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Ecotoxicology and Environmental Safety Nov 2023Arsenic (As) and copper (Cu) are two common contaminants in the environment. When organisms are exposed to As or/ and Cu in large quantities or for sustained periods,...
Arsenic (As) and copper (Cu) are two common contaminants in the environment. When organisms are exposed to As or/ and Cu in large quantities or for sustained periods, oxidative stress is induced, adversely affecting kidney function. However, the molecular mechanisms involved in As or/ and Cu-induced nephrotoxicity remain elusive. In this experiment, wild-type C57BL/6 and Nrf2-knockout mice (n = 24 each) were exposed to arsenic trioxide and copper chloride alone or in combination. Our research findings indicate that exposure to As or/ and Cu can activate the Nrf2 antioxidant pathway by upregulating the levels of Nrf2, HO-1, CAT, and downregulating the level of Keap1, thereby reducing As or/ and Cu-induced oxidative stress. Meanwhile, exposure induced kidney cell pyroptosis and apoptosis by promoting the expression of NLRP3 inflammasomes and Caspase-3, which peaked in mice co-treated with As and Cu. Subsequently, we investigated its role in As or/ and Cu-induced kidney injury by knocking out Nrf2. Our results show that after knocking out Nrf2, the expression of antioxidant factors CAT and HO-1 significantly decreased. Based on the low antioxidant capacity after Nrf2 knockout, the levels of NLRP3 inflammasome, GSDMD, and Caspase1 were significantly upregulated after exposure to As and Cu, indicating more severe cellular pyroptosis. In addition, the level of Caspase3-mediated apoptosis was also more severe. Taken together, there is crosstalk between Nrf2-mediated antioxidant capacity and apoptosis/ pyroptosis induced by exposure to As or/ and Cu. Depletion of Nrf2 alters its antioxidant capacity, ultimately leading to more severe apoptosis, pyroptosis, and nephrotoxicity.
Topics: Animals; Mice; Antioxidants; Apoptosis; Arsenic; Copper; Kelch-Like ECH-Associated Protein 1; Kidney; Mice, Inbred C57BL; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Pyroptosis
PubMed: 37801897
DOI: 10.1016/j.ecoenv.2023.115542 -
International Immunopharmacology Feb 2024Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful...
BACKGROUND
Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear.
METHODS
ApoE mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS).
RESULTS
ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation.
CONCLUSION
ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.
Topics: Animals; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Arsenic Trioxide; Toll-Like Receptor 4; Atherosclerosis; Macrophages; Plaque, Atherosclerotic; Lipoproteins, LDL; Inflammation; Apolipoproteins E
PubMed: 38237221
DOI: 10.1016/j.intimp.2023.111452 -
Cell Death & Disease Apr 2024The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and...
The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8 T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.
Topics: Arsenic Trioxide; Carcinoma, Hepatocellular; Nucleotidyltransferases; Liver Neoplasms; Humans; Animals; Membrane Proteins; Mice; Immunogenic Cell Death; Cell Line, Tumor; Interferons; Signal Transduction; Reactive Oxygen Species; Mice, Inbred C57BL
PubMed: 38684648
DOI: 10.1038/s41419-024-06685-8 -
Cell Death Discovery Jul 2023Arsenic trioxide is a first-line treatment drug for acute promyelocytic leukemia, which is also effective for other kinds of leukemia. Its side effects, however, limit... (Review)
Review
Arsenic trioxide is a first-line treatment drug for acute promyelocytic leukemia, which is also effective for other kinds of leukemia. Its side effects, however, limit its clinical application, especially for patients with complex leukemia symptoms. Combination therapy can effectively alleviate these problems. This review summarizes the research progress on the combination of arsenic trioxide with anticancer drugs, vitamin and vitamin analogs, plant products, and other kinds of drugs in the treatment of leukemia. Additionally, the new progress in arsenic trioxide-induced cardiotoxicity was summarized. This review aims to provide new insights for the rational clinical application of arsenic trioxide.
