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Objective: To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism., Methods: The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined., Results: The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells., Conclusion: ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Arsenic trioxide (ATO) has gained significant attention due to its promising therapeutic effects in treating different diseases, particularly acute promyelocytic leukemia (APL). Its potent anticancer mechanisms have been extensively studied. Despite the great efficacy ATO shows in fighting cancers, drawbacks in the clinical use are obvious, especially for solid tumors, which include rapid renal clearance and short half-life, severe adverse effects, and high toxicity to normal cells. Recently, the emergence of nanomedicine offers a potential solution to these limitations. The enhanced biocompatibility, excellent targeting capability, and desirable effectiveness have attracted much interest. Therefore, we summarized various nanocarriers for targeted delivery of ATO to solid tumors. We also provided detailed anticancer mechanisms of ATO in treating cancers, its clinical trials and shortcomings as well as the combination therapy of ATO and other chemotherapeutic agents for reduced drug resistance and synergistic effects. Finally, the future study direction and prospects were also presented., Competing Interests: Declaration of Competing Interest The authors of this review paper declare no conflicts of interest related to the content presented in this study. The review paper was written impartially and without any financial or non-financial influences that could potentially bias the outcomes or interpretations of the research findings. No external funding, grants, or affiliations with organizations or entities that might have a vested interest in the research outcomes were involved in this study. The review paper was carried out solely in the pursuit of scientific knowledge and advancement in the field of targeted drug delivery of ATO drugs for maximizing ATO anticancer potential., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, the use of arsenic trioxide (ATO) in the context of ovarian cancer chemotherapy has attracted significant attention. However, ATO's limited biocompatibility and the occurrence of severe toxic side effects hinder its clinical application. A nanoparticle (NP) drug delivery system using ATO as a therapeutic agent is reported in this study. Achieving a synergistic effect by combining starvation therapy, chemodynamic therapy, and chemotherapy for the treatment of ovarian cancer was the ultimate goal of this system. This nanotechnology-based drug delivery system (NDDS) introduced arsenic-manganese complexes into cancer cells, leading to the subsequent release of lethal arsenic ions (As 3+ ) and manganese ions (Mn 2+ ). The acidic microenvironment of the tumor facilitated this process, and MR imaging offered real-time monitoring of the ATO dose distribution. Simultaneously, to produce reactive oxygen species that induced cell death through a Fenton-like reaction, Mn 2+ exploited the surplus of hydrogen peroxide (H 2 O 2 ) within tumor cells. Glucose oxidase-based starvation therapy further supported this mechanism, which restored H 2 O 2 and lowered the cellular acidity. Consequently, this approach achieved self-enhanced chemodynamic therapy. Homologous targeting of the NPs was facilitated through the use of SKOV3 cell membranes that encapsulated the NPs. Hence, the use of a multimodal NDDS that integrated ATO delivery, therapy, and monitoring exhibited superior efficacy and biocompatibility compared with the nonspecific administration of ATO. This approach presents a novel concept for the diagnosis and treatment of ovarian cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Arsenic trioxide (ATO), one of the oldest and most frequently used poisons, is well-known in forensic science for inducing hepatotoxicity. The regulation of peroxisomal antioxidative enzyme catalase (CAT) involves intricate mechanisms at both transcriptional and post-transcriptional levels. However, the molecular mechanisms underlying the regulation of CAT gene expression in hepatic cells remain elusive. Furthermore, the regulation of CAT gene expression evident in animals administered with ATO in vivo is not well-explored, although several studies have revealed ATO-induced reductions in CAT enzymatic activity in rat livers. In this study, we revealed ATO-dependent reductions in CAT gene expression in both rat liver and Huh-7 human hepatoma cells. Our results indicate that the decline in CAT enzymatic activity can be attributed, at least in part, to the downregulation of its gene expression. The ATO-induced reduction in CAT expression was concurrent with the reduction in peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator (PGC)-1α and inactivation of PPARγ, both considered as positive regulators of CAT gene expression. Moreover, antioxidant N-acetylcysteine (NAC) demonstrated the capability to alleviate the downregulation of CAT gene expression both in vivo and in vitro. Additionally, NAC played a role in alleviating ATO-induced hepatotoxicity, potentially by mitigating the transcriptional downregulation of the CAT gene. Altogether, these results indicate that ATO exerts toxicity by inhibiting the antioxidant defense mechanism, which may be useful for forensic diagnosis of arsenic poisoning and clinical treatment of mitigating ATO-induced hepatotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Simple Summary: Acute promyelocytic leukemia (APL) stands as a remarkable success in achieving high cure rates with chemotherapy-free treatment regimens. Despite these remarkable outcomes, hematologists managing patients with APL take into consideration the distinct side effects associated with the two dual differentiation agents, i.e., all-transretinoic acid (ATRA) and arsenic trioxide (ATO). The objective of this paper is to review relevant literature data and discuss the recommended management strategies of non-hematologic early and late complications that arosein patients diagnosed with APL who were treated with ATO and ATRA-based regimens. 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. [ABSTRACT FROM AUTHOR]

