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Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth in vitro and to promote the inhibitory effects of gemcitabine (Gem) on PC in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested in vitro and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth in vitro more potently, with IC50 values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objective: To explore the effects and possible mechanisms of the arsenic trioxide (ATO) and small molecule tyrosine kinase inhibitor ponatinb on KG⁃1 cells in vitro. Methods: Effects of ATO and ponatinib on proliferation of KG⁃1 cells were detected by CCK ⁃8, and the apoptosis was assessed by Annexin V ⁃ FITC. Reverse transcription quantitative polymerase chain reaction (q ⁃ PCR) analysis was used to detect the expression of apoptosis ⁃ related genes. Western blott was performed to explore the expression levels of apoptosis⁃related proteins, fibroblast growth factor receptor 1 (FGFR1) and phosphorylated signal molecules. Results: ①Both ATO and ponatinib effectively inhibited cell proliferation by dose dependent manners. The combination of the two drugs exhibited higher proliferation inhibition rate, less colony formation and more cell apoptosis compared to the single drug treatment. ②Compared with the DMSO group, treatment with either ATO or ponatinib led to significant down⁃regulation of Bcl⁃2, up⁃regulation of Bax and Caspase⁃3 (P < 0.05). The combination of the two drugs up⁃regulated the expression of Bax and Caspase⁃3 more than single drug treatment (both P < 0.01). ③Punatinib significantly inhibited the expression of FGFR1 gene and protein (both P < 0.01), and the addition of ATO did not decrease FGFR1 expression further. Signaling pathway studies showed that ATO significantly inhibited the phosphorylation of MAPK, m ⁃ TOR, and STAT5, but had no significant effect on the phosphorylation of PI3K/AKT and STAT3. Ponatinib markedly inhibited the phosphorylation of STAT3/5, and FGFR1 expression (both P < 0.001), but had no significant effect on the phosphorylation of PI3K/AKT and MAPK. The phosphorylation level of STAT3 was further down⁃regulated by the combination of the two drugs compared with ATO or pratinib monotherapy (both P < 0.01). Conclusion: ATO and ponatinib may inhibit KG ⁃ 1 cell proliferation and colony formation and induce cell apoptosis through different mechanisms. The combination of the two drugs can further enhance the inhibitory effect on KG⁃1 cells. [ABSTRACT FROM AUTHOR]

Liver injury during arsenic treatment for acute promyelocytic leukemia was previously reported in adults, but not comprehensively in children until now. This study aims to investigate liver injury in pediatric patients with APL, changes in liver function during treatment, and compare the effects of Arsenic trioxide (ATO) and Realgar-Indigo naturalis formula (RIF) on liver function. One hundred and eighty-six patients with 3076 patient tests were analyzed, who were enrolled in the Chinese Children's Leukemia Group (CCLG)-APL2016 Protocol database between November 2016 and November 2018 in 38 hospitals across China(ChiCTR-OIN-17011227). Twenty of 164 patients (12.2%) suffered from liver injury after treatment with arsenic. In addition, sixteen (80%) cases of liver injury occurred during the induction period of treatment. What's not disheartening was that 18 (90%) cases of liver injury were transient, occurring at a median time of 17 days after exposure to arsenic. More importantly, the risk of liver injury associated with RIF was not higher than that associated with ATO (RR = 0.854, 95% CI: 0.292–2.495). Otherwise, the ALP of 18 cases of liver injury was not higher than the ULN of ALP. Thus, the incidence of liver injury associated with arsenic in pediatric patients with APL was similar to that in adult patients and the risk of liver injury associated with RIF was not higher than that associated with ATO. Since ALP was not higher in pediatric APL patients with liver injury, further research is needed to explore whether ALP is an index of liver injury in children. [ABSTRACT FROM AUTHOR]

Introduction: All-trans retinoic acid (ATRA) in combination with arsenic trioxide (ATO) is standard therapy for low-to-intermediate risk acute promyelocytic leukemia (APL). Isotretinoin, an agent used for acne vulgaris, is similar in its chemical structure and effects to ATRA, and single-case studies report a probable effectiveness in APL. Case Presentation: In this case, a patient with newly diagnosed APL was treated with isotretinoin/ATO instead of ATRA/ATO for nearly 4 weeks due to a prescription error and anyway reached a stable complete remission as if treated with ATRA/ATO. Conclusion: Treatment of APL with isotretinoin instead of ATRA could possibly be effective. [ABSTRACT FROM AUTHOR]