PubMed: 37500645
DOI: 10.1038/s41420-023-01558-z -
Cancers Jul 2023Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are... (Review)
Review
Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are due, in part, to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two targeted and highly active agents in this disease. However, there remains a considerable morbidity and mortality risk in APL secondary to clinically significant hemorrhagic and/or thrombotic events. Prevention and treatment of these coagulopathic complications remain significant impediments to further progress in optimizing outcomes for patients with APL. Moreover, the relative rarity of APL hinders adequately powered randomized controlled trials for evaluating APL coagulopathy management strategies. This review draws from peer-reviewed works falling between initial descriptions of APL in 1957 and work published prior to January 2023 and provides an updated overview of the pathophysiology of hemorrhagic and thrombotic complications in APL, outlines risk stratification parameters, and compiles current clinical best practices. An improved understanding of the pathophysiologic mechanisms driving hemorrhage and thrombosis along with the completion of well-designed trials of management strategies will assist clinicians in developing interventions that mitigate these devastating complications in an otherwise largely curable disease.
PubMed: 37444587
DOI: 10.3390/cancers15133477 -
Current Issues in Molecular Biology Dec 2023Tumor-induced lymphangiogenesis is strongly associated with the formation of tumor metastasis. Therefore, the regulation of lymphangiogenesis offers a promising target...
Tumor-induced lymphangiogenesis is strongly associated with the formation of tumor metastasis. Therefore, the regulation of lymphangiogenesis offers a promising target in cancer therapy. Arsenic trioxide (ATO) is highly effective in the treatment of patients with acute promyelocytic leukemia (APL). As ATO mediates anti-angiogenic effects on endothelial and tumor cells, we aimed to explore the impact of ATO on lymphangiogenesis in human lymphatic endothelial cells (LEC). The BrdU assay and flow cytometry analysis were used to evaluate the influence of ATO on the proliferation and cell cycle distribution of LECs. The lymphatic suppression effects of ATO were investigated in vitro using the lymphatic tube formation assay. The effects of ATO on apoptosis, mitochondrial membrane potential and endothelial cell receptors were investigated by Western blotting, ELISA, flow cytometry and qRT-PCR. The treatment of LECs with ATO attenuated cell proliferation, blocked tube formation and induced subG0/G1 arrest in LECs, thus suggesting enhanced apoptosis. Although subG0/G1 arrest was accompanied by the upregulation of p21 and p53, ATO treatment did not lead to visible cell cycle arrest in LECs. In addition, ATO caused apoptosis via the release of cytochrome c from mitochondria, activating caspases 3, 8 and 9; downregulating the anti-apoptotic proteins survivin, XIAP and cIAP-2; and upregulating the pro-apoptotic protein Fas. Furthermore, we observed that ATO inhibited the VEGF-induced proliferation of LECs, indicating that pro-survival VEGF/VEGFR signaling was affected by ATO treatment. Finally, we found that ATO inhibited the expression of the important endothelial cell receptors VEGFR-2, VEGFR-3, Tie-2 and Lyve-1. In conclusion, we demonstrate that ATO inhibits lymphangiogenesis by activating apoptotic pathways and inhibiting important endothelial cell receptors, which suggests that this drug should be further evaluated in the treatment of tumor-associated lymphangiogenesis.
PubMed: 38275666
DOI: 10.3390/cimb46010006 -
PloS One 2024Although the toxicity of arsenic depends on its chemical forms, few studies have taken into account the ambiguous phenomenon that sodium arsenite (NaAsO2) acts as a...
Sodium arsenite and arsenic trioxide differently affect the oxidative stress of lymphoblastoid cells: An intricate crosstalk between mitochondria, autophagy and cell death.