Objective: The effects of arsenic trioxide (As 2 O 3 ) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As 2 O 3 -induced apoptosis in liver cancer cells., Methods: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As 2 O 3 was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As 2 O 3 was detected using immunofluorescence, Western blot assay and transmission electron microscopy., Results: Upon treatment with As 2 O 3 , the viability of HepG2 and SMMC-7721 cells was decreased in a time- and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As 2 O 3 , as shown by flow cytometry. Apoptosis in liver cancer cells treated with As 2 O 3 was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression. Furthermore, As 2 O 3 treatment induced autophagy in liver cancer cells; this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As 2 O 3 inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As 2 O 3 -induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As 2 O 3 on cell viability. Serum starvation increased autophagy and amplified the effect of As 2 O 3 on cell death., Conclusion: As 2 O 3 induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As 2 O 3 may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As 2 O 3 against liver cancer. Please cite this article as: Deng ZT, Liang SF, Huang GK, Wang YQ, Tu XY, Zhang YN, Li S, Liu T, Cheng BB. Autophagy plays a pro-apoptotic role in arsenic trioxide-induced cell death of liver cancer. J Integr Med. 2024; 22(3): 295-302., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

The toxicity of drugs and other related agents attracts considerable attention from basic scientists to clinicians. Humankind has been passionate about the availability of cheap and readily available agent against organotoxicity. Therefore this paper investigated the effects of ethanolic leaves extract of Irvingia gabonensis on arsenic trioxide-induced liver damage in Wistar rats using appropriate standard methods. The results show administration of arsenic trioxide caused significant (P0.05) serum increase in the activities of alanine aminotransferases and alkaline phosphatase (ALT and ALP) of the Wistar rats. There was significant (p0.05) decrease in the activities of serum aspartate aminotransferases (AST) after the administration of arsenic trioxide. There were also significant (p0.05) reduction in the serum level of total protein, albumin and globulin and statistically significant (p0.05) increase in serum level of total bilirubin after administration of arsenic trioxide to the rats. This suggests damage to liver by arsenic trioxide, which are further supported by the histopathological findings such as periportal infiltrates of inflammatory cells, vascular ulceration, ductal epitheliosis and focal necrosis. Administration of extract of Irvingia gabonensis ameliorated both the histopathological and biochemical manifestation in the liver. In conclusion, the results from the histopathological and biochemical analyses suggested damage caused by arsenic trioxide and the potential of extract of Irvingia gabonensis in ameliorating the liver damage. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δwm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy. [ABSTRACT FROM AUTHOR]

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Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia. [ABSTRACT FROM AUTHOR]

Mass spectrometry-based omics technologies are increasingly used in perturbation studies to map drug effects to biological pathways by identifying significant molecular events. Significance is influenced by fold change and variation of each molecular parameter, but also by multiple testing corrections. While the fold change is largely determined by the biological system, the variation is determined by experimental workflows. Here, it is shown that memory effects of prior subculture can influence the variation of perturbation profiles using the two colon carcinoma cell lines SW480 and HCT116. These memory effects are largely driven by differences in growth states that persist into the perturbation experiment. In SW480 cells, memory effects combined with moderate treatment effects amplify the variation in multiple omics levels, including eicosadomics, proteomics, and phosphoproteomics. With stronger treatment effects, the memory effect was less pronounced, as demonstrated in HCT116 cells. Subculture homogeneity was controlled by real-time monitoring of cell growth. Controlled homogeneous subculture resulted in a perturbation network of 321 causal conjectures based on combined proteomic and phosphoproteomic data, compared to only 58 causal conjectures without controlling subculture homogeneity in SW480 cells. Some cellular responses and regulatory events were identified that extend the mode of action of arsenic trioxide (ATO) only when accounting for these memory effects. Controlled prior subculture led to the finding of a synergistic combination treatment of ATO with the thioredoxin reductase 1 inhibitor auranofin, which may prove useful in the management of NRF2-mediated resistance mechanisms. [ABSTRACT FROM AUTHOR]

