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Biomedicines Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that...
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy.
PubMed: 37761021
DOI: 10.3390/biomedicines11092580 -
Life Sciences Nov 2023This study aimed to explore whether low-intensity ultrasound (LIUS) combined with low-concentration arsenic trioxide (ATO) could inhibit the proliferation of glioma and,...
AIMS
This study aimed to explore whether low-intensity ultrasound (LIUS) combined with low-concentration arsenic trioxide (ATO) could inhibit the proliferation of glioma and, if so, to clarify the potential mechanism.
MAIN METHODS
The effects of ATO and LIUS alone or in combination on glioma were examined by CCK8, EdU, and flow cytometry assays. Western blot analysis was used to detect changes in expression of apoptosis-related proteins and their effects on the EGFR/AKT/mTOR pathway. The effects of ATO and LIUS were verified in vivo in orthotopic xenograft models, and tumor size, arsenic content in brain tissue, survival, and immunohistochemical changes were observed.
KEY FINDINGS
LIUS enhanced the inhibitory effect of ATO on the proliferation of glioma, and EGF reversed the proliferation inhibition and protein changes induced by ATO and LIUS. The anti-glioma effect of ATO combined with LIUS was related to downstream AKT/mTOR pathway changes caused by inhibition of EGFR activation, which enhanced apoptosis of U87MG and U373 cells. In vivo experiments showed significant increases in arsenic content in brain tissue, as well as decreased tumor sizes and longer survival times in the combined treatment group compared with other groups. The trends of immunohistochemical protein changes were consistent with the in vitro results.
SIGNIFICANCE
This study showed that LIUS enables ATO to exert anti-glioma effects at a safe dose by inhibiting the activation of EGFR and the downstream AKT/mTOR pathway to regulate apoptosis. LIUS in combination with ATO is a promising novel method for treating glioma and could improve patient prognosis.
PubMed: 37730111
DOI: 10.1016/j.lfs.2023.122103 -
Journal of Hazardous Materials Sep 2023Historical mining and mineral processing at the former Giant Mine (Yellowknife, NT, Canada) created an enduring legacy of arsenic (As) and antimony (Sb) contamination....
Historical mining and mineral processing at the former Giant Mine (Yellowknife, NT, Canada) created an enduring legacy of arsenic (As) and antimony (Sb) contamination. Approximately 237,000 tonnes of arsenic trioxide roaster waste (ATRW) generated between 1948 and 1999 remains stored on-site in underground chambers. We studied the chemical forms and phase associations of As and Sb to improve understanding of ATRW environmental behavior. Although arsenolite [AsO] is the principal As and Sb host, we also observed minor associations of As with Fe oxides. Arsenic K-edge X-ray absorption spectroscopy (XAS) revealed As(III) dominated ATRW, with some As(V) and As(-I) also present. Arsenic coordination and bonding is consistent with arsenolite, while scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) showed minor As association with Fe oxides and arsenopyrite [FeAsS]. Antimony K-edge XAS revealed variable proportions of Sb(III) and Sb(V), with Sb-O, Sb-Sb and Sb-As bonding consistent with stibioclaudetite [AsSbO] or Sb-substituted arsenolite. Electron microprobe analysis (EMPA) results showed variable but quantitative Sb substitution for As in arsenolite grains, possibly influencing ATRW solubility and reactivity under environmental conditions. Overall, our results reveal complex As and Sb phase associations with important implications for ongoing remediation efforts and long-term environmental fate of ATRW solids.
PubMed: 37459758
DOI: 10.1016/j.jhazmat.2023.132037 -
American Journal of Translational... 2023Arsenic is one of the greatest hazards as an environmental carcinogen. At the same time it is also a promising anticancer agent, that can be used to treat acute...
