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We report the case of a 42-year-old female diagnosed with acute promyelocytic leukemia (APL), who developed differentiation syndrome (DS) on day 14 during induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with sudden-onset dyspnea, abdominal pain, tachycardia, and fever. Her laboratory findings were remarkable for acute kidney injury (AKI), worsening leukocytosis, thrombocytopenia, and lactic acidosis. She was also found to have flash pulmonary edema and a pericardial effusion. Despite immediate dexamethasone and methylprednisolone administration along with cessation of induction therapy, she continued to worsen and suffered a non-shockable cardiac arrest. Return of spontaneous circulation (ROSC) was achieved, but she was in profound shock requiring multiple vasopressors. The patient suffered repeat cardiac arrest later that day and passed away within 24 hours. DS is a potentially life-threatening complication in APL treatment, occurring in about 25% of APL patients and posing significant treatment challenges.

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]

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments. [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]

Arsenic trioxide (ATO) has emerged as a potent therapeutic agent for various malignancies, particularly solid tumors. However, its clinical utility is hindered by challenges such as poor bioavailability, rapid systemic clearance, and nonspecific toxicity. To address these limitations, nanocarrier systems have been developed to enhance the delivery of ATO, thereby improving its therapeutic efficacy, while minimizing adverse effects. This review discusses the physicochemical properties and mechanisms of action of ATO, as well as the challenges associated with its traditional delivery methods. Various nanocarrier platforms--including liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers and carbon-based materials--are explored for their ability to improve the pharmacokinetics and biodistribution of ATO. Targeting strategies, including passive and active targeting are also examined to facilitate tumor-specific delivery. Recent advancements in clinical applications demonstrate the potential of ATO-loaded nanocarriers to enhance antitumor activity and reduce off-target toxicity. Future perspectives highlight the need for personalized nanomedicine approaches and the integration of combination therapies to further improve treatment outcomes for patients with solid tumors. This review underscores the promising role of nanocarrier systems in revolutionizing ATO therapy and contributing to more effective cancer treatments. [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]

Introduction: Arsenic trioxide (As2O3) is an environmental contaminant that may cause hepatic injuries. As2O3-induced liver injuries are detected as an underlying cause of hepatocellular carcinoma (HCC) around the globe. The present study aimed to investigate the potential of Gardenia latifolia (GL) extracts against oxidative stress and apoptotic activity in HCC-induced rats and to explore in silico molecular docking analysis of phytocompounds of G. latifolia. Methods: The present study was designed to investigate the hepato-protective effect of ethanol and n-hexane extract of G. latifolia. Phytochemical analysis was performed using gas-chromatography-mass spectrometry (GC-MS), and the identified metabolites were used for computational docking analysis. The binding potential and inhibitory effect of the identified metabolites against inflammatory markers were assessed. Fifty male albino rats were selected for the in vivo study and were randomly divided into five groups, with 10 rats in each group. Group I is the control group. Hepatotoxicity was induced in groups II, III, IV, and V with 350 mg/kg/day of As2O3. Group II was taken as positive control, Group III and IV were treated with ethanol and n-hexane extract of G. latifolia, respectively, and Group V was treated with cisplatin 3.0 mg/kg/day. At the end of treatment, different stress and liver biomarkers were also analyzed. Results and Discussion: The quantitative phytochemical profiling revealed a high content of total flavonoid and tannins found at 5.731 ± 0.1856 mg quercetin equivalent (QE)/g and 86.31 ± 14.20 mg tannic acid equivalent (TAE)/g in G. latifolia n-hexane extract, while a significant concentration of TFC was 276.821 ± 2.19 mg gallic acid equivalent (GAE)/g, in ethanolic extract. GC-MS analysis resulted in the identification of 26 metabolites in ethanol extract while 32 metabolites in n-hexane extract, respectively. Both the extracts restored the abnormal levels of stress markers (p < 0.05) in Groups III and IV, and were comparable to the comparative control group V, which was given cisplatin as the standard drug. The histopathological examination revealed the regeneration of hepatocytes, dilated sinusoidal cells, necrosis, and distorted hepatic architecture observed in arsenic trioxide hepatotoxic liver. Among the top most identified metabolites from GC-MS analysis, stigmasterol exhibited -8.3 and -7.1 kcal/mol in silico binding affinities against cyclooxygenase-2 (COX-2), and interleukin (IL-6), respectively, while Dasycarpidan-1-methanol exhibited the best binding affinities of -6.8 and -7.2 kcal/mole against matrixmetalloprotinease (MMP)-3 and heat shock protein-90 (HSP-90), respectively. 6-AH-cAMP showed the best docking score of -7.5 kcal/mol for the vascular endothelial growth factor (VEGF) macromolecule. Metabolite Dasycarpidan-1-methanol, acetate represented drug like properties so it was further analyzed by MD simulation and stable dynamic nature of protein ligand complex was evaluated. Conclusion: In conclusion, the effective therapeutic potential of G. latifolia extracts targeted oxidative stress, increasing antioxidant activities and inhibiting inflammation and liver complications at early stages. Further research on the molecular level may further explore the anticancer potential of this plant against various types of cancers. [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]

