 15 años con diagnóstico de LPA, atendidos en el Hospital Universitario San Vicente Fundación, entre los años 2012 a 2020. Resultados. Un total de 32 pacientes fueron incluidos. La edad media del diagnóstico fue 37 años. El 84,4% de los pacientes tenía la traslocación (15;17) en el cariotipo, y el 93,75% tenían FISH positivo. El 12,5% de los casos tenían cariotipo complejo. La mortalidad en los primeros 30 días fue del 15,6%, siendo el sangrado la causa de muerte más frecuente. Todos los pacientes que sobrevivieron alcanzaron la remisión completa (84,3%). En un promedio de seguimiento de 24 meses, el 14,8% de los casos recayeron. En el análisis bivariado se encontró relación entre sexo masculino y tener cariotipo complejo (p=0,015). No se encontró relación entre cariotipo complejo y mortalidad temprana (p=0,358), tampoco entre cariotipo complejo y recaída (p=0,052). Conclusiones. Se presentan las características clínicas y citogenéticas de una cohorte de pacientes con LPA en Colombia. El sangrado en el sistema nervioso central fue la principal causa de mortalidad temprana, todos los pacientes que sobrevivieron alcanzaron la remisión completa con la terapia de inducción. Las tasas de mortalidad, remisión completa y recaída fueron similares a las reportadas por otras series latinoamericanas, pero inferiores a estudios provenientes de países europeos. Contrario a lo reportado en otros estudios, no se encontró relación entre el cariotipo complejo y la mortalidad temprana o recaída.

Introduction. Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML), characterized by a particularly aggressive clinical behavior, that in the absence of treatment is usually fatal. The objective of this work was to determine the clinical and cytogenetic characteristics of a cohort of patients with APL, in order to evaluate their relationship with the outcome and prognosis of these patients. Methodology. An observational, descriptive, retrospective study of patients older than 15 years with a diagnosis of APL treated at the Hospital Universitario San Vicente Fundación, between 2012 and 2020, was carried out. Results. A total of 32 patients were included. The mean age at diagnosis was 37 years, 84.4% of the patients had the t(15;17) in the karyotype, and 93.75% had positive FISH. 12.5% of cases had a complex karyotype. Mortality in the first 30 days was 15.6%, with bleeding being the most common cause of death. All patients who survived achieved complete remission (84.3%). In an average follow-up of 24 months, 14.8% of cases relapsed. In the bivariate analysis, a relationship was found between the male sex and having a complex karyotype (p<0.015). No relationship was found between complex karyotype and early mortality (p=0.358), nor between complex karyotype and relapse (p=0.052). Conclusions. We present the clinical and cytogenetic characteristics of a cohort of patients with APL in Colombia. Central nervous system bleeding was the main cause of early mortality, with all surviving patients achieving complete remission on induction therapy. Mortality, complete remission and relapse rates were similar to those reported by other Latin American series, but lower than studies from European countries. Contrary to what has been reported in other studies, no relationship was found between complex karyotype and early mortality or relapse

CLINICOPATHOLOGICAL STUDY OF ACUTE PROMYELOCYTIC LEUKEMIA: AN EXPERIENCE FROM A TEACHING HOSPITAL IN INDIA

Data on the clinicopathological features of acute promyelocytic leukemia (APL) patients from India is limited. Present study was a cross sectional study which included 18 patients of APL. Medical records of these 18 patients were reviewed to collect their clinical details and laboratory results. High risk patients (total leucocyte count >10,000/cmm) were treated with modified APML 4 protocol.Low risk patients (total leucocyte count <10,000/cmm) were treated with protocol APL- 0406-Intergroup Study AL WP GIMEMA-DSIL protocol. Outcomes in terms of complete remission were assessed in both these groups. Mean haemoglobin levels was 7.03gm%, mean total leucocyte count was 30,462per cmm, mean platelet count was 27,222/cmm. Bone marrow was reported as suggestive of APL in 17 cases while in 1 case, BM aspirate was inadequate. Average percentage of abnormal promyelocytes in bone marrow was 84.25%. PT was prolonged in 15 cases, while APTT was prolonged in 3 cases. Flow cytometry analysis was done in 12 patients. All patients were CD45, MPO, CD13, CD33 and CD64 positive. Chromosomal analysis was possible in 11 cases. t(15;17)(q22;21) was identified in 6 cases (54.62%). 3 cases (27.27%) showed normal karyotype. 2 (18.18%) cases had additional cytogenetic abnormalities. All patients under high risk category attained CR. 1 patient under low risk category with additional cytogenetic abnormality died 6 days after induction therapy was started. 10 (55.55%) patients developed complications such as neutropenic sepsis, intracranial hemorrhage, differentiation syndrome, cerebral venous sinus thrombosis, pseudotumorcerebri, QTc interval prolongation, and pneumonia.