Simple Summary: Relapses of acute promyelocytic leukemia (APL) remain a challenge despite the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Given the variability in salvage therapies and emerging evidence supporting the deferral of hematopoietic cell transplantation (HCT) in patients receiving ATO, we analyzed the outcomes of a multicentric cohort of 67 relapsed APL patients. Better outcomes were reported with ATO ± ATRA compared to chemo-based regimens and ATRA ± Gemtuzumab ozogamicin (GO). A significant survival advantage was observed for patients undergoing HCT in the chemo-based cohort (p = 0.017), but not in the ATO-based group (p = 0.12). Achieving molecular complete remission (CR) post salvage therapy emerged as the main prognostic factor for second relapses in both univariate and multivariate analyses. Our findings support the efficacy of ATO-based therapies in first relapse and enhance the role of molecular remission as an independent outcome predictor in both first and second APL relapses. Background: The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has radically improved the prognosis of acute promyelocytic leukemia (APL), with cure rates above 80%. While relapse occurs in less than 20% of cases, addressing this issue remains challenging. Identifying effective salvage therapies for relapsed APL is crucial to improve patient outcomes. Methods: A retrospective analysis was performed on a multicentric cohort of 67 APL patients in first relapse, treated in three Italian hematology centers from June 1981 to November 2021. The overall survival (OS) and cumulative incidence of relapse (CIR) were calculated, and predictive factors were assessed using Cox regression models. Results: Overall, 61 patients (91%) received ATO ± ATRA (40.3%), chemo-based regimens (40.3%), or ATRA ± Gemtuzumab ozogamicin (GO) (10.4%). Complete remission (CR) was achieved in 98.2% of patients (molecular CR, n = 71.4%). With a median follow-up time of 54.5 months, the 5-year OS was 73% in the ATO ± ATRA group, 44% in the chemo-based group, and 29% in the ATRA ± GO group (p = 0.035). The 5-year OS rate was also higher for transplant recipients vs. non-recipients within the chemo-based cohort (50% vs. 33%, p = 0.017), but not in the ATO-based cohort (p = 0.12). ATO-based salvage therapy resulted in better OS in both univariate (p = 0.025) and multivariate analyses (p = 0.026). The 2-year CIR was higher in patients without molecular CR vs. patients in molecular CR (66% vs. 24%, p = 0.034). Molecular CR was a significant predictor of second relapse in both univariate (p = 0.035) and multivariate analyses (p = 0.036). Conclusions: Our findings support the efficacy of ATO-based therapies in first relapse of APL and confirm the achievement of molecular remission as an independent outcome predictor in both first and second APL relapse. [ABSTRACT FROM AUTHOR]

In patients with relapsed or refractory neuroblastoma (NB), the limited efficacy of conventional chemotherapies necessitates the exploration of new treatment options. Previous studies have highlighted the anti-tumor properties of arsenic trioxide (ATO) in high-risk NB (HR-NB). This study aims to assess the effectiveness and safety of ATO combined with salvage chemotherapy regimens, featuring cyclophosphamide and topotecan, as a foundational treatment for children with relapsed or refractory NB. Eleven patients (four relapsed, seven refractory NB) were retrospectively analyzed for efficacy and treatment relevance. Salvage treatments, incorporating ATO (0.18 mg/kg daily for 8 h intravenously on days 1 to 10), were administered upon disease progression or relapse, with assessments conducted every two cycles. Treatments had 63.6% efficacy, with six cases of partial response, one case of stable disease, and four cases of disease progression. The overall response rate was 54.5%, and the disease control rate was 63.6%. Importantly, the systemic toxicity experienced by patients following salvage chemotherapy with ATO was mild. Salvage chemotherapy regimens featuring ATO demonstrated potential for prolonging disease stabilization for relapsed or refractory HR-NB patients, exhibiting both favorable efficacy and safety profiles. This suggests further clinical exploration and promotion of this therapeutic approach in the treatment of NB. Clinical perspectives summary: Point 1. The inadequate effectiveness of traditional chemotherapy in individuals with recurrent or resistant neuroblastoma (NB) necessitates the investigation of novel therapeutic approaches. Point 2. Arsenic trioxide (ATO)-based salvage treatments are both effective and less toxic in relapsed or refractory NB. Point 3. Salvage chemotherapy regimens incorporating ATO have shown promise in extending disease stabilization in relapsed or refractory high-risk NB patients, with favorable efficacy and safety profiles, which suggests further clinical exploration and promotion of this therapeutic approach in the treatment of NB. [ABSTRACT FROM AUTHOR]

Background: Small 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. Methods: The 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. Results: In 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. Conclusions: Synergistically, 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. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) is now part of the standard regimen for the treatment of newly diagnosed and relapsed acute promyelocytic leukemia. The availability of an oral form of ATO has greatly reduced the incidence of cardiotoxicity as compared to intravenous (IV) administration. Increasing evidence suggests that ATO has anti-inflammatory properties that may be useful for the treatment of autoimmune diseases. These include the modulation of Treg cell activation, Th1/Th2 and Th17/Treg balance, depletion of activated T cells and plasmacytoid dendritic cells, and influence of B-cell differentiation, leading to reduced autoantibody and cytokine production. ATO has also been shown to induce apoptosis of activated fibroblast-like synoviocytes through the generation of reactive oxygen species and alter the gut microbiota in collagen-induced arthritis. Despite the emergence of newer treatment modalities, the treatment of systemic lupus erythematosus (SLE), especially refractory manifestations, remains a challenge, owing to the paucity of effective biological and targeted therapies that are devoid of adverse effects. Oral ATO is an attractive option for the treatment of SLE because of the lower cost of production, convenience of administration, and reduced cardiotoxicity. This article summarizes the anti-inflammatory mechanisms of ATO and its potential application in the treatment of SLE and other rheumatic diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug‐induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)‐induced lung injury and to elucidate the underlying mechanistic pathways. Experimental Approach: We assessed the effects of nicorandil (15 mg·kg−1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg−1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin‐1, sirtuin‐3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. Key Results: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti‐inflammatory actions. On a molecular level, treatment with nicorandil down‐regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro‐RNA 132 while up‐regulating Sirt1, 3, TFAM, AMPK, and ERR‐α in lung tissue. Conclusions and Implications: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings. [ABSTRACT FROM AUTHOR]

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]

