Arsenic Trioxide Research Articles (Page 1)

Realgar-Indigo naturalis formula (RIF) is an oral form of arsenic that is effective against acute promyelocytic leukemia (APL). This multicenter, randomized, controlled trial compared the efficacy of all-trans retinoic acid (ATRA) plus RIF with ATRA plus arsenic trioxide (ATO) in a simplified regimen for non-high-risk APL. Following induction therapy with ATRA and ATO, participants were randomly assigned to receive either ATRA plus ATO or ATRA plus RIF both in a 2-week on 2-week off schedule for consolidation therapy. Once achieving molecular complete remission, the regimen was administered for a total of six cycles. All of 108 eligible patients achieved hematological complete remission after induction therapy. The median follow-up time was 29 months. The primary endpoint of 2-year disease-free survival was 97% in the ATRA-RIF arm and 98% in the ATRA-ATO arm, respectively (the ATRA-RIF arm was found to be non-inferior to the ATRA-ATO arm, [P<0.01], with a percentage difference of -1% [95% confidence interval: -4.8 to 6.9]). No deaths have been observed. Most adverse events were moderate. This study confirms the non-inferiority of RIF to ATO for non-high-risk APL, while also offering a more favorable regimen schedule for post-remission therapy (clinicaltrials gov. identifier: NCT02899169).

Differentiation syndrome (DS) is a serious complication with an unclear pathogenesis that arises following all-trans retinoic acid (ATRA) or arsenic trioxide induction therapy in acute promyelocytic leukemia (APL). DS symptoms include pyrexia, respiratory compromise, increased body mass, fluid accumulation, pulmonary infiltrates, hypotension, tachycardia, edema, and sepsis. It can also affect the kidneys and the central nervous system. The standard treatment to counteract DS involves the temporary cessation of ATRA or arsenic trioxide treatment and the administration of high-dose steroids to mitigate the inflammatory response. If left untreated, DS can be fatal. Further research has revealed that the inability to promptly recognize intracranial hemorrhage (ICH) in patients with APL may result in lethal consequences, with the cytokine storm identified as the principal factor in this scenario as well. ATRA therapy is known to induce transglutaminase 2 (TG2), which functions as a catalyst for DS development. In this study, we used NB4 cell lines and cells from a human patient with APL to investigate the ex vivo effects of ATRA and 25(OH)D3 cotreatment on NF-κB-regulated luciferase reporter gene activity. ATRA alone substantially enhanced cellular NF-κB luciferase reporter gene activity, whereas 25(OH)D3 dose-dependently reduced this activity. During ATRA-initiated cell maturation, 25(OH)D3, known as calcidiol, suppressed the mRNA expression of NF-κB (p65/p50) and Rel family members, as well as the expression of genes associated with increased NF-κB activity. 25(OH)D3 also inhibited the ATRA-induced production of cytokines (e.g., IL-8), including IL-1β, TNF-α, and MCP-1, associated with the “cytokine storm.” Combined treatment with ATRA plus 25(OH)D3 reduced cellular phospho-p65 and transglutaminase 2 (TG2) levels and increased the level of inhibitor of Rel (IκB), thereby attenuating the cytokine storm. These findings provide a molecular interpretation for clinical DS and IHC observations and may support future exploration of ATRA plus 25(OH)D3 cotreatment as a therapy for APL.

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often associated with severe long-term neurocognitive and systemic toxicities. Effective drug delivery across the blood-brain barrier remains a major hurdle, limiting the clinical efficacy of targeted therapies. Drug repurposing offers a promising strategy to accelerate treatment availability by utilizing US Food and Drug Administration-approved agents, including niclosamide, itraconazole, and arsenic trioxide, to target critical oncogenic pathways and overcome therapeutic resistance. However, challenges such as limited blood-brain barrier penetration and the lack of pediatric-specific pharmacokinetic data persist. Future research should focus on integrating comprehensive molecular profiling to guide personalized therapy selection, optimizing drug-delivery systems, and exploring rational drug combinations. Emerging technologies, including nanotechnology-based delivery systems, CRISPR-mediated gene editing, and chimeric antigen receptor-T cell therapies, hold significant potential for transforming medulloblastoma treatment paradigms but require further refinement to address toxicity, off-target effects, and biomarker development. Advancing innovative, less toxic therapeutic strategies through the integration of molecular diagnostics and precision therapies is essential to improving survival outcomes and quality of life for children with medulloblastomas.