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 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.

Abstract 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.

Dan Liu, Juan Tong, Erling Chen, Li Wang, Lei Xue, Xuhan Zhang, Na Zhao, Xing Hu, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, People’s Republic of ChinaCorrespondence: Changcheng Zheng, Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, Anhui Province, 230001, People’s Republic of China, Email zhengchch1123@ustc.edu.cnBackground: The aim of the study was to evaluate the efficacy and safety of induction and consolidation with all-trans retinoic acid (ATRA) +arsenic trioxide (ATO) +anthracyclines and maintenance with ATRA +Realgar-Indigo naturalis formula (RIF) for high-risk APL.Methods: Twenty-one patients with high-risk APL treated with ATRA+ATO+ anthracyclines for induction and consolidation and ATRA+RIF for maintenance from 2012 to 2021 were analyzed. Endpoints include morphological complete remission (CR) and complete molecular remission (CMR), early death (ED) and relapse, survival and adverse events (AEs).Results: After induction treatment, all 21 patients (100%) achieved morphological CR and 14 people (66.7%) achieved CMR. Five of the 21 patients did not undergo immunological minimal residual disease (MRD) examination after induction; however, 14 of the remaining 16 patients were MRD negative (87.5%). The median time to achieve CR and CMR was 26 days (range: 16– 44) and 40 days (range: 22– 75), respectively. The cumulative probability of achieving CR and CMR in 45 days was 100% and 76.2% (95% CI: 56.9– 91.3%), respectively. All patients achieved CMR and MRD negativity after the three courses of consolidation treatment. The median follow-up was 66 months (25– 142), with no central nervous system relapse and bone marrow morphological or molecular relapse until now, and all patients survived with 100% overall survival and 100% event-free survival. Grade 4 adverse events (AEs) were observed in 3 patients (14.3%) during the induction period including arrhythmia (n = 1), pulmonary infection (n = 1) and respiratory failure (n = 1); and the most frequent grade 3 AEs were pulmonary infection, accounting for 62.0% and 28.6%, respectively, during induction and consolidation treatment, followed by neutropenia, accounting for 42.9% and 38.1%, respectively.Conclusion: For newly diagnosed high-risk APL patients, induction and consolidation with ATRA+ATO+anthracyclines and maintenance with ATRA+RIF is a highly curative treatment approach.Keywords: high-risk acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, realgar–Indigo naturalis formula, anthracyclines, event-free survival

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

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]