Background: Cell-free DNA (cfDNA) is free DNA found in circulating blood that originates from apoptosis or necrosis, and elevated cfDNA concentrations have been reported in cancers and other diseases. Methods: In this study, the concentrations and fragment distributions of plasma cfDNA were preliminary investigated in elderly (n = 1) and paediatric (n = 1) patients with acute promyelocytic leukaemia (APL) treated with arsenic trioxide (ATO). Results: A slight increase in cfDNA concentrations was observed in the APL patients compared with healthy controls. The change in plasma cfDNA concentrations corresponded to the change in plasma arsenic concentrations during ATO treatment. The fragment distribution pattern did not differ before and during treatment. Three ladder fragments were observed in part of the cfDNA in the second consolidation therapy in an elderly APL patient and the first consolidation therapy of a paediatric APL patient, while two fragments were observed in all other treatment periods. Moreover, APL-related gene mutations were successfully genotyped from plasma cfDNA by using polymerase chain reaction-based methods and these results are consistent with those from leukocytes. Conclusion: This study is the first to report the concentrations and fragment patterns of cfDNA from APL patients treated with ATO. The results suggested that plasma cfDNA concentration in APL patients increased with ATO treatment and that cfDNA is released mainly via neutrophil extracellular traps (and/or necrosis) in addition to apoptosis. To confirm whether cfDNA concentrations and fragment patterns can be used as a biomarker for APL treated with ATO, further accumulative data are needed. [ABSTRACT FROM AUTHOR]

From at least the fifteenth to late nineteenth centuries, peasants in the Austrian province of Styria ate up to several hundred milligrams of arsenic trioxide or sulfide daily or weekly for periods up to a number of years. Taking these doses of arsenic was believed to increase muscular power and enhance the beauty and sexual attractiveness of peasant girls. There do not appear to be contemporaneous records of the known consequences of chronic arsenic exposure. The historical records of arsenic eating there are reviewed and appear to be valid. The benefits are subjective judgements by arsenic eaters. The lack of objective reports of the anticipated external and internal clinical and pathological effects of arsenic poisoning depends on a smaller number of clinical accounts and autopsy reports and the general medical literature of those times, so it is weaker, but it is consistent. Why the arsenic eaters did not show the well-known consequences of prolonged exposure to high doses of arsenic is not known. Possible explanations include increases in detoxifying metabolism in the consumers due to induced genomic changes and selection in people and in the gut microbiome, as shown in other populations. Whether these effects would suffice to protect people against their high doses of arsenic has not been explored. Although the nature and mechanisms of arsenic toxicity have been extensively described, much still remains to be discovered. [ABSTRACT FROM AUTHOR]

Objective To explore the efficacy and safety of thalidomide, arsenic trioxide, dexamethasone and ascorbic acid(TADA)regimen in the treatment of early relapsed multiple myeloma(MM)patients(tumor progression within 12 months after initial treatment). Methods This study retrospectively analyzed 62 patients on TADA chemotherapy regimen and 57 patients on bortezomib, lenalidomide, dexamethasone(velcade, revlimid, dexamethasone, VRD)chemotherapy regimen for multiple myeloma(MM)in early stage relapse, who visited the Department of Hematology of Yanbian University Hospital between 2008 and 2020. We collected the general data profile, follow-up data during 3 courses of treatment, and laboratory data of all patients before and after chemotherapy. The efficacy of the patients was assessed by overall response rate(ORR)and complete response rate(CRR), and the occurrence of adverse reactions was collected for statistical analysis. Kaplan-Meier curves were plotted for the TADA and VRD groups under different renal function conditions, cytogenetically different risk stratification, and different ISS scenarios; the prognosis of patients on the TADA chemotherapy regimen was analyzed. Results There were no statistical differences in age, gender, immunochemical subtypes, ISS staging and high-risk FISH indicators between the two groups(P>0.05). After chemotherapy, the haemoglobin and serum albumin of patients in the TADA group were significantly lower than those in the VRD group, whereas the percentage of blood calcium, blood β2 microglobulin, creatinine and bone marrow plasma cells were significantly higher than those in the VRD group(P<0.05). In addition, the incidence of peripheral neuropathy was significantly lower than that in the VRD group(P<0.05), and there was no statistically significant difference in other adverse reactions(P>0.05).Compared with those in the VRD group, the overall survival(OS)(χ²=8.201, P=0.004)and progression free survival(PFS)(χ²=7.568, P=0.006)survival curves were statistically significant in the TADA group. In the TADA group OS(χ2=3.924, P=0.048)in patients with normal and impaired renal function at the time of enrolment and PFS(χ²=9.008, P=0.003), OS(χ²=9.330, P=0.002)and PFS(χ²=16.090, P<0.001)in ISS stage Ⅰ/Ⅱ and ISS stage Ⅲ at enrolment, OS(χ²=10.149,P<0.001)in high-risk FISH and non-high-risk patients at enrolment and PFS(χ²=11.286, P<0.001)survival curve results showed statistically significant differences. Conclusion The TADA regimen has better efficacy and safety in patients with early recurrence of MM. Renal function, ISS staging and FISH stratification are important factors affecting patients' prognosis. [ABSTRACT FROM AUTHOR]

A series of phenyl β-carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of β-carbonyl selenides by replacing the o-amide group with an o-ester group. The best results as an antioxidant agent were observed for O-((1R,2S,5R)-(−)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was O-(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was O-(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate. [ABSTRACT FROM AUTHOR]