Evaluación hepática en pacientes con leucemia promielocítica tratados con el protocolo LPM-TOA / Hepatic evaluation in patients with promyelocytic leukemia treated with the LPM-TOA protocol

Introducción: Con el protocolo LPM-TOA para el tratamiento de la leucemia promielocítica se obtienen excelentes resultados, se prolonga la sobrevida global y es posible la curación de los enfermos. En la de inducción a la remisión se utilizan dos drogas, una antraciclina y trióxido de arsénico, y en la consolidación los enfermos reciben de nuevo una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad hepática tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó estudio longitudinal prospectivo que incluyó20 pacientes tratados con dicho protocolo, todos con más de dos años de haberlo suspendido. Se revisaron las historias clínicas para evaluar mediante los valores iniciales y evolutivos de las enzimas hepáticas, la función hepática inicial y evolutiva. Se determinó el índice de Ritis para predecir evolución a la cronicidad de existir daño hepático. Resultados: Hombres y mujeres se presentaron con la misma frecuencia y la media para la edad del sexo masculino fue 36,39 y para el femenino 39, con desviación estándar de ±14,02 y ±9,43, respectivamente. La variedad morfológica más frecuente fue la hipergranular, el promedio del índice de Ritis fue de solo 1,006 con desviación estándar de 0,745. Conclusiones: No hubo evidencias clínica ni enzimática de toxicidad hepática tardía en los pacientes estudiados(AU)

Introduction: With the LPM-TOA protocol for the treatment of acute promyelocytic leukemia, excellent results are obtained, overall survival is prolonged and the patients are cured, in the induction to remission two drugs are used, an anthracycline and arsenic trioxide, and in consolidation the patients again receive a high dose of arsenic. Objective: To assess late liver toxicity in patients with promyelocytic leukemia treated according to the PML-TOA protocol. Methods: A prospective longitudinal study was carried out that included 20 patients treated with this protocol, all with more than two years of having suspended treatment. The clinical histories were reviewed and by means of the initial and evolutionary values of liver enzymes, the initial and evolutionary liver function was evaluated and the Ritis index was determined to predict evolution to chronicity if there is liver damage. Results: Men and women presented with the same frequency and the mean age for males was 36.39 and for females it was 39, with a standard deviation of ± 14.02 and ± 9.43 respectively. The most frequent morphological variety was hypergranular, the average Ritis index was only 1.006 with a standard deviation of 0.745. Conclusions: There was no clinical or enzymatic evidence of late liver toxicity in the patients studied(AU)

Evaluación cardiovascular en pacientes con leucemia promielocítica tratados con el protocolo LPM-TOA / Cardiovascular evaluation of patients with promyelocytic leukemia treated with the PML-ATO protocol

Introducción: Con el protocolo LPM-TOA para tratamiento de la leucemia promielocítica, se han obtenido excelentes resultados, ya que se logra sobrevida global prolongada y posible curación de los enfermos. En la inducción se utilizan dos drogas cardiotóxicas: las antraciclinas y el trióxido de arsénico y en la consolidación los enfermos reciben una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad cardíaca tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó un estudio observacional descriptivo, prospectivo y longitudinal que incluyó 20 pacientes tratados con protocolo LPM-TOA, seguidos en consulta entre enero y julio 2019. Los pacientes tenían más de dos años de haber recibido las drogas cardiotóxicas. Se revisaron las historias clínicas y se determinó la fracción de eyección ventricular izquierda y la deformidad longitudinal global, mediante ecocardiograma. Resultados: Se presentaron hombres y mujeres con igual frecuencia, edad promedio 41,5 ± 11,0 años. Durante la inducción, en menos de la mitad de los enfermos se suspendió el arsénico por elevación del segmento QT corregido; en la mayoría solo se suspendió por uno o dos días. La mayor parte de los pacientes tuvo la fracción de eyección ventricular izquierda con valores entre 61 y 70 por ciento y la deformidad longitudinal global fue - 24 - 22 por ciento Conclusiones: En los pacientes estudiados, el tiempo de haber recibido el trióxido de arsénico y la dosis recibida, no influyó en la función cardíaca(AU)