OBJECTIVES
Arsenic is one of the greatest hazards as an environmental carcinogen. At the same time it is also a promising anticancer agent, that can be used to treat acute promyelocytic leukemia (APL) and some other tumors. Arsenic trioxide (ATO) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells. However, the molecular mechanisms that govern these paradoxical effects of arsenic in bladder cancer remain unclear. We speculate that they share the common mechanism that arsenic binds to the target proteins and subsequently impacts the expression of downstream genes.
METHODS
To address this issue, three Gene Set Enrichments (GSE) were loaded from the Gene Expression Omnibus (GEO) database with four expression matrices. Three of them were mice samples at exposure times of 1, 2, and 12 weeks, and the last was a human urothelial cell (HUC1) sample. Differentially expressed genes (DEGs) from 4 expression groups were identified at iDEP and analyzed at Metascape and Cytoscape for signaling pathway analysis and protein-protein interaction (PPI) analysis. The web-portals UALCAN and GEPIA were used to analyze the role of DEGs in the crosstalk between carcinogenic and anticancer effects. The putative downstream genes of arsenic binding proteins were retrieved using the Cistrome Data Browser. Real-time PCR was used to validate the expression of DEGs.
RESULTS
The signaling pathways referred to lipid metabolism. Responses to various stimuli or hormones were overrepresented in 4 expression matrices. The PPI network emphasized the role of KRAS and TNF signaling in different groups. Furthermore, BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10 played an important role in the crosstalk between carcinogenic and anticancer effects in bladder cancer. Arsenic may impact the activity of ACTB, BACH1, NME2, RBBP4, PARP1, and PML by direct binding, and thus influence the expression of downstream genes such as PAX6, MLLT11, LTBP1, PCSK5, ZFP36, COL8A2, and IL1R2.
CONCLUSION
Arsenic exerted carcinogenic and anticancer functions by altering the expression of crosstalk genes such as BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10, and these were due to arsenic binding proteins.
PubMed: 37969188
DOI: No ID Found -
Frontiers in Pharmacology 2024The toxicity of arsenic is widely recognized globally, mainly harming human health by polluting water, soil, and food. However, its formulations can also be used for... (Review)
Review
The toxicity of arsenic is widely recognized globally, mainly harming human health by polluting water, soil, and food. However, its formulations can also be used for the clinical treatment of diseases such as leukemia and tumors. Arsenic has been used as a drug in China for over 2,400 years, with examples such as the arsenic-containing drug realgar mentioned in Shennong's Herbal Classic. We have reviewed references on arsenic over the past thirty years and found that research has mainly focused on clinical, pharmacological, and toxicological aspects. The finding showed that in clinical practice, arsenic trioxide is mainly used in combination with all-trans retinoic acid (ATRA) at a dose of 10 mg/d for the treatment of acute promyelocytic leukemia (APL); realgar can be used to treat acute promyelocytic leukemia, myelodysplastic syndrome, and lymphoma. In terms of pharmacology, arsenic mainly exerts anti-tumor effects. The dosage range of the action is 0.01-80 μmol/L, and the concentration of arsenic in most studies does not exceed 20 μmol/L. The pharmacological effects of realgar include antiviral activity, inhibition of overactivated lactate dehydrogenase, and resistance to malaria parasites. In terms of toxicity, arsenic is toxic to multiple systems in a dose-dependent manner. For example, 5 μmol/L sodium arsenite can induce liver oxidative damage and promote the expression of pro-inflammatory factors, and 15 μmol/L sodium arsenite induces myocardial injury; when the concentration is higher, it is more likely to cause toxic damage.
PubMed: 38495096
DOI: 10.3389/fphar.2024.1338725 -
Frontiers in Oncology 2023
PubMed: 37441418
DOI: 10.3389/fonc.2023.1238486 -
Chemical Science Jun 2024Drug resistance in tumor cells remains a persistent clinical challenge in the pursuit of effective anticancer therapy. XIAP, a member of the inhibitor of apoptosis...