Development of AS1411aptamer-conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study. AS1411aptamer was used as ligand to target nucleolin, which is highly expressed on the surface of melanoma cancer cells. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA) to increase the loading efficiency and stability of the liposomes. The liposomal structure was characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and field emission scanning electron microscopy (FESEM). In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in murine melanoma (B16) and mouse embryonic fibroblast (MEF) cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5% and 58.7 ± 4.2%, respectively. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice of both groups survived until the end of treatment and showed body weight gain. The tumor protrusion completely disappeared in 50% of the mice in these groups. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in healthy mice tissues. However, unlike the CHAL group, which showed an initial increase in tumor volume, a specific antitumor effect was observed in the AP-CHAL group from the beginning of treatment. The results showed that AP-CHAL can be used as an effective drug delivery system with high potential in the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, immune-mediated skin disease with no cure. Intravenous arsenic trioxide (ATO) has been used to treat psoriasis in animal studies. However, the high toxicity of ATO limits its application to clinics for systemic administration. The aim of this study was to fabricate sustained-release ATO liposome gels (ATO-Lip-Gels) to be used for the treatment of psoriasis. The ATO Liposomes were prepared using a zinc acetate gradient method. ATO concentrations were analyzed by HPLC-HG-AFS. The ATO-Lip-Gels were characterized with respect to size, zeta potential, and entrapment efficiency. Stability, in vitro drug release, and in vivo efficacy were also evaluated. The optimal formulation of ATO-Lip was ATO (0.45%), S100 (9%), and cholesterol (1.5%) (W/V) in 0.3 mol/L zinc acetate and incubated for 10 min. In the in vitro drug release study, ATO-Lip-Gels exhibited a slower release profile of ATO than that from Gels only. Compared with the model group, ATO-Lip-Gels-H significantly reduced PASI scores after psoriasis in mice and was superior to tacrolimus at day 5. HE staining showed that the pathological changes caused by psoriasis in mice were significantly improved in the treatment groups, and ATO-Lip-Gels-H had the best effect among the treatment groups. ATO-Lip-Gels applied topologically to imiquimote-induced psoriatic plaque models significantly reduced the levels of key psoriatic cytokines such as IL-6 and TNF-α. We have developed ATO-Lip-Gels for the treatment of psoriasis, which demonstrated higher efficacy with the benchmark, Tacrolimus, and can be an alternative to the conventional treatment with Tacrolimus. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice. [ABSTRACT FROM AUTHOR]

De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2 expression, nuclear localization, and upregulation of bonafide NRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic‐induced neurotoxicity is a well‐recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic‐based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any‐grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1–2 severity (85%), with grade 3 events in 12% and grade 4–5 in 3%. The incidence of neurotoxicity increased with BMI (non‐obese: 16%, obesity class I: 25%, obesity class II–III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II–III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II–III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre‐emptive dose reductions should be considered for obese patients receiving high doses of arsenic. [ABSTRACT FROM AUTHOR]

Curcumin loaded in micelles of block copolymers of ω-methoxypoly(ethylene glycol) and N-(2-hydroxypropyl) methacrylamide modified with aliphatic dilactate (CD) or aromatic benzoyl group (CN) were previously reported to inhibit human ovarian carcinoma (OVCAR-3), human colorectal adenocarcinoma (Caco-2), and human lymphoblastic leukemia (Molt-4) cells. Myeloblastic leukemia cells (K562) are prone to drug resistance and differ in both cancer genotype and phenotype from the three mentioned cancer cells. In the present study, CD and CN micelles were prepared and their effects on K562 and normal cells were explored. The obtained CD and CN showed a narrow size distribution with diameters of 63 ± 3 and 50 ± 1 nm, respectively. The curcumin entrapment efficiency of CD and CN was similarly high, above 80% (84 ± 8% and 91 ± 3%). Both CD and CN showed suppression on WT1-expressing K562 and high cell-cycle arrest at the G2/M phase. However, CD showed significantly higher cytotoxicity to K562, with faster cellular uptake and internalization than CN. In addition, CD showed better compatibility with normal red blood cells and peripheral blood mononuclear cells than CN. The promising CD will be further investigated in rodents and possibly in clinical studies for leukemia treatment. [ABSTRACT FROM AUTHOR]

The use of all‐trans retinoic acid and arsenic trioxide resulted in favourable therapeutic responses in standard‐risk acute promyelocytic leukaemia (APL) patients. However, resistance to these agents has made treating the high‐risk subgroup more problematic, and possible side effects limit their clinical dosages. Numerous studies have proven the cytotoxic properties of Gaillardin, one of the Inula oculus‐christi‐derived sesquiterpene lactones. Due to the adverse effects of arsenic trioxide on the high‐risk subgroup of APL patients, we aimed to assess the cytotoxic effect of Gaillardin on HL‐60 cells as a single or combined‐form approach. The results of the trypan blue and MTT assays outlined the potent cytotoxic properties of Gaillardin. The flow cytometric analysis and the mRNA expression levels revealed that Gaillardin attenuated the proliferative capacity of HL‐60 cells through cell cycle arrest and induced apoptosis via reactive oxygen species generation. Moreover, the results of synergistic experiments indicated that this sesquiterpene lactone sensitizes HL‐60 cells to the cytotoxic effects of arsenic trioxide. Taken together, the findings of the present investigation highlighted the antileukemic characteristics of Gaillardin by inducing G1 cell cycle arrest and triggering apoptosis. Gaillardin acts as an antileukemic metabolite against HL‐60 cells and this study provides new insight into treating APL patients, especially in the high‐risk subgroup. [ABSTRACT FROM AUTHOR]

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]

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19–3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease. [ABSTRACT FROM AUTHOR]