Thermodynamic theory was employed in this study to investigate the feasibility of separating antimony (Sb) from crude arsenic (As) using vacuum sublimation. Ab initio molecular dynamics simulations are used to calculate the structure, stability, and diffusion properties of AsmSbn (m + n ≤ 6) clusters. As4, As3Sb, As2Sb2, and AsSb3 are the possible clusters in this thermodynamic calculation, and the molecular dynamics results confirmed their structural stability and stabilization in the gas phase. As4 had the largest diffusion coefficients, which is the reason it separates from the Sb-containing clusters (As3Sb, As2Sb2, and AsSb3) during gas-phase diffusion and condensation processes. The experimental results show that As vapor was transformed from crystalline to amorphous with increasing subcooling, and the Sb-containing clusters that enter the gas phase were mainly condensed and deposited at the proximal end of the heating zone. Not considering the volatilization rate, the removal rate of Sb in products can reach 99.35% by increasing the condensation disk and expanding the condensation zone; thus, experiments confirmed that industrial crude arsenic can realize deep Sb removal after vacuum sublimation. [ABSTRACT FROM AUTHOR]

This document provides an overview of recent research on drug resistance and novel targets for cancer therapy. It emphasizes the challenges posed by the complex nature of cancer cells and the importance of discovering new bioactive molecules and techniques to overcome resistance mechanisms. The document includes research articles on the use of drug combinations and repurposing of drugs to enhance antitumoral effects. It also highlights the development of new active molecules and techniques, as well as the role of the tumor microenvironment in cancer resistance. The document concludes with review articles discussing drugs to avoid resistance and new novel cancer-related targets. Overall, this collection of articles aims to provide a comprehensive overview of research areas and new approaches to cancer therapies. [Extracted from the article]

The toxicity of drugs and other related agents attracts considerable attention from basic scientists to clinicians. Humankind has been passionate about the availability of cheap and readily available agent against organotoxicity. Therefore this paper investigated the effects of ethanolic leaves extract of Irvingia gabonensis on arsenic trioxide-induced liver damage in Wistar rats using appropriate standard methods. The results show administration of arsenic trioxide caused significant (P˂0.05) serum increase in the activities of alanine aminotransferases and alkaline phosphatase (ALT and ALP) of the Wistar rats. There was significant (p˃0.05) decrease in the activities of serum aspartate aminotransferases (AST) after the administration of arsenic trioxide. There were also significant (p˂0.05) reduction in the serum level of total protein, albumin and globulin and statistically significant (p˃0.05) increase in serum level of total bilirubin after administration of arsenic trioxide to the rats. This suggests damage to liver by arsenic trioxide, which are further supported by the histopathological findings such as periportal infiltrates of inflammatory cells, vascular ulceration, ductal epitheliosis and focal necrosis. Administration of extract of Irvingia gabonensis ameliorated both the histopathological and biochemical manifestation in the liver. In conclusion, the results from the histopathological and biochemical analyses suggested damage caused by arsenic trioxide and the potential of extract of Irvingia gabonensis in ameliorating the liver damage.