This study aimed to develop a co-administration strategy of arsenic trioxide (ATO) with its metabolite dimethylarsinic acid (DMAV) to alleviate ATO metabolism and improve the effective concentration of arsenite (iAsIII, the primary active forms of ATO in physiological environments) and ultimately reduce the clinical dose and hepatotoxicity of ATO. We successfully established an APL model by transplanting NB4 cells into BALB/c nude mice. In vivo validation of antileukemic effects and hepatotoxicity employed high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry, alanine aminotransferase, aspartate transaminase and H&E staining. CCK8, flow cytometry, intracellular Ca2+ imaging and western blot analysis were employed to explore the underlying mechanism of ATO+DMAV induced hepatotoxicity. ATO+DMAV groups significant enhanced antileukemic effects and iAsIII concentration in a leukemia xenotransplantation model, while without incurring additional hepatotoxicity compared to ATO monotherapy. Meanwhile, CCK8 results of ATO+DMAV and its drug-containing serum further elucidated the overall effects of ATO+DMAsV in alleviating ATO metabolism to exert antileukemic and hepatotoxicity efficacy. Finally, results revealed that ATO+DMAV induced hepatotoxicity through the "calcium dyshomeostasis-ER stress" axis-mediated cells apoptotic pathway. The combination strategy of ATO and metabolite can provide valuable references for future reducing clinical dosage of ATO and enhancing medication safety.

To identify early risk factors for disseminated intravascular coagulation (DIC), particularly severe DIC (grade 4-5), in paediatric acute promyelocytic leukaemia (APL). One hundred and eighty-six paediatric APL patients enrolled in the Chinese Children Leukemia Group (CCLG)-APL 2016 study across 38 hospitals nationwide were grouped based on the occurrence and severity of DIC during induction therapy. DIC occurred in 52.2% of patients during induction therapy, with 7.5% developing grade 4-5 DIC. Significant differences were observed between the DIC and non-DIC groups in the proportion of patients with initial white blood cells (WBC) ≥5 × 109/L, initial platelets (PLT) ≤26 × 109/L and arsenic trioxide (ATO) use (p < 0.05). Multivariate analysis identified initial PLT ≤26 × 109/L (p = 0.002, odds ratio [OR] = 2.679, 95% confidence interval [CI]: 1.438-4.992) as an independent risk factor, while induction therapy using realgar-indigo naturalis formula (RIF) was a protective factor (p = 0.030, OR = 0.465, 95% CI: 0.232-0.929). Further analysis revealed that Fms-like tyrosine kinase 3 (FLT3) mutation (p = 0.023, OR = 11.742, 95% CI: 1.405-98.149), initial PLT ≤26 × 109/L (p = 0.017, OR = 13.784, 95% CI: 1.598-118.905) and initial bone marrow blasts ≥90% (p = 0.030, OR = 5.289, 95% CI: 1.178-23.744) were significant risk factors for grade 4-5 DIC. Initial WBC ≥5 × 109/L and PLT ≤26 × 109/L are associated with an increased risk of DIC, with PLT ≤26 × 109/L as an independent risk factor. Compared with ATO, RIF is a protective factor during induction therapy. Additionally, FLT3 mutation, PLT ≤26 × 109/L and initial bone marrow blasts ≥90% are independent risk factors for grade 4-5 DIC.