A letter published in the Annals of Hematology discusses the need for a diagnostic test with a short turnaround time for acute promyelocytic leukemia (APL). The authors conducted a proteomic analysis to identify a unique protein biomarker in APL. They found that cystatin F, a secretory protein found in extracellular space and body fluids, was significantly overexpressed in APL cells compared to other types of leukemia and healthy control cells. The authors suggest that cystatin F could be a potential biomarker for the rapid diagnosis of APL and the initiation of appropriate therapies. [Extracted from the article]

Objectives: To determine the safety and efficacy of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) in the first-line treatment of patients with large (5 cm ≤ maximum diameter < 10 cm) or huge (maximum diameter ≥ 10 cm) hepatocellular carcinoma (HCC). Methods: Patients were randomly allocated to the CBATO-TACE group and the conventional transcatheter arterial chemoembolization (cTACE) group. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS), treatment response, and treatment-related adverse events (TRAEs). The extrahepatic collateral arteries, liver function, and liver fibrosis after the first TACE were also evaluated. Results: From September 2018 to September 2020, a total of 207 patients who underwent TACE were consecutively enrolled in this study. The median PFS was 9.5 months (range: 8.0 – 11.0) in the CBATO group, which was significantly longer than that in the cTACE group (6.0 months, range: 4.0–6.0) (p < 0.0001). Patients in the CBATO group had a median OS of 22 months (range: 20.0 – 27.0) compared with 16 months (range: 15.0 – 20.0) in the cTACE group (p = 0.0084). The most common TRAEs were fever (p = 0.043), and nausea and vomiting (p = 0.002), which were more observed in the cTACE group. In addition, the progressive disease time, pulmonary metastasis rate (p = 0.01), the mean number of extrahepatic collateral arteries (p = 0.01), and average number of TACE sessions (p = 0.025) were significantly decreased in the CBATO group. Conclusions: CBATO-TACE achieved better therapeutic outcomes and similar safety profile compared to cTACE in large or huge HCC patients. Furthermore, CBATO-TACE was able to reduce extrahepatic collateral arteries production and extrahepatic lung metastasis. Clinical relevance statement: Our study showed that CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) were effective and safe for the treatment of large and giant HCC. In addition, CBATO-TACE can reduce lateral hepatic branch artery formation and extrahepatic pulmonary metastasis, which provides a new treatment approach for unresectable HCC. Key Points: • We compare long-term efficacy and safety of transcatheter arterial chemoembolization with CalliSpheres® beads loaded with arsenic trioxide (CBATO-TACE) and conventional transcatheter arterial chemoembolization (cTACE) in patients with large (5 cm ≤ maximum diameter < 10 cm) or huge HCC (maximum diameter ≥ 10 cm). • Compared with cTACE, CBATO-TACE significantly improved therapeutic outcomes, overall survival, and progression-free survival in patients with large or huge HCC. The safety assessment suggested that CBATO-TACE is a safe treatment that improves the quality of life and has good treatment adherence. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukaemia is a highly curable sub type of acute myeloid leukaemia and about 90% of these patients have good chance of survival with current all transretinoic acid based arsenic tri oxide or chemotherapy. However, a rare complication, pseudotumour cerebri may arise following All Trans Retinoic Acid (ATRA) therapy, which may provide obstacle to continue this promising therapy. We present the case report of a young female patient with acute promyelocytic leukaemia treated with Arsenic trioxide (ATO) and ATRA that subsequently develop abrupt onset of lateral rectus palsy and decreased visual acuity due to pseudotumour cerebri. We treated the patient with acetazolamide and kept her at frequent follow up. There was significant improvement of her lateral rectus palsy as well as visual acuity following treatment with acetazolamide that allowed us to continue the primary All Trans Retinoic Acid (ATRA) based treatment. [ABSTRACT FROM AUTHOR]

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]

Arsenic trioxide (ATO) might be effective for myelodysplastic syndrome (MDS) by apoptosis induction and demethylation. But ATO has not been widely recommended for small sample and conflicting conclusion of existing trials. This review aimed to systematically evaluate the efficacy of regimens containing ATO for the MDS and explore optimal combination. Randomized clinical trials (RCTs) about ATO regimens were retrieved from China National Knowledge Infrastructure, Embase and PubMed. With odds ratio (OR) as the effect size, network meta-analysis (NMA) and component network meta-analysis (CNMA) were conducted by R and 'netmeta' package, after study selection, quality assessment and data extraction. Thirty-night RCTs were included with a total of 2125 patients, including 1235 treated by ATO containing regimen. With support therapy alone as reference, no inconsistency and heterogeneity were observed. Although NMA did not demonstrate better efficacy of ATO alone, the result of CNMA indicated that ATO was effective in the improvement of overall remission (ORR) [OR = 2.09(1.61, 2.71)] and complete remission (CR) [OR = 1.66(1.25, 2.21)]. Five ATO-containing regimens reported could effectively improve ORR, some of them benefit in CR or hematological improvement (HI) as well. ATO + Traditional Chinese Medicine (TCM), ATO + Thalidomide (T)+TCM, ATO + Chemotherapy (Chem)+T + TCM were regarded as the optimal combination, which improved both ORR, CR and HI in theory. ATO did not increase the risk of common adverse events compared to supportive therapy [(OR = 0.90(0.67, 1.21)]. ATO may be an effective and well-tolerant option for patients with myelodysplastic syndrome. [ABSTRACT FROM AUTHOR]