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, significantly contributes to cancer‐related mortality, presenting a dearth of efficacious treatment strategies. Previously, our studies have substantiated the potent cytotoxicity of arsenic trioxide (ATO) against NB cells, however, the specific underlying mechanism remains elusive. Here, we first identified ATO as a novel GPX4 inhibitor, which could trigger the ferroptosis in NB cells. In vitro, ATO significantly inhibited the proliferation and migration ability of NB cells SK‐N‐AS and SH‐SY5Y, and induced ferroptosis. Furthermore, the iron chelator deferoxamine reversed ATO‐mediated intracellular reactive oxygen species accumulation and hindered the generation of the lipid peroxidation product malondialdehyde. Conversely, ferric ammonium citrate notably intensified its cytotoxic effects, especially on retinoic acid (RA)‐resistant SK‐N‐AS cells. Subsequently, the quantitative real‐time polymerase chain reaction results showed ATO significantly inhibited the transcription of GPX4 in NB cells. Remarkably, immunoblotting analysis revealed that MG132 exhibited a notable effect on elevating GPX4 levels in NB cells. Nevertheless, pretreatment with MG132 failed to reverse the ATO‐mediated decrease in GPX4 levels. These findings suggested that ATO reduced the GPX4 expression level in NB cells by mediating GPX4 transcriptional repression rather than facilitating ubiquitinated degradation. In conclusion, our research has successfully indicated that ATO could induce ferroptosis and initiate lipid peroxidation by regulating the transcriptional repression of GPX4, and ATO holds promise as a potential anti‐tumor agent in NB, specifically for patients with RA‐resistant HR‐NB. [ABSTRACT FROM AUTHOR]

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL. [Display omitted] • 416 inhibited the progression of ATRA-sensitive APL in vitro and in vivo. • 416 overcame ATRA resistance in vitro and in vivo. • 416 induced apoptosis and differentiation of NB4 cells by targeting DHODH. • Dysregulation of Bcl-2 and c-Myc by PML/RARα in NB4-R1 cells led to ATRA resistance. • 416 overcame ATRA resistance by downregulating Bcl-2 and c-Myc. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). Methods: We treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML. Results: The combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs. Conclusions: Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling. [ABSTRACT FROM AUTHOR]

This letter discusses the impact of treatment for Acute Promyelocytic Leukemia (APL) with Arsenic Trioxide (ATO) and All-trans Retinoic Acid (ATRA) on fertility. The authors conducted a retrospective study at a tertiary care institute in North India, focusing on patients between the ages of 18 and 40 who had completed therapy and were in molecular remission. Out of the 60 patients included in the study, 11 patients (19.3%) successfully conceived children post-therapy without the use of fertility therapy, and no adverse pregnancy outcomes or congenital abnormalities were reported. The study suggests that ATO treatment for APL does not appear to decrease fertility in patients. [Extracted from the article]

Xanthohumol is a cancer chemopreventive agent that can interfere with the initiation, promotion, and progression phase of carcinogenesis via a variety of inhibitory mechanisms. Xanthohumol was reported as an effective agent against leukemia/lymphoma cells. In the present study, we investigated the effect of xanthohumol and its natural and semisynthetic derivatives against various canine leukemia/lymphoma cell lines. Xanthohumol, three hops minor prenylflavonoids (xanthohumol C, xanthohumol D, α,β-dihydroxanthohumol) and four derivatives obtained by biotransformation (xanthohumol 4′-O-β-D-(4‴-O-methyl)-glucopyranoside) as well as by chemical modification (1″,2″-dihydroxanthohumol K, 2,3-dehydroisoxanthohumol, (Z)-6,4′-dihydroxy-4-methoxy-7-prenylaurone) were tested for their antiproliferative and pro-apoptotic activities against the following canine leukemia/lymphoma cell lines: CLBL-1 (B-cell lymphoma), CLB70 (B-cell leukemia), and GL-1 (B-cell leukemia). The compounds were tested at a final concentration range of 0.1–30 µM for 48 h. All eight of the tested flavonoids exerted concentration-dependent cytotoxicity in the selected canine lymphoma/leukemia cell lines. Three compounds markedly decreased the viability of all cell lines with IC50 in the range of 0.5 to 8 μM. Double-staining of the treated cells with AnnexinV and propidium iodide revealed that the dying cells were mostly in the late apoptosis stage. ROS production and changes in mitochondrial potential were detected. Western blot analysis showed a decreased expression of Bcl-2. Canine lymphoma and leukemia cell lines are sensitive to xanthohumol derivatives, and the compounds acted through an apoptotic cell-death mechanism. These compounds, either used alone or in combination with other therapies, may be useful for the treatment of canine leukemia/lymphoma. [ABSTRACT FROM AUTHOR]

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsIII was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)- modified liposome (LP) was established firstly to encapsulate As III in arsenic-nickel complex by nickel acetate gradient method. The As III -loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release As III which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of As III in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60 CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf- AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrinmodified As III liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects. [ABSTRACT FROM AUTHOR]

