Study on the mechanism of astragalus glycyrrhiza decoction regulating SIRT1 / FOXO1 pathway to prevent QT interval prolongation induced by arsenic trioxide based on metabolomics / 中国临床药理学与治疗学

AIM: To explore the protective effect of astragalus glycyrrhiza decoction (AGD) on arsenic trioxide (ATO)-induced QT interval prolongation and its mechanism based on metabonomics. METHODS: The model of ATO-induced QT interval prolongation in rats was established, and ECG, blood routine, and metabonomics were detected, and the key targets were collected combined with network pharmacology. The possible candidate genes and pathways for the protective effect of AGD were screened by GO and KEGG enrichment analysis and then verified by experiments in vitro. RESULTS: AGD could significantly alleviate the ATO-induced QT interval of SD rats. GO enrichment analysis was mainly related to inflammatory response, reactive oxygen species, oxidative stress, inner cell vesicles, folds, inner cell vesicles, SMAD binding, R-SMAD binding, and signal receptor activator activity. KEGG analysis showed that it was mainly concentrated in the PI3K-Akt signal pathway, lipid and arteriosclerosis, FOXO signal pathway, TNF signal pathway, HIF-1, and other signal pathways. Through the H9c2 cell model in vitro, it was verified that AGD could reverse the expression of SIRT1 and FOXO1 proteins. CONCLUSION: AGD may improve the ATO-induced QT interval prolongation and reduce the cardiotoxicity of ATO by regulating the SIRT1 / FOXO1 signal pathway.

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.

Research progress in nephrotoxicity and prevention of arsenic trioxide / 中国药理学通报

Aim Arsenic trioxide (ATO, As203 ) can effectively treat acute promyelocyte leukemia (APL) and other malignant tumors.However.ATO has been found to have nephrotoxic effects during the treatment process, which limits the clinical application of ATO.Studies have shown that the use of ATO can interfere with the body's oxidation, causing to oxidative stress, damage DNA repair pathways, and induce DNA mutations.leading to cell cancer.This is currently one of the important mechanisms of ATO nephrotoxicity.Apoptosis, DNA methyl a- tion caused by ATO are also causes of nephrotoxicity.This article summarizes the research and prevention of ATO nephrotoxicity mechanism.

CircRNA-32011 regulates apoptosis induced by arsenic trioxide in cardiac myocytes / 中国药理学通报

Aim To investigate the effect of circRNA- 32011 on myocardial apoptosis induced by arsenic triox- ide (ATO).Methods Primary cardioniyocytes of suckling neonate mouse were treated with ATO ( final concentration 10 (xniol • L_1 ) for 24 h.Then cell via¬bility was measured by M IT assay.The mKNA expres¬sion levels of Bel-2/ Bax and circRNA-3201 I were de¬tected by KT-PCK.Bcl-2/Bax protein expression lev¬els were detected by Western blot.Overexpression and knock down circHNA-32011 respectively by plasmid and siHNA were used to verify its function in ATO-in- duced cardiomyocyte apoptosis.Results Myocardial cell viability decreased, Bel-2 expression significantly decreased while Bax expression increased in ATO group compared with the control group.CircKNA- 32011 was down-regulated in ATO ineuhated cardio¬niyocytes.Ovcrex press ion of circRNA-32011 in ATO- incubated cardioniyocytes increased myocardial cell vi¬ability and Bel-2 expression and decreased the expres¬sion of Bax.Knockdown of circRNA-32011 could fur¬ther reduce cardiomyoevte activity and Bel-2 expression and increase the experssion of Bax induced by ATO.Conclusions CircRNA-32011 protects cardiac myo¬cytes from apoptosis induced by arsenic trioxide, which may provide a new potential therapeutic strategy for ATO-induced myocardial injury.

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.

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.

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.

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

Synergistic killing effects of Stattic and arsenic trioxide on acute myeloid leukemia THP1 cell line and underlying mechanism / 西安交通大学学报(医学版)

【Objective】 To investigate the effects and mechanism of STAT3 inhibitor Stattic combined with arsenic trioxide (ATO) on the survival and apoptosis of acute myeloid leukemia (AML) THP1 cells. 【Methods】 CCK8 assay was used to detect the effects of Stattic combined with ATO on cell viability, flow cytometry was used to detect cellular apoptosis and ROS levels, and Caspase 3/7 Glo assay was used to determine Caspase 3/7 activity. qPCR was used to detect mRNA expression levels of GCLM, GCLC and HO-1 genes, and Western blotting was used to detect protein expression levels of P-STAT3, STAT3 and Nrf2. 【Results】 Stattic significantly inhibited the level of phosphorylated STAT3, aggravated the inhibitory effect of ATO on THP1 cell viability, and enhanced the apoptosis and reactive oxygen species (ROS) induced by ATO. Stattic significantly inhibited the expression of ATO-upregulated Nrf2 and the expression of Nrf2 downstream genes including HO-1, GCLM and GCLC. 【Conclusion】 Stattic can enhance the effects of ATO-mediated viability inhibition and apoptosis. The mechanism may be related to the increased ROS via inhibition of Nrf2 and Nrf2 downstream gene expression.