This article discusses the management challenges of treating acute promyelocytic leukemia (APL) in a patient with Wilson's disease (WD), a copper accumulation disorder. The article describes a case of a 22-year-old female patient with WD who developed APL and underwent treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The patient's liver cirrhosis and organ dysfunction posed challenges in delivering leukemia-directed therapy, but dose adjustments were made based on liver enzyme levels. The patient achieved remission with manageable liver toxicities. The article emphasizes the complexity of managing such cases and the need for further research in this area. [Extracted from the article]

The remarkable effect of arsenic trioxide (ATO) was verified, but side effects are generally observed in acute promyelocytic leukemia (APL) patients, especially leukocytosis and hepatotoxicity. Our aims are to study predictors and reduce ATO-induced side effects without inhibiting efficacy. Sulfhydryl in ATO-treated APL patients was detected by the Spectra Max M5 microplate reader. And patients were divided into high and low sulfhydryl groups according to median sulfhydryl concentration. The onset time of leukocytosis and the peak value of WBC were compared. Correlations between hepatotoxicity indicators and sulfhydryl concentrations were analysed. The concentration of sulfhydryl before treatment was significantly higher in the high sulfhydryl group. Leukocytosis ((7.0 ± 5.5) vs. (14.6 ± 8.5) day) and the peak value of WBC occurred earlier in the low sulfhydryl group ((10.8 ± 5.9) vs. (19.3 ± 5.5) day) than in the high group, and the peak value was significantly lower in the low sulfhydryl group ((24.04 ± 15.05) × 109/L) than in the high group ((42.95 ± 25.57) × 109/L). The elevated liver enzymes were smaller in the higher sulfhydryl group between time points before treatment and the treatment one week later (ΔALT 66.57 vs. 9.85 U/L, ΔAST 59.52 vs. 17.76 U/L), as between time points before treatment and peak value. There was a negative correlation between sulfhydryl and elevated liver enzymes. Higher sulfhydryl compounds contribute to ameliorating ATO-induced leukocytosis and hepatotoxicity in APL patients. The low sulfhydryl before treatment can advance the onset of leukocytosis. For patients with higher sulfhydryl in the early stage, close monitoring of liver enzymes is warranted instead of prophylactic applying any hepatoprotective intervention, to maintain ATO efficacy. [ABSTRACT FROM AUTHOR]

to review the current diagnostic and therapeutic landscape of AML in Latin America as a reflection of other low- and middle-income countries and regions of the world. Encompassing both acute promyelocytic and non-promyelocytic disease types. We reviewed the literature and study registries concerning epidemiological features of patients with AML/APL treated in Latin America, as well as evaluated diagnostic and genetic stratification and patient fitness assessment challenges, the importance of early mortality and supportive care capacity, intensive and non-intensive chemotherapy alternatives, consolidation, and maintenance strategies including novel agents and hematopoietic stem cell transplantation. Although most of the current technologies and treatment options are available in the region, a significant fraction of patients have only limited access to them. In addition, mortality in the first weeks from diagnosis is higher in the region compared to developed countries. Disparities in access to technologies, supportive care capacity, and availability of novel agents and HSCT hinder results in our region, reflecting barriers common to other LMICs. Recent developments in the diagnosis and treatment of this disease must be implemented through education, collaborative clinical research, and advocacy to improve outcomes. [ABSTRACT FROM AUTHOR]

The naturally occurring metalArsenic (AS) poses a hazard to human health as itcan generate oxygen free radicals and oxidative stress.The build-up of free radicals may cause chronic renalinsufficiency and abrupt renal failure. The significant lignan in flaxseed, secoisolariciresinol diglucoside (SDG), provides various health benefits. The current research investigates the preventive benefits of SDG against Arsenic trioxide (As2O3)-induced kidney damage. Four groups of healthy Wistar rats were equally distributed and received daily injections for 5 days as follows: Group1 got injections (IP) of saline as a control; Group2 got subcutaneous (SC) injections of SDG at 10mg/kg/day; Group-3 got intraperitoneal (IP) injections of Arsenic trioxide (As2O3) at 20 mg/kg/day, and Group-4 got 20 mg/kg/day As2O3 IP followed by 10 mg/kg/day SDG subcutaneously one hour later. The impact of As2O3 on the kidney was measured using a variety of indicators including the Greatest Distributable, ROS levels in renal tissues, and malondialdehyde (MDA), as well as two renal function markers the blood urea nitrogen (BUN) and serum creatinine (CREA). Besides the histological examinations, the antioxidant molecule glutathione was evaluated, and so were the functions of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px). Arsenic trioxide (As2O3) enhanced MDA generation, oxygen free radicals, and As2O3levels in kidney tissue while decreasing SODand GSH-Px activity, and the ratio of reduced glutathione to oxidized glutathione. Moreover, serum As2O3 elevated BUN and serum CREA activity. As2O3 induced kidney damage, according to histopathological alterations. Interestingly, SDG treatment reduced ROS generation in serum and kidney and restored antioxidant enzyme levels. In addition, the SDG-treated rats showed significant improvement in all nephrotoxic features. According to the results of this investigation, SDG exhibited an exceptional restorative impact on Arsenic trioxide-mediated kidney cytotoxicity. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) treatment effectively prolongs the overall survival of patients with acute promyelocytic leukemia (APL). Mutations in the oncogene PML::RARA were found in patients with ATO-resistant and relapsed APL. However, some relapsed patients do not have such mutations. Here, we performed microarray analysis of samples from newly diagnosed and relapsed APL, and found different microRNA (miRNA) expression patterns between these two groups. Among the differentially expressed miRNAs, miR-603 was expressed at the lowest level in relapsed patients. The expression of miR-603 and its predicted target tropomyosin-related kinase B (TrkB) were determined by PCR and Western blot. Proliferation was measured using an MTT assay, while apoptosis, cell cycle and CD11b expression were analyzed using flow cytometry. In APL patients, the expression of miR-603 was negatively correlated with that of TrkB. miR-603 directly targeted TrkB and downregulated TrkB expression in the APL cell line NB4. miR-603 increased cell proliferation by promoting the differentiation and inhibiting the apoptosis of NB4 cells. This study shows that the miR-603/ TrkB axis may be a potent therapeutic target for relapsed APL. [ABSTRACT FROM AUTHOR]