Acute promyelocytic leukemia (APL) in children accounts for 5–10% of AML cases and is associated with the t(15;17) translocation and PML::RARA fusion gene.Although considered cytogenetically favorable, it carries a high rate of early mortality due to severe hemorrhagic events.These hemorrhages, particularly intracranial or pulmonary, are the leading cause of early death.Diagnosis relies on cytomorphology and confirmation of PML-RARA, found in 95% of cases.Bone marrow typically shows hypogranular and agranular blasts with irregular, monocytoid nuclei and occasional Auer rods.Standard treatment combines all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).This regimen achieves over 85% overall survival at 5 years with relapse rates below 5%.However, early death rates from coagulopathy have not significantly improved.Early identification and treatment are crucial to reduce life-threatening complications.APL remains a hematologic emergency requiring immediate intervention.

This report presents a rare case of bilateral exudative retinal detachment (ERD) as an early manifestation of differentiation syndrome (DS) in a woman in her early 30s undergoing induction therapy for acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide. Nineteen days into therapy, she presented with bilateral blurring of vision. Ocular examination revealed bilateral multiple small closely spaced ERDs. Fundus autofluorescence and optical coherence tomography revealed focal retinal pigment epithelial disruptions. No systemic features of DS were recognised by the treating oncologist. ATRA was withheld, and systemic and topical corticosteroids were initiated, leading to complete resolution of subretinal fluid and full recovery of vision. ATRA was successfully reintroduced without recurrence of symptoms. This case highlights the potential for ocular findings to precede systemic signs of DS and underscores the importance of early ophthalmic evaluation and timely intervention to preserve vision and ensure uninterrupted leukemia treatment.

This article evaluates and summarizes mechanisms, clinical presentations, comparative assessments, and treatments of cardiotoxicity associated with select classes of anticancer agents, including (1) anthracyclines; (2) arsenic trioxide; (3) HER2-directed therapies; (4) fluoropyrimidines; (5) immunomodulatory drugs (IMiDs); (6) oral kinase inhibitors targeting BTK, the fusion kinase encoded by BCR-ABL1, and the VEGF signaling pathway; and (7) immune checkpoint inhibitors (ICIs). Specific examples of oral kinase inhibitors are also discussed. Together, the evidence highlights and illustrates important breakthroughs and/or opportunities for pharmacists to advance cardio-oncology pharmacy practice. Cardiotoxicity associated with anticancer agents is a common complication in many patients with cancer. The improvement in the life expectancy of patients with cancer has led to a heightened awareness and demand for mitigation strategies in patients at risk of developing long-term anticancer treatment-related adverse effects. Advances in understanding of the pathogenesis associated with drug-induced cardiotoxicity have led to improved surveillance, risk de-escalation for specific therapies (eg, arsenic trioxide), optimization of cardioprotection and harmonization strategies (eg, for anthracyclines), and specific treatment plan modifications or supportive care (eg, for oral kinase inhibitors, fluoropyrimidines, ICIs, and IMiDs), among other approaches. Non-treatment-related factors such as aging, genetic predisposition, and cardiovascular disease contribute to cardiotoxicities; however, some of the mechanisms of drug-induced cardiotoxicity remain poorly characterized. Strategies to mitigate the cardiotoxicity of anticancer therapies and identify patients who may require time-sensitive interventions or long-term follow-up represent promising opportunities to improve the quality and safety of care in the emerging field of cardio-oncology pharmacy.

Chemical co-exposures are important contributors to adverse biological responses yet remain poorly understood, especially in the context of prenatal development. Sonic hedgehog (Shh) signaling is an essential developmental pathway that is sensitive to small molecule disruption and directly linked to common and etiologically complex human birth defects. Numerous mechanistically diverse small molecule Shh pathway antagonists have been identified, but their interactions in pathway disruption have received minimal attention. We established a tractable co-culture model in which autonomous SHH ligand production initiates this complex inter- and intracellular signal transduction cascade and culminates in activation of a GLI-responsive luminescent reporter. Compounds reported to target SHH ligand processing (RU-SKI 43, AY 9944, U18666A), SMO-mediated signal transduction (cyclopamine, vismodegib, piperonyl butoxide, cannabidiol), and GLI transcription factors (GANT 61, arsenic trioxide) reduced Shh pathway-driven reporter activity with AC50 values in the low micromolar range or below. We then evaluated chemical interactions among Shh pathway inhibitors using isobolographic analysis. Co-exposure assays revealed additive interactions from combined SMO and GLI inhibition, while disruption of SMO and cholesterol dynamics synergistically decreased Shh pathway activity. Unexpectedly, piperonyl butoxide synergized with other SMO inhibitors, and further characterization of piperonyl butoxide's impacts on Shh signaling supported an additional mechanism of inhibition independent of SMO. In zebrafish embryos, combined exposure to piperonyl butoxide and cyclopamine also produced a synergistic increase in craniofacial dysmorphogenesis. These findings demonstrate the importance of tractable models that recapitulate complex signal transduction pathways to empirically test for additive and synergistic chemical interactions in risk assessment.