Introduction: The PML-ATO protocol for the treatment of promyelocytic leukemia has obtained excellent results, achieving high overall survival rates and the possible healing of patients. Two cardiotoxic drugs are used in the induction process: anthracyclines and arsenic trioxide, whereas during consolidation patients receive a high dose of arsenic. Objective: Evaluate the late cardiotoxicity in patients with promyelocytic leukemia treated by the PML-ATO protocol. Methods: An observational prospective longitudinal descriptive study was conducted of 20 patients treated with the PML-ATO protocol and followed-up in outpatient consultation from January to July 2019. More than two years had elapsed since the patients received the cardiotoxic drugs. A review was carried out of the patients' medical records and echocardiographic determination was made of left ventricular ejection fraction and overall longitudinal deformity. Results: Men and women presented the same frequency; mean age was 41.5 ± 11.0 years. During induction, arsenic was suspended in less than half the patients due to corrected QT elevation. In most it was only suspended for one or two days. Most patients had left ventricular ejection fraction values between 61 percent and 70 percent, whereas overall longitudinal deformity was - 24 percent - 22 percent. Conclusions: In the patients studied, cardiac function was not affected by the time elapsed since arsenic trioxide administration or the dose received(AU)

Leucemia promielocítica aguda. Estado del arte / Acute promyelocytic leukemia. State of the art

RESUMEN La leucemia promielocítica aguda (LPA) es un subtipo de leucemia mieloide aguda (LMA) que se origina por una traslocación balanceada entre los cromosomas 15 y 17, involucra al gen que codifica para el receptor alfa del ácido retinoico (RARA) en el cromosoma 17 y el de la leucemia promielocítica (PML) en el cromosoma 15, lo que da origen a la traslocación t(15;17) PML/RARA. Dicho reordenamiento origina la proteína de fusión PML/RAR alfa, que bloquea la diferenciación de las células madre mieloides en el estadio de promielocito. La LPA afecta con mayor frecuencia a adultos jóvenes y conlleva un alto riesgo de mortalidad temprana, en especial por el desarrollo de una coagulopatía grave, que sin tratamiento es definitivamente fatal. El diagnóstico temprano, el tratamiento de soporte y la introducción de fármacos que promueven la diferenciación terminal de los promielocitos patológicos como la tretinoina, también conocida como ácido todo transretinoico (ATRA) o trióxido de arsénico (ATO), ha hecho que en la actua-lidad esta sea una enfermedad curable con altas tasas de remisión completa.

SUMMARY Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) that results from a balanced translocation between chromosomes 15 and 17, which involves the gene encoding the retinoic acid receptor alpha (RARA) on chromosome 17 and the gene for promyelocytic leukemia (PML) on chromosome 15, causing the translocation t (15; 17) PML / RARA. This rearrangement originates the PML / RAR alpha fusion protein, which blocks the differentiation of myeloid stem cells at the promyelocyte stage. APL affects young adults more frequently and carries a high risk of early mortality, especially due to development of severe coagulopathy that, without treatment, is invariably fatal. Early diagnosis, supportive treatment, and the introduction of drugs that promote the terminal differentiation of pathological promyelocytes such as alltrans retinoic acid (ATRA) and arsenic trioxide (ATO), have currently made this a curable disease with high rates of complete remission.

Research progress of arsenic trioxide in anti-liver cancer mechanism and treatment of hepatocellular carcinoma / 国际肿瘤学杂志

Arsenic trioxide (ATO) is involved in a variety of biological processes of hepatocellular carcinoma (HCC) cells, including apoptosis induction, proliferation inhibition, invasion and metastasis inhibition, and tumor stem cell inhibition. ATO has a variety of therapeutic approaches in the treatment of HCC, mainly including single drug therapy, combined local therapy, combined systemic therapy, and so on. Further research on the anti-cancer mechanism and clinical application of ATO is expected to provide new ideas for the treatment of liver cancer.