Aim: Cu2O nanoparticles were synthesized using an extract from S. latifolium algae (SLCu2O NPs). Their effect on PANC-1 cells and the expression of two drug resistance-related lncRNAs were evaluated in comparison with Arsenic trioxide. Materials & methods: SLCu2O NPs were characterized using XRD, SEM, and TEM microscopies. The effects of SLCu2O NPs on cell cytotoxicity, cell cycle, and apoptosis, and expression of two drug resistance-related lncRNAs were examined using MTT assay, flow cytometry, and real-time PCR, respectively. Results: SLCu2O NPs demonstrated anti-cancer properties against PANC-1 cells comparable to Arsenic trioxide, and the expression of lncRNAs increased upon treatment with them. Conclusion: SLCu2O NPs demonstrate anti-cancer properties against PANC-1 cells; however, using gene silencing strategies along with SLCu2O NPs is suggested. Article highlights Copper nanoparticles have been proposed as a novel anti-cancer agent in cancer research including Pancreatic cancer. Copper oxide nanoparticles synthesis via physicochemical routs restricted their use in further cancer research or future clinical applications due to using highly toxic chemicals, high energy consumption, and high cost of synthesis. In this study, Cu2O nanoparticles were synthesized using an extract from S. latifolium algae to address environmental concerns. The XRD patterns of the S. latifolium-derived Cu2O nanoparticles showed the prominent peaks attributed to planes (110), (111), (200), (220), (311), and (222) that confirm the formation of the single-phase cubic structure with Pn-3m space group. Scanning electron microscopy confirm the spherical-cubic shape of S. latifolium-derived Cu2O nanoparticles with the average size of 40–50 nm. S. latifolium-derived Cu2O nanoparticles induced cell cytotoxicity on PANC-1 cells with IC50 of 72.75 and 65.4 μg/ml at 24 and 48 h, respectively. S. latifolium-derived Cu2O nanoparticles induced S-phase cell cycle arrest and apoptosis in PANC-1 cells. S. latifolium-derived Cu2O nanoparticles showed comparable effects to arsenic trioxide in terms of cell cytotoxicity, colony formation, cell cycle arrest, and apoptosis. S. latifolium-derived Cu2O nanoparticles increased the expression of two drug-resistant related lncRNAs, HOTAIR and HOTTIP, which may suggest using gene silencing strategies along with these nanoparticles. [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]

Glioblastoma (GBM) is a malignant primary brain tumor and an essential contributor to morbidity and mortality globally. Arsenic trioxide (ATO) exerts specific roles in preventing tumor growth. This study investigated the role of ATO in GBM cell behaviors and stemness. The effects of ATO on the malignant behavior of GBM cells, tumor stemness, and epithelial-mesenchymal transition (EMT) factors in mouse tumor tissues were explored. Targets of ATO in GBM were predicted using multiple databases. Subsequently, the expression of retinoic acid-related orphan receptor beta (RORB), WNT-1, β -Catenin, and c-Myc expression were examined in GBM cells before and after ATO treatment. ATO inhibited the malignant behavior of GBM cells in vitro and slowed down the GBM growth in vivo by inhibiting the stemness. The inhibitory effect of ATO on GBM was achieved by promoting RORB levels and strengthening the antagonism to β -Catenin to inhibit Wnt signaling, thus inhibiting tumor growth. Collectively, ATO induced RORB levels in GBM cells and strengthened the antagonistic effect on β -Catenin, thus inhibiting WNT signaling and tumor growth. [ABSTRACT FROM AUTHOR]

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment. Steady-state protein levels of cyclin D1 are controlled by phosphorylation- and SUMOylation-mediated proteasome degradation. Inhibition of cyclin D1 degradation leads to B lymphocyte transformation and develops Mantle cell lymphoma-like phenotype. [Display omitted] [ABSTRACT FROM AUTHOR]

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]