A 30-year-old female, with no prior co-morbidities, presented with chief complaints of headache for 4 days, deviation of the angle of the mouth towards the right side for 4 days, vomiting for 1 day and altered sensorium for 1 day. On general physical examination, her vitals were normal. Her Glasgow Coma Scale was E4V5M6. Neurological examination showed left-sided hemiplegia and left facial palsy. Diffusion-weighted imaging-magnetic resonance imaging was suggestive of acute infarct. Complete haemogram showed anaemia, thrombocytopenia; leucocytosis with 60% promyelocytes. Diagnosis of acute promyelocytic leukaemia was made. The patient was started on injection arsenic trioxide. However, the patient lapsed into a deep coma and started to bleed in the form of ecchymotic patches. Non-contrast computed tomogram brain was suggestive of right capsuloganglionic bleed with midline shift coagulation profile suggested of disseminated intravascular coagulation. The patient later succumbed to death. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma. [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]

Arsenic is a carcinogen that can cause skin, lung, and bladder cancer. While DNA double‐strand breaks (DSBs) have been implicated in arsenic‐induced carcinogenesis, the exact mechanism remains unclear. In this study, we performed genetic analysis to examine the impact of arsenic trioxide (As2O3) on four different DSB repair pathways using the human pre‐B cell line Nalm‐6. Random integration analysis showed that As2O3 does not negatively affect non‐homologous end joining or polymerase theta‐mediated end joining. In contrast, chromosomal DSB repair analysis revealed that As2O3 decreases the efficiency of homologous recombination (HR) and, less prominently, single‐strand annealing. Consistent with this finding, As2O3 decreased gene‐targeting efficiency, owing to a significant reduction in the frequency of HR‐mediated targeted integration. To further verify the inhibitory effect of arsenic on HR, we examined cellular sensitivity to olaparib and camptothecin, which induce one‐ended DSBs requiring HR for precise repair. Intriguingly, we found that As2O3 significantly enhances sensitivity to those anticancer agents in HR‐proficient cells. Our results suggest that arsenic‐induced genomic instability is attributed to HR suppression, providing valuable insights into arsenic‐associated carcinogenesis and therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from Sadenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3. Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC). Results: Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity. Discussion: The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed. [ABSTRACT FROM AUTHOR]

Melatonin is a powerful biological agent that has been shown to inhibit angiogenesis and also exerts anti‐inflammatory effects. It is well known that new blood vessel formation (angiogenesis) has become an urgent issue in leukemia as well as solid tumors. Acute promyelocytic leukemia (APL) is a form of liquid cancer that manifests increased angiogenesis in the bone marrow of patients. Despite high‐rate curable treatment with all‐trans‐retinoic acid (ATRA) and recently arsenic‐trioxide (ATO), early death because of hemorrhage, coagulopathy, and Disseminated intravascular coagulation (DIC) remains still a concerning issue in these patients. It is, therefore, urgent to seek treatment strategies with antiangiogenic capabilities that also diminish coagulopathy and hyperfibrinolysis in APL patients. In this study, a coculture system with human umbilical vein endothelial cells (HUVECs) and NB4 APL cells was used to investigate the direct effect of melatonin on angiogenesis and its possible action on tissue factor (TF) and tissue‐type plasminogen activator‐1 (TPA‐1) expression. Our experiments revealed that HUVEC‐induced angiogenesis by cocultured NB4 cells was suppressed when melatonin alone or in combination with ATRA was added to the incubation medium. Melatonin at concentrations of 1 mM inhibited tube formation of HUVECs and also decreased interleukin‐6 secretion and VEGF mRNA expression in HUVEC and NB4 cells. Taken together, the results of this study demonstrate that melatonin inhibits accelerated angiogenesis of HUVECs and ameliorates the coagulation and fibrinolysis indices stimulated by coculturing with NB4 cells. [ABSTRACT FROM AUTHOR]

This scholarly investigation presents pioneering drug candidates for combating leukemia, distinguished by reduced side effects and elevated efficacy. The study focuses on azo compounds for their selective targeting against cancerous cells, and customizable properties. Novel azo compounds, DMTPC and DMTPD, were skillfully synthesized via diazotization of 3‐(4‐Methyl‐1H‐imidazol‐1‐yl)‐5‐(trifluoromethyl)aniline with dimedone and meldrum's acid. Comprehensive characterization employed advanced analytical techniques like 1H‐NMR, 13C‐NMR, LC‐MS, FT‐IR, and XRD. UV‐Vis and fluorescence spectrophotometers scrutinized absorption and fluorescence properties in diverse solvents. Theoretical DFT computations provided optimized geometries, vibrational frequencies, NMR chemical shifts, absorption wavelengths, HOMOs‐LUMOs, Mulliken charges, and molecular orbital energies. Encouragingly, experimental and theoretical values aligned well. ADME properties and toxicity profiles were evaluated using online web servers. Molecular dynamics simulations explored interactions of DMTPC and DMTPD with the leukemia inhibitory factor protein (PDB ID: 1EMR) compared to Nilotinib. Molecular docking studies indicated DMTPC′s promising potential with a binding energy of −8.8 kcal/mol, approaching Nilotinib's −9.4 kcal/mol. This investigation accentuates the burgeoning research paradigm of exploiting azo compounds in the formidable battle against leukemia, opening new avenues for breakthroughs in this field. [ABSTRACT FROM AUTHOR]