Chemotherapy is one of the most important treatment options in the treatment of all types of leukemia, but multi-drug resistance often precludes the success of this treatment. In this study, anticancer properties of heterocyclic salicylaldimines and their Cu(II) complexes on K562 human chronic myelogenous leukemia cell line were investigated. Doxorubicin was used as positive control. Compounds (C1-8 and doxorubicin) were placed to 96-well culture plate in triplicate order at doses of 1, 10, 100, 1000 µM and then K562 cells were seeded into the wells at the dose of 105/ml. After 72 h incubation, colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide test was performed to determine half-maximal inhibitory concentration values of each compound. Antiproliferative effects of compounds were determined using carboxyfluorescein succinimidyl ester assay. Apoptosis induction potential of each compound determined by mitochondrial membrane potential analysis (Rho123), cleaved caspase-3 expression analysis by flow cytometry and immunofluorescent staining and cell morphology analysis by giemza, hematoxylin and eosin and Papanicolaou protocols. The metal complexes of the compounds had stronger cytotoxic effects and cleaved caspase-3 expression than their ligands. Mitochondrial membrane potential was found at low levels in cells treated with Schiff base compounds and doxorubicin. In the cell morphology analyzes, chromatin condensation and marginalization, changes in the cell membrane, ghost cells and apoptotic bodies were observed as evidence of apoptosis formation. Among the tested heterocyclic Schiff base compounds, the powerful cytotoxic and apoptosis-inducing potential of Bis((9-((cycloheptylimino)methyl)-1,1,7,7-tetramethyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-yl)oxy)copper complex (C6) draws attention as a promising compounds withal a need for further in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

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.

Acute myeloid leukemia (AML) is the most common hematopoietic malignancy with abnormal lipid metabolism. However, currently available information on the involvement of the alterations in lipid metabolism in AML development is limited. In this study, we demonstrate that FABP5 expression facilitates AML cell viability, protects AML cells from apoptosis, and maintains triglyceride production. Our bioinformatics analysis revealed that FABP5 expression was upregulated and correlated with unfavorable overall survival of AML patients. FABP5 expression may be used to distinguish normal and AML with high accuracy. FABP5-based risk score was an independent risk factor for AML patients. AML patients with highly expressed FABP5 predicted resistance to drugs. In vitro study showed that FABP5 expression was remarkably elevated in primary AML blasts and an AML cell line. Silencing FABP5 expression attenuated AML cell viability, reduced triglyceride production and lipid droplet accumulation, and induced apoptosis. We utilized AutoDock online tool to identify lycorine as an FABP5 inhibitor by binding FABP5 at amino acid residues Ile54, Thr56, Thr63, and Arg109. Lycorine treatment downregulated the expression levels of FABP5 and its target PPARγ, impaired AML cell viability, triggered apoptosis, and reduced triglyceride production in AML cells. These results demonstrate that FABP5 is critical for AML cell survival and highlight a novel metabolic vulnerability for AML. [ABSTRACT FROM AUTHOR]

Arsenic (As) as a neurotoxic environmental pollutant has attracted extensive attention. Curcumin (Cur) is a natural antioxidant that shows an excellent protective effect against arsenic trioxide (ATO)–induced toxicity in many animal organs. However, the mechanism of Cur against ATO-induced hypothalamic toxicity in ducks has not yet been fully elucidated. Here, ducks were treated with ATO and/or Cur during 28 days; the results showed that ATO exposure induced growth retardation, messy feathers, and abnormal posture in ducks. Moreover, ATO caused neuron vacuolar degeneration and disintegration in the hypothalamus of ducks. Simultaneously, ATO induced blood–brain barrier damage, downregulated the expression of ZO-1, Occludin, and mediated NF‐κB activation, resulting in an increase in inflammatory factors (TLR-4, NF-κB, TNF-α, IL-2, and IL-6). Furthermore, ATO increased the production of pyroptosis-related factors (Caspase-1, IL-18, IL-1), exacerbating the inflammatory damage through NLRP3-mediated inflammasome activation. Cur, on the other hand, exerted excellent inhibitory effects on inflammation and pyroptosis. In summary, our study revealed that ATO triggered inflammation and pyroptosis by modulating NF-κB/NLRP3 signaling pathways in the hypothalamus of ducks, and Cur can alleviate inflammation and pyroptosis caused by ATO. Therefore, as a plant extract, Cur has the potential to prevent and cure ATO-induced hypothalamus toxicity. [ABSTRACT FROM AUTHOR]