Reactive oxygen species (ROS) and the oxidative damage are the main factors involved in tissue damage caused by arsenic trioxide. In the present study, we investigated the protective effects of royal jelly on the parameters of oxidative stress and histopathological damage to lung tissue due to arsenic trioxide toxicity. Forty male Wistar albino rats received arsenic trioxide and royal jelly orally for 30 days and were randomly divided into eight groups of five; The first group received normal saline at a dose of 1 mg/kg, the second group received royal jelly at a dose of 150 mg/kg, the third group received arsenic trioxide at a dose of 1 mg/kg, the fourth group received arsenic trioxide (1 mg/kg) with Royal jelly at a dose of 150 mg/kg, the fifth group received arsenic trioxide (1 mg/kg) with royal jelly at a dose of 100 mg/kg, the sixth group received arsenic trioxide (1 mg/kg) with royal jelly at a dose of 50 mg/kg, the seventh group received arsenic trioxide (1 mg/kg) with vitamin E at a dose of 100 mg/kg, and the eighth group received arsenic trioxide (1 mg/kg) with vitamin E and royal jelly (both) at a dose of mg/kg 100. Oxidative stress parameters including malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were evaluated. Damage to lung tissue was also assessed by hematoxylin-eosin (H&E) tissue staining. The results of the present study revealed that arsenic trioxide increased the level of MDA and decreased the levels of GPx, SOD and CAT. Royal jelly treatment decreased MDA levels and increased GPx, SOD and CAT concentrations in lung tissue. The severity of lung tissue damage was also reduced. In general, Royal Jelly reduced oxidative stress and lung tissue damage. [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]

Background: To investigate the effects of arsenic trioxide (ATO) on human colorectal cancer cells (HCT116) growth and the role of transient receptor potential melastatin 4 (TRPM4) channel in this process. Methods: The viability of HCT116 cells was assessed using the CCK-8 assay. Western blot analysis was employed to examine the protein expression of TRPM4. The apoptosis of HCT116 cells was determined using TUNEL and Flow cytometry. Cell migration was assessed through the cell scratch recovery assay and Transwell cell migration assay. Additionally, Transwell cell invasion assay was performed to determine the invasion ability of HCT116 cells. Results: ATO suppressed the viability of HCT116 cells in a dose-dependent manner, accompanied by a decline in cell migration and invasion, and an increase in apoptosis. 9-phenanthroline (9-Ph), a specific inhibitor of TRPM4, abrogated the ATO-induced upregulation of TRPM4 expression. Additionally, blocking TRPM4 reversed the effects of ATO on HCT116 cells proliferation, including restoration of cell viability, migration and invasion, as well as the inhibition of apoptosis. Conclusion: ATO inhibits CRC cell growth by inducing TRPM4 expression, our findings indicate that ATO is a promising therapeutic strategy and TRPM4 may be a novel target for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity. Synopsis: The promyelocytic leukemia protein (PML) is essential to sustain clear cell renal cell carcinoma (ccRCC) expansion via p53 inhibition and the PML-targeting drug arsenic trioxide exerts cancer inhibitory functions in ccRCC. PML is overexpressed and efficiently partitioned into PML-NBs in ccRCC. PML inhibition blocks ccRCC expansion in vitro and in vivo. Targeting ccRCC non-oncogenic addiction to PML via gene silencing or arsenic trioxide unleashes p53-dependent growth arrest and apoptosis. Arsenic trioxide is effective at inhibiting expansion of ccRCC cells with wild type and mutant p53. The promyelocytic leukemia protein (PML) is essential to sustain clear cell renal cell carcinoma (ccRCC) expansion via p53 inhibition and the PML-targeting drug arsenic trioxide exerts cancer inhibitory functions in ccRCC. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).

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 Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.

