Combination Of Arsenic Trioxide Research Articles

DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.

Combining Chemotherapy Agents and Autophagy Modulators for Enhanced Breast Cancer Cell Death

Purpose: Autophagy, governed by genes with dual roles in cell death and survival, plays a crucial role in cancer persistence. Arsenic trioxide (ATO), carboplatin (CP), and cyclophosphamide (CY) are used to treat various cancers. ATO impedes cell proliferation and triggers apoptosis in cancer cells. CP, a platinum-based drug, damages cancer cell DNA, while CY acts as an alkylating agent, disrupting cell proliferation. This study investigates the combined effects of ATO, CP, and CY on inducing apoptosis and modulating autophagy in triple-negative breast cancer (TNBC) cell lines, BT-20 and MDA-MB-231. Methods: The cytotoxic effects of ATO, CP, and CY, alone and in combination, were evaluated using the MTT assay on BT-20 and MDA-MB-231 cells. Apoptosis and cell cycle progression were analyzed by annexin-V FITC/PI staining and flow cytometry. Gene expression of autophagy- and apoptosis-related markers, including Beclin 1, LC3, caspase 3, and BCL2, was quantified using RT-PCR. Data were analyzed using GraphPad Prism 4.0 with one-way ANOVA followed by Dunnett's test. Results: The The combination of ATO, CP, and CY significantly reduced cell viability and enhanced apoptosis, evidenced by increased caspase-3 activity and reduced BCL2 expression. Cell cycle arrest in the G1 phase was observed, alongside elevated autophagy markers Beclin 1 and LC3. Conclusion: The combination of ATO, CP, and CY induces synergistic effects in promoting apoptosis and autophagy in TNBC cell lines. These findings suggest that this combination therapy could be a promising approach to enhancing treatment efficacy in aggressive breast cancers, offering new insights into potential therapeutic strategies.

Combination of arsenic trioxide and apatinib synergistically inhibits small cell lung cancer by down-regulating VEGFR2/mTOR and Akt/c-Myc signaling pathway via GRB10

BackgroundSmall cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes.MethodsThe current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC.ResultsIn combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3β/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues.ConclusionsSynergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.

Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy.

The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities.

The Potential Transcriptomic and Metabolomic Mechanisms of ATO and ATRA in Treatment of FLT3-ITD Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA. RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment. A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway. The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.

Vitamin C enhances the sensitivity of osteosarcoma to arsenic trioxide via inhibiting aerobic glycolysis

Osteosarcoma (OS) is a common malignant tumor disease in the department of orthopedics, which is prone to the age of adolescents and children under 20 years old. Arsenic trioxide (ATO), an ancient poison, has been reported to play a critical role in a variety of tumor treatments, including OS. However, due to certain poisonous side effects such as cardiotoxicity and hepatotoxicity, clinical application of ATO has been greatly limited. Here we report that low doses of ATO (1 μM) observably reduced the half-effective inhibitory concentration (IC50) of vitamin C on OS cells. Compared with the treatment alone, the synthetic application of vitamin C (VitC, 800 μM) and ATO (1 μM) significantly further inhibited the proliferation, migration, and invasion of OS cells and promoted cell apoptosis in vitro. Meanwhile, we observed that the combined application of VitC and ATO directly suppresses the aerobic glycolysis of OS cells with the decreased production of pyruvate, lactate, and ATP via inhibiting the expression of the critical glycolytic genes (PGK1, PGM1, and LDHA). Moreover, the combination of VitC (200 mg/kg) and ATO (1 mg/kg) with tail vein injection significantly delayed OS growth and migration of nude mice by inhibiting aerobic glycolysis of OS. Thus, our results demonstrate that VitC effectively increases the sensitivity of OS to low concentrations of ATO via inhibiting aerobic glycolysis to alleviate the toxic side effects of high doses of arsenic trioxide, suggesting that synthetic application of VitC and ATO is a promising approach for the clinical treatment of human OS.