As complex mixtures of carcinogenic metalloids, arsenic compounds have been reported to possess anticytotoxic and antitumor effects. In this study, we evaluated the in vitro protective effects of arsenic compounds tetraarsenic oxide and arsenic trioxide against 3-methylcholanthrene-induced toxicity in human keratinocytes. Human keratinocytes were treated with varying concentrations of arsenic compounds alone or in combination with 3-methylcholanthrene. Treatment with arsenic compounds did not significantly affect cell viability, whereas, 3-methylcholanthrene significantly reduced the viability of human keratinocytes. Furthermore, both tetraarsenic oxide and arsenic trioxide decreased the expression of cytochrome P4501A1 at messenger ribonucleic acid and protein levels in human keratinocytes cells treated with 3-methylcholanthrene. In addition, these arsenic compounds increased the expression of nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1, which was shown to be inhibited by 3-methylcholanthrene treatment. Together, these findings suggest that tetraarsenic oxide and tetraarsenic oxide significantly inhibit 3-methylcholanthrene-induced cytotoxicity in human keratinocytes by decreasing the expression of cytochrome P4501A1 and increasing the expression of nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1. Additionally, tetraarsenic oxide was found to be more effective than arsenic trioxide against 3-methylcholanthrene-induced cytotoxicity in vitro. [ABSTRACT FROM AUTHOR]

Summary: Arsenic trioxide (ATO) and all‐trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high‐risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate‐ and high‐risk disease received a further 2 years of maintenance with ATRA, 6‐mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow‐up. The mean (SD) estimated 5‐year event‐free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5‐year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long‐term outcomes in the real‐world setting. [ABSTRACT FROM AUTHOR]

Urbanisation and industrialisation are on the rise all over the world. Environmental contaminants such as potentially toxic elements (PTEs) are directly linked with both phenomena. Two PTEs that raise greatest concern are arsenic (As) and lead (Pb) as soil and drinking water contaminants, whether they are naturally occurring or the consequence of human activities. Both elements are potential carcinogens. This paper reviews the mechanisms by which As and Pb impair metabolic processes and cause genetic damage in humans. Despite efforts to ban or limit their use, due to high persistence both continue to pose a risk to human health, which justifies the need for further toxicological research.

CaSiO 3 is highly resistant to sintering and can trap arsenic at high temperatures in the boiler furnace. However, the trapping capacity of CaSiO 3 for arsenic does not meet the requirements of practical applications, and it is easy to react with acidic gases, which significantly affects the adsorptive property of arsenic. In this paper, the effect of Al modification on the As 2 O 3 adsorption behaviour on the CaSiO 3 (001) surface was systematically investigated using a density functional theory. By comparing the magnitude of adsorption energy of different sites, the active site of As 2 O 3 adsorbed on the surface of CaSiO 3 (001) was determined to be Ca, and the adsorption activity of As 2 O 3 by the silicon oxygen chain composed of [SiO 4 ] tetrahedron is deficient. The Si atoms in the [SiO 4 ] tetrahedral structure are directly replaced by Al atoms, the difference in bond length and bond energy between Al–O bond and Si–O bond is used to promote the redistribution of surface charge and the increase of local structural bond angle of CaSiO 3 (001), leading to the exposure of new active sites (Si-top and Al-top sites) on the silicon oxygen chain. The new active site can realize the chemical adsorption of As 2 O 3 , the higher adsorption energy of the Al-top site is attributed to the stronger s-p orbital hybridization between Al and O atoms after doping, which is more conducive to the charge transfer between As 2 O 3 and the adsorbent surface. In this work, influence of SO 2 and HCl gases on the adsorption of As 2 O 3 by modified silicon oxygen chains was also discussed. The results show that SO 2 and HCl in the flue gas may occupy the Al-top site on the silicon oxygen chain through chemical adsorption, and reduce the activity of this site, thereby affecting the adsorption of As 2 O 3. However, the exposed Si-top sites owing to Al doping show good acidic gas resistance, which in turn help the surface of Al–CaSiO 3 (001) can also maintain stable adsorption of As 2 O 3 in SO 2 and HCl atmosphere. [Display omitted] • The active site of As 2 O 3 adsorption on CaSiO 3 (001) surface was determined to be Ca-top site. • Successfully enhanced the adsorption activity of CaSiO 3 (001) surface to As 2 O 3 by Al doping silicon oxygen chains. • The s-p orbital hybridization between Al and O is strong, which is conducive to charge transfer in the reaction process. • The doped Al-CaSiO 3 (001) surface has certain acid resistance. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a group of hematological malignancies characterized by clonal proliferation of immature myeloid cells. Lipid rafts are highly organized membrane subdomains enriched in cholesterol, sphingolipids, and gangliosides and play roles in regulating apoptosis through subcellular redistribution. Flotillin1 (FLOT1) is a component and also a marker of lipid rafts and had been reported to be involved in the progression of cancers and played important roles in cell death. However, the role of FLOT1 in AML remains to be explored. In this study, we found that increased expression of FLOT1 was correlated with poor clinical outcome in AML patients. Knockdown of FLOT1 in AML cells not only promoted cell death in vitro but also inhibited malignant cells engraftment in vivo. Mechanically, FLOT1 knockdown triggered apoptosis and pyroptosis. FLOT1 overexpression promoted AML cell growth and apoptosis resistance. Our findings indicate that FLOT1 is a prognostic factor of AML and may be a potential target for AML treatment. [ABSTRACT FROM AUTHOR]