Drug resistance in tumor cells remains a persistent clinical challenge in the pursuit of effective anticancer therapy. XIAP, a member of the inhibitor of apoptosis protein (IAP) family, suppresses apoptosis its Baculovirus IAP Repeat (BIR) domains and is responsible for drug resistance in various human cancers. Therefore, XIAP has attracted significant attention as a potential therapeutic target. However, no XIAP inhibitor is available for clinical use to date. In this study, we surprisingly observed that arsenic trioxide (ATO) induced a rapid depletion of XIAP in different cancer cells. Mechanistic studies revealed that arsenic attacked the cysteine residues of BIR domains and directly bound to XIAP, resulting in the release of zinc ions from this protein. Arsenic-XIAP binding suppressed the normal anti-apoptosis functions of BIR domains, and led to the ubiquitination-dependent degradation of XIAP. Importantly, we further demonstrate that arsenic sensitized a variety of apoptosis-resistant cancer cells, including patient-derived colon cancer organoids, to the chemotherapy drug using cisplatin as a showcase. These findings suggest that targeting XIAP with ATO offers an attractive strategy for combating apoptosis-resistant cancers in clinical practice.
PubMed: 38846391
DOI: 10.1039/d4sc01294a -
Cancers Mar 2024The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid... (Review)
Review
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.
PubMed: 38539495
DOI: 10.3390/cancers16061160 -
Risk Management and Healthcare Policy 2023Infusion rate is one of the essential elements that should be included in all intravenous orders. Patients may experience adverse consequences or risks associated with... (Review)
Review
BACKGROUND
Infusion rate is one of the essential elements that should be included in all intravenous orders. Patients may experience adverse consequences or risks associated with inappropriate infusion. Meanwhile, there is growing pressure on the chemotherapy unit to deliver treatment quickly, efficiently, and safely, and thus it is very necessary to improve the chemotherapy process and service to cancer patients. Clinicians should consider how to further standardize infusion therapy, and innovate new infusion strategies to increase efficacy, reduce toxicity, improve patient satisfaction and save health resource costs. Sporadic studies have evaluated the effects of infusion rates of anticancer agents on clinical outcomes, economic benefits, and administration efficiency. However, an update review has not been available.
METHODS
Relevant literature was identified by search of PubMed until September 2023.
RESULTS
Infusion rates may have significant effect on the efficacy of anticancer agents (e.g., methotrexate, fluorouracil, and arsenic trioxide). Slow infusion is safer for platinum compounds, doxorubicin and carmustine, whereas fast infusion is safer than slow infusion of gemcitabine. Optimal flow rates of paclitaxel and fluorouracil are based on the balance between multiple risks of toxicity. Optimal infusion rate may bring economic benefits. If efficacy and safety are not compromised, shortened infusion may result in higher patient satisfaction, improved institutional efficiency and more nursing time available for other activities (e.g., biosimilar products, endostar). Other concerns about infusion rate include clinical indications (eg, paclitaxel and rituximab, methotrexate), severity and type of hypersensitivity reactions (e.g., platinum compounds), formulation features (e.g., paclitaxel, doxorubicin), and genetic polymorphism (e.g., gemcitabine, methotrexate).
CONCLUSION
The latest knowledge of infusion rate concerns will enhance the appropriateness and accuracy in intravenous administration. Interdisciplinary teams should collaborate and implement relevant risk management and healthcare policy. It is worthwhile to conduct comparative studies of intravenous therapy with different infusion speeds.
PubMed: 38024501
DOI: 10.2147/RMHP.S442692 -
Blood Cancer Journal Dec 2023Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (AsS), is highly effective in treating adult acute promyelocytic... (Randomized Controlled Trial)
Randomized Controlled Trial
Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (AsS), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.
Topics: Child; Humans; Arsenic; Arsenic Trioxide; Arsenicals; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin
PubMed: 38052803
DOI: 10.1038/s41408-023-00949-w