Background. Differentiation syndrome (DS) is a potentially fatal complication of therapy for acute promyelocytic leukemia (APL) with an incidence of up to 48 %. To date, no reliable DS risk factors have been found, with the exception of leukocytosis at the APL onset.Aim. To determine the risk factors associated with DS in patients with APL during induction therapy with arsenic trioxide (ATO) and tretinoin (ATRA).Materials and methods. The study included 39 patients with APL, 29 (74.4 %) of them were classified as low-risk according to ELN (European Leukemia Net), 10 (25.6 %) were classified as high-risk. At the disease onset, cytological and molecular (chimeric transcript PML::RARα, FLT3-ITD mutation) bone marrow studies were performed, the expression of 28 differentiation antigens by blood and bone marrow blast cells was determined (markers of early precursors, myeloid and lymphoid differentiation, cell adhesion molecules, chemokine receptors, integrins, selectin), body mass index (BMI) and the leukocytes number dynamics during induction course were assessed. All patients received ATRA and ATO therapy. Patients from the high-risk group at the onset received 1–3 injections of idarubicin (12 mg/m2) and dexamethasone (8–10 mg/m2 2 times a day) to prevent DS until leukocytosis reduced. In cases of DS, dexamethasone was prescribed at a dose of 10 mg/m2 2 times a day; in cases of severe DS, the induction course was interrupted.Results. Of the 39 patients, 12 (30.8 %) were diagnosed with DS: 20 % of high-risk patients (2/10) and 34.5 % of low-risk patients (10/29). There was no statistically significant association of leukocytosis more than 10 × 109 /L at onset, microgranular morphology of blast cells, bcr3-variant PML::RARα, FLT3-ITD mutation with DS. In multivariate analysis, the probability of DS was associated with BMI ≥30 kg/m2 and mean fluorescence intensity of CD38 antigen by blast cells, regardless of risk group. based on the results of the ROC-analysis, the threshold value of mean CD38 fluorescence intensity was set at 25,000 cu, if exceeded, DS is highly likely to develop.Conclusion. the high incidence of DS among low-risk patients is probably due to the lack of prophylactic glucocorticosteroids administration for the development of leukocytosis during ATRA and ATO therapy. BMI ≥30 kg/m2 and mean CD38 fluorescence intensity more than 25,000 cu were identified as statistically significant DS risk factors.

BACKGROUND: Arsenic trioxide (ATO) regimen is now the standard of care for acute promyelocytic leukemia (APL). The complete remission and possible cure are reported to be 50%–80% of APL patients. Prolongation of the QT interval has been consistently observed in clinical trials with ATO, which is known to have a direct effect on cardiac repolarization with the recommendations for management include electrocardiogram (ECG) monitoring, discontinuation of drugs that prolong the QT interval, and careful repletion of serum potassium and magnesium. OBJECTIVES: To study the incidence and clinical consequences of QT prolongation in a sample of Iraqi APL patients treated with ATO. PATIENTS AND METHODS: A prospective, cross-sectional study was conducted on 24 adult patients with newly diagnosed APL at Baghdad Teaching Hospital. ECG was performed at baseline and twice weekly till the end of induction treatment course. Corrected QT interval was calculated based on Bazett and Fridericia formulas (QTc interval of more than 500 ms is considered dangerous): Serum potassium, calcium, and magnesium levels were also measured simultaneously. RESULTS: The mean QT at baseline was 424 ± 18 ms and 402 ± 15 ms by Bazett and Fridericia, respectively, and at the end of induction, the mean QT was 436 ± 20 ms and 418 ± 20 ms by Bazett and Fridericia, respectively. The rate of developing prolonged QT was 62.5% by Bazet, in which 15 patients developed prolonged QT (at any time point). The comparison between prolonged and dangerous QT groups by Bazet showed significant difference, in which QT-related complications were associated with dangerous QT (>500 ms) prolongation significantly, while Fridrica method did not label these patients as having dangerous QT prolongation. The change in QT started as early as 1 week after treatment, the comparison between baseline QT and QT at week 1 showed that there was significant increase in QT. The electrolytes analysis and comparison with baseline results for potassium, magnesium, and calcium showed that there were no significant differences over time for tested electrolytes. CONCLUSION: Bazett formula is useful to monitor Iraqi patients with APL who are treated with ATO for the detection of dangerous prolongation of QT.