Arsenic–iron precipitate was treated using a carbon thermal magnetization reduction method in order to recover arsenic and iron. Arsenic–iron precipitate mixed with coke powder was roasted at a low temperature; arsenic was recovered in the form of As2O3, and iron was recovered in the form of Fe3O4. The volatilization rate of arsenic was 97.45%, and the content of arsenic in the precipitate was decreased to 0.60%. Iron and arsenic were recovered in the form of Fe3O4 and As2O3 with a purity of 99.91 wt.% under the conditions of a roasting temperature of 650 °C, coke powder addition of 25 wt.%, a roasting time of 180 min, and an argon flow rate of 10 L/min. The volatilization of arsenic was controlled by a chemical controlling step at 20–100 min, and this was switched to a diffusion controlling step at 120–180 min by kinetic experiments. The reaction mechanism of arsenic and iron under carbon thermal magnetization reduction was as follows: in the early stage of the reaction, a large amount of FeAsO4 was decomposed into As2O3 and Fe3O4; in the middle and late stages of the reaction, FeAsO4 was continuously decomposed and reduced, and the content of Fe3O4 was continuously increased until all iron was magnetized to generate Fe3O4, and the decomposed As2O3 volatilized into dust. Arsenic reacted with CaO to generate Ca3(AsO4)2, and this may be the reason why arsenic could not be removed completely. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Dysregulation of mRNA translation can contribute to the development and progression of cancer whilst also having an impact on the prognosis of different types of malignancies. Eukaryotic translation initiation factors (eIFs) have been reported to serve a key role in the initiation of mRNA translation. However, little was known about the association between eIF6 and lung adenocarcinoma (LUAD) progression. We aimed to elucidate the roles of eIF6 in LUAD tumorigenesis. Methods: Bioinformatic analysis was conducted to assess the clinical significance of eIF6 in LUAD. CCK-8, colony formation assays were used to evaluate the biological roles of eIF6. The subcutaneous model was used to assess the in vivo roles of eIF6. Results: In the present study, it was found that eIF6 expression was significantly higher in LUAD samples compared with that in normal lung tissues. Higher expression levels of eIF6 were found to be associated with more advanced clinical stages of LUAD and poorer prognoses in patients with LUAD. Subsequently, overexpression of eIF6 was demonstrated to promote LUAD cell proliferation, migration and invasion, which are features of metastasis, in vitro. By contrast, inhibition of eIF6 induced cell cycle arrest and apoptosis in LUAD cells. Further bioinformatics analysis and experimental assays revealed that eIF6 expression positively correlated with the mRNA expression of stemness-associated genes in LUAD cells. Targeting eIF6 suppressed the sphere formation capacity of LUAD cells. In addition, data from the subcutaneous xenograft model in vivo also suggested that eIF6 deficiency could significantly delay tumor growth and improve the prognosis of mice. Targeting eIF6 rendered LUAD cells sensitive to arsenic trioxide treatment. Conclusion: The present study suggest that eIF6 can serve as a prognostic biomarker and a potential therapeutic target for patients with LUAD. [ABSTRACT FROM AUTHOR]