The coarse arsenic fume is an inevitable product of the gold roasting and smelting process in the treatment of complex arsenic-containing gold concentrate. The way it is effectively disposed of safely, environmentally friendly, and recovered as resources, has become a technical problem for the gold and non-ferrous metal smelting industry. In the production process of a gold smelting company, the mass fractions of arsenic trioxide, gold, and silver in the coarse arsenic fume are 86. 50 %,1. 1 g/t, and 11 g/t, respectively. The coarse arsenic fume is treated using closed fluidization transportation of coarse arsenic fume, multi-stage gradient temperature-controlled distillation, multi-stage slow-cooling crystallization of arsenic, leaching of gold and silver from arsenic-removal slag and recycling of arsenic-removal tail gas. This technology has been successfully applied on an industrial scale. The primary product obtained has an arsenic trioxide mass fraction of 99. 51 %,and the arsenic recovery rate reaches 99. 10 %. The gold and silver recovery rates are 81. 17 % and 79. 94 % respectively. The industrial application of the purification and production of arsenic trioxide from coarse arsenic fume successfully transforms coarse arsenic fume hazardous waste into a secondary high-value resource, overcoming the technical bottlenecks of producing high-purity arsenic trioxide from coarse arsenic fume both domestically and internationally. The comprehensive recovery, recycling, and clean production of coarse arsenic fume resources have significant environmental, economic, and social benefits, demonstrating wide-ranging value for promotion and application. [ABSTRACT FROM AUTHOR]

• The expression of MXRA7 was upregulated in patients with APL. • Knocking down of MXRA7 promoted the differentiation of APL cells. • Knockdown of MXRA7 inhibited the malignancy of APL cells in mice. The biology of the matrix remodeling-associated 7 (MXRA7) gene has been ill defined. Bioinformatic analysis of public data sets revealed that MXRA7 messenger RNA (mRNA) was highly expressed in acute myeloid leukemia (AML), especially acute promyelocytic leukemia (APL). High expression of MXRA7 was associated with poor overall survival of patients with AML. We confirmed that MXRA7 expression was upregulated in patients with APL and cell lines. Knockdown or overexpression of MXRA7 did not affect the proliferation of NB4 cells directly. Knockdown of MXRA7 in NB4 cells promoted drug-induced cell apoptosis, whereas overexpression of MXRA7 had no obvious influence on drug-induced cell apoptosis. Lowering MXRA7 protein levels in NB4 cells promoted all-trans retinoic acid (ATRA)–induced cell differentiation possibly through decreasing the PML-RARα level and increasing PML and RARα levels. Correspondingly, overexpression of MXRA7 showed consistent results. We also demonstrated that MXRA7 altered the expression of genes involved in leukemic cell differentiation and growth. Knockdown of MXRA7 upregulated the expression levels of C/EBPB, C/EBPD , and UBE2L6, and downregulated the expression levels of KDM5A, CCND2 , and SPARC. Moreover, knockdown of MXRA7 inhibited the malignancy of NB4 cells in a non-obese diabetic-severe combined immune-deficient mice model. In conclusion, this study demonstrated that MXRA7 influences the pathogenesis of APL via regulation of cell differentiation. The novel findings about the role of MXRA7 in leukemia not only shed light on the biology of this gene but also proposed this gene as a new target for APL treatment. [ABSTRACT FROM AUTHOR]

In patients with acute promyelocytic leukaemia (APL), differentiation syndrome (DS) is a life‐threatening complication caused by the differentiating effect of all‐trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Leucocytosis is frequently observed during induction therapy for APL and is intimately associated with the development of DS and its severity. The management of DS is particularly important due to the high likelihood of excellent outcomes for APL patients who successfully complete induction therapy.Commentary on: Cicconi et al. Leukocytosis during induction therapy with all‐trans‐retinoic acid and arsenic trioxide in acute promyelocytic leukemia predicts for differentiation syndrome and treatment‐related complications. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19759. [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]

The phytochemical investigation of Dialium corbisieri seeds led to the isolation of five monoterpenoid indole alkaloids along with a phytoserotonin, 1-6 and among the known compounds, the spectroscopic data of (5S)-methoxy-akuammiline (1) was reported for the first time. The structures were elucidated based on nuclear magnetic resonance spectroscopic techniques such as ultraviolet, infrared, high-resolution electrospray ionization time-of-flight mass spectrometry, and electron-capture dissociation spectrum calculations. The isolated compounds were evaluated for their cytotoxicity and cell progression in the human acute promyelocytic leukemia HL60 cell line. [ABSTRACT FROM AUTHOR]

This review surveys patent information and fundamental literature sources on the technological foundations of producing high-purity arsenic and its compounds in the leading countries: Russia (USSR), USA, Japan, Germany, and China. The 1960–1979 literature sources on the following issues are summarized:—recovery of elemental arsenic from various raw materials;—production of high-purity (99.99999 wt %) arsenic and its compounds;—devices and equipment for recovery and purification of elemental arsenic and arsenic-containing substances. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]