PEGylated magnetic nanographene oxide for targeted delivery of arsenic trioxide and sec-o-glucosylhamaudol in tumor treatment with improved dual-drugs synergistic effect

Arsenic trioxide (ATO) is a promising chemotherapeutic agent, but its clinical application is limited due to its poor pharmacokinetics and dose-limited toxicity. Moreover, the combination of ATO and sec-o-glucosylhamaudol (SOG) can improve the therapeutic effect of hepatoma. In this study, PEGylated magnetic nanographene oxide (PEG@MGO) was used as magnetic carriers to enhance the targeting ability of the drug delivery system. ATO and SOG are loaded on the surface of PEG@MGO nanoparticles through electrostatic interactions. This biocompatible nanocomposite shows magnetic susceptibility, pH sensitivity, and high loading capacity of the drugs. The in vitro cytotoxicity study of human hepatoma cell line (HepG2) cells showed more significant cytotoxicity and obvious synergistic effect between ATO and SOG compared with that of single drug-loaded nanoparticles via MTT assay. In vitro cellular uptake was observed by Prussian blue staining and fluorescently labeling. The results demonstrated a high cellular internalization rate of PEG@MGO. The ATO and SOG co-loaded nanodrug significantly inhibits the growth of tumors in vivo, which might be due to the oxidative stress and proapoptotic effect. This type of multidrug nanocomposite offers a promising alternative for cancer therapy.Graphical A pH-sensitive polyethylene glycol-modified magnetic graphene oxide loaded with ATO and SOG (PEG@MGO@ATO + SOG) was prepared for the magnetically targeted and efficient synergistic-chemo cancer therapy, which exhibited high specificity and good biocompatibility.

Treating low- and intermediate-risk acute promyelocytic leukemia with and without chemotherapy: A comparison in a tertiary care center.

Acute promyelocytic leukemia (APL) comprises approximately 10% of acute myeloid leukemia (AML) cases. Both options of treatment (ATRA-ATO and ATRA-chemotherapy) were discussed with patients with low- and intermediate-risk APL, pros and cons explained in details, and treatment regimen selected after getting informed written consent. Total 71 patients were included in the study; among these patients, 3 were negative for both FISH for t (15,17) and RT-PCR for promyelocytic leukemia retinoic acid receptor alpha, and 36 patients with APL had white blood cell count at diagnosis >10 × 109/l. Total 30 patients with newly diagnosed as low- and intermediate-risk-APL fulfilled all inclusion criteria, treated and followed for a minimum period of 2 years up to June, 2016. Fifteen patients liked to be treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), while rest of the 15 patients preferred treatment with ATRA and chemotherapy. Combination of ATRA and ATO is equally effective, less toxic, and more feasible in comparison to ATRA and chemotherapy for patients with low- and intermediate-risk APL and is a viable option for this subset of patients, especially in countries with limited resources.

Abstract 1601: Potentiation of arsenic trioxide in glioblastoma

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. Possessing a five-year survival rate of 6.8%, new therapeutic options are a necessity in order to increase patient quality of life and survival outcomes. Arsenic trioxide (ATO) is an FDA approved drug for the treatment of relapsed or refractory acute promyelocytic leukemia. Clinical trials of ATO in combination with radiation and temozolomide show therapeutic effects in a modest subset of glioblastoma patients. ATO resistance in GBM cell lines is associated with MNK1-eIF4E upregulation. Additionally, diminished response to ATO is linked to resistance to oxidative stress via increased glutathione levels and NrF2 pathway expression. We sought to target each of these proposed mechanisms of resistance in order to develop a suite of compounds for use in combination therapies, with the goal of sensitizing GBM models to ATO. Six GBM PDX models were dosed with ATO at varying concentrations and monitored for the IC50 value of treatment. The cell lines exhibited a 20-fold difference in sensitivity, indicative of an underlying innate resistance to ATO. We performed drug dose response studies of patient-derived glioma cells treated with ATO in combination with the nutraceutical compounds Chrysin and Silibinin. Combination treatments using Chrysin and Silibinin showed potentiation of the cytotoxic effects of ATO. Confirmation of the mechanism for induced sensitivity to ATO will be explored by measuring shifts in glutathione content and susceptibility to oxidative stress in response to treatment using nutraceutical compounds. In addition, drug dosing with combination therapies utilizing the MAPK interacting serine/threonine kinase 1 (MNK1) inhibitors eFT-508 and EFT-206 also show synergistic effects in GBM cell lines. The eIF4E phosphorylation response to treatment of both ATO alone ATO MNK1i combination therapies will be monitored and analyzed for potential translational effects. Each of these compounds were selected based on safe use determined in clinical trials (MNK1 inhibitors) or over-the-counter availability (nutraceuticals). All four companion approaches show low pharmacological liabilities in crossing the blood brain barrier. Future studies involving these compounds will consist of testing these suggested combination therapies in vivo by observing their effectiveness in orthotopic, GBM tumor bearing mice. Identification and development of sensitization targets for ATO will allow for greater effectiveness of treatment and a greater potency of the drug in combating resistance which arises in response to treatment. Discovery of a predictive molecular signature of synergy from ATO and other targeted agents may pave the way for a successful clinical trial of these combinations in an identifiable subpopulation of GBM patients. Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Potentiation of arsenic trioxide in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1601.

Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis.

Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn's disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease. We evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl2), also known to trigger the production of ROS. In preliminary experiments in vitro, ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo, in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g significantly alleviated clinical signs such as the thickening of the skin (p<0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc. In conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage.

Coagulopathy in Patients with Low/Intermediate Risk Acute Promyelocytic Leukemia treated with First Line Arsenic Trioxide in Combination with All-Trans Retinoic Acid: A Monocentric Experience.

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The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth.

Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment. To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress. In this study, we examined the effectiveness of ATO and D-VC on xenograft models-AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS. The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy.

Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis

Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. And a specific drug that is closely related to the mechanism is urgently required to sensitize GEM. Here, tissue inhibitor of matrix metalloproteinases 1 (TIMP1) and phosphorylated mammalian target of rapamycin (p-mTOR) were found to be substantially elevated in PDAC patients and were associated with worse overall survival. The TIMP1/PI3K/AKT/mTOR pathway was found in GEM-resistant PDAC cells and was revealed to be involved in epithelial-mesenchymal transition (EMT) and apoptosis. Furthermore, arsenic trioxide (ATO), a basic therapeutic drug for acute promyelocytic leukemia, mediated TIMP1 reduction by inducing reactive oxygen species generation and hampered the subsequent PI3K/AKT/mTOR axis. Moreover, the combination of ATO and GEM cooperatively suppressed the TIMP1/PI3K/AKT/mTOR pathway, synergistically inhibited EMT and promoted apoptosis. In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.

Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside.

The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative "Trojan horse" agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC's non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.

Combinatorial Effect of Arsenic and Herbal Compounds in Telomerase-Mediated Apoptosis Induction in Liver Cancer.

Tumour illness and its resistance against existing anticancer therapies pose a serious health concern globally despite the progressive advancement of therapeutic options. The prevailing treatment of HCC using numerous antitumor agents has inflated long-lived complete remissions, but a percentage of individuals still die due to disease recurrence, indicating a need for further exploration of possible anti-tumour regimes. We aim to boost the effectiveness of the HCC treatment by conducting current investigations evaluating the effect of arsenic trioxide (ATO) with different herbal compounds like quercetin and aloe-emodin against liver tumour via inhibition of telomerase, a pro-cancer enzyme. The anticancer activity of ATO with herbal compounds was investigated in human control liver cell line (Wrl-68) and cancer liver cell line (HepG2) at different time intervals. Viability and cytotoxicity in response to combinatorial drugs were assessed in vitro by trypan blue dye exclusion assay and MTT and WST assay. Apoptosis was analysed by annexin V/PI assay, and the expression of telomerase and apoptosis-regulating proteins was evaluated by immunoblotting and qRT-PCR. Arsenic trioxide in combination with quercetin and aloe-emodin reduced cell viability in cancerous cells compared to normal cells by inducing apoptosis, downregulating telomerase and Bcl-2 (anti-apoptotic protein) and upregulating the expression of Bax (pro-apoptotic protein). ATO exhibited significant anticancer effects due to the synergistic effects of quercetin and aloe-emodin in liver tumour cells. The current study data collectively suggest that a successful inhibition of cancer growth by the combination of ATO and tested herbal medicines against liver tumour growth is via the inhibition of telomerase activity.

Brusatol From Brucea javanica Suppresses Arsenic Trioxide-Induced PD-L1 Upregulation Through Inhibition of NRF2 in Leukemia Cells

Overexpression of programed death-ligand 1 (PD-L1) is associated with poor prognosis in leukemia. Moreover, antitumor pharmaceuticals have been shown to induce immunoresistance, leading to reduced efficacy. Previous studies have indicated that arsenic trioxide (ATO) promotes immune evasion by inducing PD-L1 expression in solid tumors; however, little is known about its role in leukemia. A proportion of patients with acute promyelocytic leukemia were resistant to ATO therapy. Thus, this study aimed to investigate the effect of ATO on the expression of PD-L1 in leukemia cells and the underlying mechanism mediated through the nuclear factor erythroid 2 related factor (NRF2) protein. Brusatol, extracted from Brucea javanica, was selected as a unique NRF2 inhibitor, and we evaluated the possibility of using a regimen combining ATO/Brusatol in leukemia therapy. Promyelocytic NB4 and lymphocytic Jurkat cells were treated with ATO and brusatol either alone or in combination. We found that ATO significantly upregulated the expression of PD-L1 in NB4 and Jurkat cells at both the protein and mRNA levels compared with its expression in the untreated cell group. Mechanistically, ATO increased nuclear NRF2 expression and the extent of NRF2 binding to the PD-L1 promoter. Pharmacological inhibition of NRF2 by brusatol significantly blocked this effect, thereby reducing ATO-induced PD-L1 expression. In addition, the combination of brusatol and ATO showed stronger cytotoxicity than ATO alone indicated by cell counting kit-8 assay. Therefore, brusatol may further enhance the antileukemia effect of ATO not only by inhibiting ATO-induced PD-L1 expression but also by enhancing ATO-induced cytotoxicity. Our study provides a rationale for the clinical application of ATO/brusatol combination therapy.

Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.

Arsenic trioxide and Erlotinib loaded in RGD-modified nanoliposomes for targeted combination delivery to PC3 and PANC-1 cell lines.

During the past few years, advances in drag delivery have provided many opportunities in the treatment of various diseases and cancer. Arsenic trioxide (ATO) and Erlotinib (Erlo) are two drugs, approved by the United States Food and Drug Administration to treat cancer, but their use is limited in terms of the toxicity of ATO and the low solubility of Erlo. This study aimed to prepare arginine-glycine-aspartic acid (RGD)-decorated nanoliposomes (NLPs) containing Erlo and ATO (NLPs-ATO-Erlo-RGD) to increase the solubility and reduce the toxicity of Erlo and ATO for cancer treatment. The results of transmission electron microscopy and dynamic light scattering showed that NLPs were synthesized uniformly, with spherical shape morphology and particle sizes between 140 and 160nm. High-performance liquid chromatography and ICP-MS results showed that about 90% of the drug was loaded in the NLPs. In comparison with NLPs-ATO-Erlo, NLPs-ATO-Erlo-RGD demonstrated considerable toxicity against the αvβ3 overexpressing PC3 cell line in the MTT experiment. It had no effect on the PANC-1 cell line. In addition, apoptosis assays using Annexin V/PI demonstrated that NLPs-ATO-Erlo-RGD generated the highest apoptotic rates in PC3 cells when compared with NLPs-ATO-Erlo and the combination of free ATO and Erlo. Furthermore, treatment with NLPs-ATO-Erlo-RGD in (p<0.05) PC3 cell line significantly reduced EGFR level. It is concluded NLPs-ATO-Erlo-RGD as a novel drug delivery system may be a promising platform for the treatment of cancer.

A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice.

Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro, among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo, in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl2 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress.

A combined arsenic trioxide/tetrandrine nanoparticle formulation with improved inhibitory effect against promyelocytic leukemia

Co-loading nanoparticles encapsulated in a copolymer carrier is a very effective strategy for anti-tumor treatment. A combination of arsenic trioxide (ATO) and tetrandrine (TET) synergistically inhibits tumor angiogenesis and lung metastasis. Moreover, TET reduces the cardiotoxicity of ATO. However, the bioavailability of this combination is limited due to poor solubility. In this study, co-loading nanoparticle formulations were developed by co-loading poly(lactic-co-glycolic acid) (PLGA) nanoparticles with ATO and TET (ATO/TET@PLGA) and by co-loading methoxypoly(ethylene glycol)-poly(lactide) (mPEG-PLGA) nanoparticles with ATO and TET (ATO/TET@mPEG-PLGA). The sonication emulsion-solvent volatilization method was employed. The combination ratio of ATO and TET was determined by results of the MTT assay, which showed that when the TET: ATO ratio was 3/4, the best synergistic anti-tumor effect was achieved. Transmission electron microscopy and particle size analysis of the nanoparticles showed that the particle size was below 100 nm mPEG-PLGA was an excellent carrier for constructing ATO/TET co-loading nanoparticles based on characterization, release study, and pharmacokinetics results. The average encapsulation efficiencies of ATO and TET were 89.78% and 82.80%, respectively. In vivo distribution experiments showed that the drugs had an improved targeting effect in the liver and bone when formulated as nanoparticles. In vitro anti-tumor studies showed that ATO/TET@mPEG-PLGA had stronger cytotoxicity than ATO alone or ATO/TET intravenous emulsion and could induce apoptosis in HL-60 cells to a greater extent. Additionally, ATO/TET@mPEG-PLGA could induce G2/M cell cycle arrest. In conclusion, ATO/TET@mPEG-PLGA has excellent anti-tumor activity as a co-delivery system of ATO and TET.