Preparation of mitochondrial targeted calcium arsenite/doxorubicin lipid nanoparticles and the in vitro study in reversing tumor drug resistance / 药学学报

This study aims at the critical role of P-glycoprotein (P-gp) in tumor drug resistance, taking advantage of the adenosine triphosphate (ATP) dependence of P-gp mediated drug transport and efflux across the cell membrane. Mitochondrial targeted calcium arsenite/doxorubicin (DOX) lipid nanoparticles were constructed via hydrothermal method and thin-film dispersion method for reversing tumor drug resistance. The results showed that the lipid nanoparticles were uniform in size and well dispersed with a mean particle size of (261 ± 7) nm, zeta potential of (-9.6 ± 1.3) mV. The DOX loading efficiency and encapsulation efficiency were 22.6% and 84.0%. The in vitro drug release profile was pH-dependent; the drug accumulation at mitochondria was significantly increased, which then caused overload of calcium and inhibition of P-gp and ATP, thereby reversing tumor drug resistance. The simultaneously released arsenite ion and DOX could synergistically kill the tumor cells. In summary, the lipid nanoparticles prepared in this study have uniform particle size, high drug loading efficiency and encapsulation efficiency, excellent colloidal stability, pH responsiveness, and impressive ability to reverse tumor drug resistance, which may hold great potential in further clinical applications.

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-

Arsenic Trioxide Combining Leflunomide Activates Nrf2-ARE-HO-1 Signaling Pathway and Protects Heart Xenografts / 中国结合医学杂志

OBJECTIVE@#To investigate the molecular mechanisms underlying the effects of arsenic trioxide (As@*METHODS@#Transplantation of LVG hamster hearts to Lewis rats was performed by anastomosis of vessels in the neck using end-to-end anastomosis with a non-suture cuff technique. Four groups of recipient rats (n=6 in each) were treated with normal saline (control), As@*RESULTS@#Expression of Nrf2-ARE-HO-1 signaling pathway was upregulated in heart xenografts in rats treated with As@*CONCLUSION@#Combination treatment with As

Effects of arsenic trioxide on migration, invasion and apoptosis of hepatocellular carcinoma HepG2 cells / 生物医学工程学杂志

The article aims to explore the optimal concentration of arsenic trioxide (As O ) on HepG2 of liver cancer cells, and the effect of As O on the migration, invasion and apoptosis of HepG2 cells. In this study, the activity of HepG2 cells treated with 0, 1, 2, 4, 8, 16, 32 μmol/L As O was tested by CCK-8 method, the semi-inhibitory concentration (IC50) was calculated, and the morphological changes of HepG2 cells were observed after the action of As O at IC50 concentration for 12, 24, 48 h. The effect of As O on cell migration and invasion ability was verified by wound healing experiment and Transwell invasion experiment. Western blot and qRT-PCR were used to detect the effects of As O on the gene and protein expression levels related to cell migration, invasion and apoptosis. The results showed that, compared with the control group, the activity of HepG2 cells decreased with the increase of the concentration of As O treatment, showing a dose-dependent effect, and its IC50 was 7.3 μmol/L. After 24 hours' treatment with 8 μmol/L As O , HepG2 cells underwent significant apoptosis, and its migration and invasion abilities were significantly reduced. In addition, the protein expression levels of RhoA, Cdc42, Rac1 and matrix metalloproteinase-9 (MMP-9) were down-regulated, the protein and mRNA expression levels of anti-apoptotic gene Bcl-2 were significantly down-regulated, and the protein and mRNA expression levels of pro-apoptotic genes Bax and Caspase-3 were significantly up-regulated. The above results indicate that certain concentration of As O can inhibit the migration and invasion of hepatocellular carcinoma cells and promote the apoptosis of hepatocellular carcinoma cells.

Effect of arsenic trioxide-loaded CalliSpheres beads in the treatment of rabbits with VX2 liver tumor / 临床肝胆病杂志