Although the toxicity of arsenic depends on its chemical forms, few studies have taken into account the ambiguous phenomenon that sodium arsenite (NaAsO2) acts as a potent carcinogen while arsenic trioxide (ATO, As2O3) serves as an effective therapeutic agent in lymphoma, suggesting that NaAsO2 and As2O3 may act via paradoxical ways to either promote or inhibit cancer pathogenesis. Here, we compared the cellular response of the two arsenical compounds, NaAsO2 and As2O3, on the Burkitt lymphoma cell model, the Epstein Barr Virus (EBV)-positive P3HR1 cells. Using flow cytometry and biochemistry analyses, we showed that a NaAsO2 treatment induces P3HR1 cell death, combined with drastic drops in ΔΨm, NAD(P)H and ATP levels. In contrast, As2O3-treated cells resist to cell death, with a moderate reduction of ΔΨm, NAD(P)H and ATP. While both compounds block cells in G2/M and affect their protein carbonylation and lipid peroxidation, As2O3 induces a milder increase in superoxide anions and H2O2 than NaAsO2, associated to a milder inhibition of antioxidant defenses. By electron microscopy, RT-qPCR and image cytometry analyses, we showed that As2O3-treated cells display an overall autophagic response, combined with mitophagy and an unfolded protein response, characteristics that were not observed following a NaAsO2 treatment. As previous works showed that As2O3 reactivates EBV in P3HR1 cells, we treated the EBV- Ramos-1 cells and showed that autophagy was not induced in these EBV- cells upon As2O3 treatment suggesting that the boost of autophagy observed in As2O3-treated P3HR1 cells could be due to the presence of EBV in these cells. Overall, our results suggest that As2O3 is an autophagic inducer which action is enhanced when EBV is present in the cells, in contrast to NaAsO2, which induces cell death. That's why As2O3 is combined with other chemicals, as all-trans retinoic acid, to better target cancer cells in therapeutic treatments.
Topics: Arsenic Trioxide; Arsenites; Humans; Oxidative Stress; Mitochondria; Sodium Compounds; Arsenicals; Autophagy; Cell Line, Tumor; Oxides; Cell Death; Membrane Potential, Mitochondrial; Herpesvirus 4, Human; Adenosine Triphosphate; Hydrogen Peroxide; Lipid Peroxidation; Burkitt Lymphoma
PubMed: 38728286
DOI: 10.1371/journal.pone.0302701 -
Nucleus (Austin, Tex.) Dec 2024Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from... (Review)
Review
Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from the assembly of scaffolding PML proteins and various partners. Recent crystal structure analyses revealed essential self-interacting domains, while liquid-liquid phase separation contributes to their formation. PML bodies orchestrate post-translational modifications, particularly stress-induced SUMOylation, impacting target protein functions. Serving as hubs in multiple signaling pathways, they influence cellular processes like senescence. Dysregulation of PML expression contributes to diseases, including cancer, highlighting their significance. Therapeutically, PML bodies are promising targets, exemplified by successful acute promyelocytic leukemia treatment with arsenic trioxide and retinoic acid restoring PML bodies. Understanding their functions illuminates both normal and pathological cellular physiology, guiding potential therapies. This review explores recent advancements in PML body biogenesis, biochemical activity, and their evolving biological roles.
Topics: Humans; Promyelocytic Leukemia Nuclear Bodies; Nuclear Proteins; Promyelocytic Leukemia Protein; Transcription Factors; Leukemia, Promyelocytic, Acute
PubMed: 38411156
DOI: 10.1080/19491034.2024.2321265 -
Genome Biology Dec 2023Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point...
BACKGROUND
Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.
RESULTS
We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2-which are common events in adult gliomas and myeloid leukemias-also disrupt the formation of PML bodies.
CONCLUSIONS
We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.
Topics: Adult; Child; Humans; Brain Neoplasms; Glioma; Histones; Mutation; Promyelocytic Leukemia Nuclear Bodies
PubMed: 38066546
DOI: 10.1186/s13059-023-03122-5 -
Advanced Science (Weinheim,... Jul 2023Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the...
Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au-cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor-associated antigens release through ATO-induced ferroptosis and photothermal-induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1-6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long-term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti-programmed death-ligand 1 (PD-L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.
Topics: Mice; Humans; Animals; Contrast Media; Photothermal Therapy; Phototherapy; Hyperthermia, Induced; Mice, Inbred Strains; Ultrasonography; Liver Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37162268
DOI: 10.1002/advs.202300878