Effect of Arsenic Trioxide Combined with Dihydroartemisinin on THP-1 Cells Proliferation and Apoptosis / 中国实验方剂学杂志

Objective:To investigate the effects of arsenic trioxide combined with dihydroartemisinin on proliferation, cell cycle, and apoptosis of THP-1 cells, and explore the mechanism. Method:The thiazolyl blue （MTT） method was applied to detect the effect of different concentrations of arsenic trioxide, dihydroartemisinin and arsenic trioxide combined with dihydroartemisinin on the proliferation of THP-1 cells. Annexin V/propidium iodide（PI）assay was used to detect the change of THP-1 cell cycle and apoptosis．Western blot was performed to assess the expression of cysteine protease-3（Caspase-3）, cleaved Caspase-3, B-lymphocytoma-2（Bcl-2） and Bcl-2 associated X protein （Bax）. The changes of cell morphology were observed under high intension microscope. Result:Compared with blank group, arsenic trioxide and dihydroartemisinin both exhibited obvious antiproliferative effect on the human acute monocytic leukemia cell line THP-1 in time-dose dependence （P<0.01）. After 48 h, compared with the same dose of arsenic trioxide or that of dihydroartemisinin alone, the inhibition effect of 1 µmol·L-1 arsenic trioxide combined with 2 µmol·L-1 dihydroartemisinin on proliferation of THP-1 cells was significantly stronger （P<0.01）. Compared with the control group, arsenic trioxide combined with dihydroartemisinin significantly arrested the cells in G1 phase （P<0.01）, induced the downregulation of Caspase-3 and Bcl-2 （P<0.01） and upregulation of cleaved Caspase-3 significantly（P<0.05）. Conclusion:Arsenic trioxide combined with dihydroartemisinin can significantly inhibit the proliferation and induce apoptosis of THP-1 cells. The possible mechanism may be related to arrest the cells in G1 phase, reduce the expression of Caspase-3 and Bcl-2, increase the expression of cleaved Caspase-3.

Protective Effect of Salvianolic Acid B on Arsenic Trioxide-induced HepaRG Human Hepatocyte Injury / 中国实验方剂学杂志

Objective::To investigate the protective effect of salvianolic acid B on HepaRG hepatocyte injury induced by arsenic trioxide (As2O3 ) and its mechanism. Method::HepaRG cells were incubated with 5μmol·L-1 As2O3 for 24 h to induce hepatocyte injury. The cells were divided into control group, model group, salvianolic acid B 10 μmol·L-1 group, salvianolic acid B 10 μmol·L-1+ As2O3 group, salvianolic acid B 5 μmol·L-1+ As2O3 group, and salvianolic acid B 2.5 μmol·L-1+ As2O3 group. HepaRG cells were preincubated with salvianolic acid B for 2 h and then incubated with As2O3 for 24 h. At the end of the incubation, cell viability was detected by thiazolyl blue tetrazolium bromide assay, apoptosis was observed by Hoechst33342 fluorescence staining, apoptosis rate was detected by annexin V-FITC/propidium iodide double staining flow cytometry, and mitochondrial membrane was observed by JC-1 fluorescence staining. Western blot was used to detect the protective effect of expressions of relevant proteins Bcl-2, Bax, Akt, p-Akt on salvianolic acid B in the liver. Result::As2O3 concentration-dependently reduced the survival rate of HepaRG cells(P<0.01), salvianolic acid B had no effect on normal cell viability for 2 h, pre-incubation with salvianolic acid B(5, 10 μmol·L-1) for 2 h significantly increased the decreased cell survival rate caused by As2O3 (P<0.01). As2O3 significantly increased hepatocytes apoptosis rate(P<0.01), while pre-incubation with salvianolic acid B(10 μmol·L-1) deceased apoptosis rate(P<0.01). Incubation with As2O3 for 24 h caused decrease of mitochondrial membrane potential, pre-incubation with salvianolic acid B maintained mitochondrial membrane potential, indicating that the anti-apoptotic effect of salvianolic acid B were related to the mitochondrial pathway modulation. Western blot analysis showed that salvianolic acid B promoted the ratio of Bcl-2/Bax and promoted p-Akt/Akt compared with As2O3 group(P<0.01). Conclusion::Salvianolic acid B has a protective effect on hepatocyte injury induced by As2O3, and its mechanism is related to maintenance of mitochondrial function and inhibition of hepatocyte apoptosis.

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.