ObjectiveTo investigate the effect of arsenic trioxide-loaded CalliSpheres beads (CBATO) in transarterial chemoembolization (TACE) in the treatment of rabbits with VX2 liver tumor. MethodsA total of 120 tumor-bearing rabbits were divided into control group, CalliSpheres beads (CB) group (blank beads for TACE), CBATO group, and conventional TACE (cTACE) group (arsenic trioxide lipiodol for TACE) using a random number table, with 30 rabbits in each group. Five rabbits in each group were sacrificed at 12 hours and on days 3, 7, and 14 after TACE, and immunohistochemistry was used to measure the proliferation index and apoptosis percentage of tumor cells in the residual tumor area. The tumor necrotic volume was measure on day 7 after TACE, and the growth rate and necrosis rate of tumor cells were calculated. Ten rabbits were randomly selected from each group for the observation of survival time. An analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the Kaplan-Meier survival analysis was used to evaluate survival time, and the log-rank test was used for comparison. ResultsOn day 7 after TACE, the CBATO group had a significantly lower growth rate and a significantly higher necrosis rate of tumor cells than the cTACE group, the CB group, and the control group (all P＜0.05). At each time point after TACE, there were significant differences in the proliferation index and apoptosis percentage of tumor cells between the CBATO group and the other three groups (all P＜0.05). The median survival time was 26 days in the CBATO group, 18.5 days in the CB group, 22 days in the cTACE group, and 15.5 days in the control group, and the CBATO group had a significantly longer survival time than the other three groups (χ2=3.95, 8.99, and 13.47, P=0.049, P=0.003, and P＜0.01). ConclusionCBATO has a better effect than cTACE and CB in the treatment of rabbits with VX2 liver tumor and can significantly improve tumor necrosis rate, promote the apoptosis of tumor cells, and prolong the survival time of experimental animals.

Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon- inhibition

Arsenic trioxide (AsO) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of AsO induced apoptosis of pDCs mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, AsO preferentially inhibited IFN- secretion as compared to other cytokines such as TNF-, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, AsO induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4 T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN- inhibition, and regulatory phenotype induced by AsO. Collectively, our data suggest that AsO could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.

Preparation and in vitro evaluation of pH-sensitive drug releasing As2O3-loaded liposome / 中草药

Objective: To prepare pH-sensitive drug releasing As2O3 loaded liposome (CaAs-LP) and evaluate it in vitro. Methods: CaAs-LP was prepared by thin film dispersion and ion precipitation method. The particle size, PDI, and Zeta potential of CaAs-LP were measured by Malvern particle size analyzer; The morphology of the liposome was investigated by transmission electron microscopy; The drug loading and entrapment efficiency of CaAs-LP by inductively coupled plasma emission spectrum. In vitro release characteristics of CaAs-LP under different pH conditions were investigated by dialysis bag method. MTT assay was used to investigate the toxicity of carrier and CaAs-LP to MCF-7, U87 and HepG2 cells. Results: The prepared CaAs-LP were spherical and well-dispersed with particle size of (117.16 ± 1.94) nm. The encapsulation efficiency and the drug loading rate of CaAs-LP were (74.31 ± 2.11)% and (8.31 ± 0.13)%, respectively. In vitro release studies showed that CaAs-LP had the characteristics of sustained release and pH sensitive drug release, which can achieve specific drug release in the tumor environment. The carrier displayed remarkable biocompatibility in MCF-7, U87, HepG2 and L02 cells. MTT assay showed that the median lethal concentrations (IC50 values) of MCF-7, U87 and HepG2 cells were 11.91, 4.90 and 19.41 μmol/L, while L02 was 27.59 μmol/L, respectively, which showed strong inhibiting effect on tumor cells. Conclusion: CaAs-LP reveals significantly sustained and pH sensitive release characteristics. CaAs-LP is a potential drug delivery system against solid tumor with tumor micro-environment responsive.

Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system / 中草药

Arsenic trioxide, a mineral drug of Chinese medicine material medica with significant therapeutic effect, has been approved by USA Food and Drug Administration (FDA) for the treatment of acute promyelocytic leukemia. In recent years, it has also been found to have a great therapeutic effect on the treatment of solid tumors. The anti-tumor mechanisms mainly include promoting apoptosis, inhibiting Hedgehog signaling pathway, reversing drug resistance and inhibiting angiogenesis. However, the poor targeting ability in vivo, the rapid renal clearance rate, and the toxic and side effects of high dose on normal tissues of arsenic trioxide limit the application and clinical transformation for the treatment of solid tumor. On the basis of traditional nanoparticles, the novel drug delivery system improves the drug aggregation, controlling-release and diagnosis in tumor sites, which is of great significance in accurate treatment, improvement of bioavailability and reduction of toxic and side effects. Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system in recent years was summarized and analyzed in this paper, in order to provide ideas for the in-depth research and clinical application of arsenic trioxide.

Protective Effect of Different Medicinal Parts of Nandina domestica on Arsenic Trioxide Hepatotoxicity and Hephrotoxicity / 中国实验方剂学杂志

Objective::To compare the effect of different medicinal parts of Nandina domestica in reducing toxicity of anti-tumor drug arsenic trioxide, so as to provide the scientific basis for its further development and application. Method::Chronic arsenic trioxide poisoning model was used in this paper. Totally 56 SD rats were randomly divided into normal group, model group (arsenolite 40 mg·kg-1), sodium 2, 3-dimercapto-1-propanesulfonate group (sodium 2, 3-dimercapto-1-propanesulfonate 25 mg·kg-1+ arsenolite 40 mg·kg-1), Nandinae Radix group (Nandinae Radix 20 g·kg-1+ arsenolite 40 mg·kg-1), Nandinae Caulis group (Nandinae Caulis 20 mg·kg-1+ arsenolite 40 mg·kg-1), Nandinae Folium group (Nandinae Folium 20 g·kg-1+ arsenolite 40 mg·kg-1), and Nandinae Fructus group (Nandinae Fructus 20 g·kg-1+ arsenolite 40 mg·kg-1). The intragastric administration lasted for 10 days. After the last administration, urine was collected within 24 hours, serum, kidney and liver tissue samples were collected after operation, and serum creatinine (SCr) and urine creatinine (UCr) levels were measured, in order to calculate endogenous creatinine clearance rate (CCr). At the same time, the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in liver and kidney of rats in each group were detected. Some kidneys and livers were fixed with formaldehyde, and the histopathological changes were observed under microscope after hematoxylin-eosin staining. Result::Compared with the model group, the rats in combination group of Nandinae Radix, Nandinae Caulis, Nandinae Fructus have a heavier body mass (P<0.01), the kidney coefficient was lower (P<0.01), the levels of UCr and CCr were significantly increased (P<0.01), the content of MDA in renal tissue was decreased significantly (P < 0.01), the level of MDA in liver tissue was decreased (P < 0.05), whereas the activities of SOD and CAT were significantly increased (P<0.01), the pathological damage of liver and kidney was alleviated. There was no significant difference in the activity of SOD in the liver between the Nandinae Folium combination group and the model group, but the changes of the other indexes were consistent with those of the above three groups. Conclusion::Nandinae Radix, Nandinae Caulis, Nandinae Fructus have significant protective effects on liver and kidney toxicity induced by arsenic trioxide oxidative stress, and Nandinae Folium was the least effective among them.

Effect of Total Alkaloids from Nandina domfestica in Attenuating Arsenic Trioxide and Its LC-MS / 中国实验方剂学杂志

Objective::To study the effect of total alkaloids of Nandina domestica in attenuating arsenic trioxide, and analyze chemical constituents of alkaloids extract of Nandina, in order to provide the theoretical basis for studying the effect of N. domestica in attenuating arsenic trioxide with alkaloids extract of N. domestica as effective fraction. Method::The model of acute liver injury induced by arsenic trioxide was used to compare the effects on heart and liver functions of mice between arsenic trioxide alone and total alkaloids of N. domestica combined with arsenic trioxide. The detoxification of total alkaloids on arsenic trioxide was evaluated based on biochemical parameters and pathological report. Peakview (Version1.2, AB SCIEX) software was used to process the mass spectrometry data of total alkaloids of N. domestica. The structures of determined compounds were identified by molecular weight of compound (molecular formula), secondary fragments, chromatographic peak retention and literature information. Result::Among biochemical indicators, creatine kinase(CK), lactate dehydrogenase(LDH), blood urea nitrogen(BUN), malondialdehyde(MDA), alanine aminotransferase(ALT) and amino transferase of aspartate(AST) of the arsenic trioxide group were increased, while elimination rates of Na+ -K+ -adenosine triphosphate(ATP), superoxide dismutase(SOD), catalase(CAT) and serum creatinine(SCr) were decreased, compared with those of the combination group. CK and LDH of the alkaloids extract group were more obviously increased than those of the N. domestica extract group, but with no remarkable difference. In histomorphometric examination, edema of mouse heart cells was improved, and some kidney and liver damages in rats were alleviated. Totally 25 alkaloids of alkaloid extract were identified. Among them, 18 were known, and 7 were unknown, including 3 structural types, in which apomorphine alkaloids were mostly. Conclusion::Heart, kidney and liver damage degrees of the combination group were significantly alleviated compared with the arsenic trioxide group. The total alkaloids fraction extracted and purified have a significant attenuation in arsenic trioxide toxicity. The detoxification of total alkaloids extract was equal to that of N. domestica extract. Furthermore, apomorphine alkaloids, such as nantenine and domesticine, can be used as index components to establish a quality control method for total alkaloids.