Arsenic trioxide is used in the treatment of acute promyelocytic myeloid leukemia. QT prolongation is a potential risk with arsenic therapy and formulae which correct the QT for heart rate (QTc) may over-estimate the risk of torsades de pointes. We aimed to apply the QT nomogram, a risk assessment tool which predicts arrhythmogenic risk in drug-induced QT prolongation, to QT monitoring during arsenic therapy. This retrospective series of 29 patients treated with arsenic for acute promyelocytic myeloid leukemia found the QTc was elevated in 17/284 (6%) ECGs, of which only 4/284 (1%) were above the QT prolongation threshold, when plotted on the QT nomogram. Across the study period, there was a total of five patients with QTc ≥500 ms. Treatment was withheld in 14 instances for QTc prolongation, of which only two plotted above the QT prolongation threshold on the QT nomogram. There were no instances of arrhythmia.

Arsenic trioxide enhances the inhibitory effect of lenvatinib on hepatocellular carcinoma through HMOX1-mediated ferroptosis.

Development of arsenic nanoparticles: a novel topical therapy for psoriasis enhancing skin deposition and preventing relapse for long-term efficacy in imiquimod-induced rat model.

Arsenic compounds in cancer therapy: mechanistic insights and antitumor activity.

Glutathione S-transferase Theta 2 causes drug resistance by inhibiting arsenic trioxide-induced ferroptosis in pancreatic ductal adenocarcinoma.

Overcoming resistance in RET-altered cancers through rational inhibitor design and combination therapies.

This study investigated the effects of indoxyl sulfate (IS), an endogenous metabolite and uremic toxin, on arsenic trioxide pharmacokinetics in acute promyelocytic leukemia patients with varying renal function. Plasma IS levels demonstrated a significant positive correlation with monomethylarsonic acid and dimethylarsinic acid concentrations in patients (P < .0001). In adenine-induced renally impaired rats, IS similarly correlated with elevated plasma inorganic arsenic (iAs), monomethylarsonic acid, and dimethylarsinic acid levels. Protein expression analysis indicated a downregulation of renal aquaporin (AQP) 7 and AQP3. In vitro studies confirmed that IS selectively inhibits AQP7 expression (62.1% reduction at 100 μM) through aryl hydrocarbon receptor activation in human embryonic kidney 293T cells, while AQP3 remained unaffected. Collectively, IS increases plasma arsenic concentration in renally impaired acute promyelocytic leukemia patients via aryl hydrocarbon receptor-mediated suppression of renal AQP7. SIGNIFICANCE STATEMENT: This study reveals that indoxyl sulfate inhibits renal aquaporin 7 via aryl hydrocarbon receptor activation, increasing plasma arsenic in arsenic trioxide-treated acute promyelocytic leukemia patients with renal impairment. As the first demonstration of this mechanism, to our knowledge, it provides crucial insights for optimizing therapy and reducing toxicity risks.

Reprogramming SUMO-primed ubiquitylation: opportunities in oncology and neurology.

Abstract The Giant Mine (1948–1999) generated 16 Mt of Au‐bearing mill tailings (2800 mg kg−1) originating from a mixture of flotation tailings (84.8 wt%), calcine residues (14.4 wt.%), and arsenic trioxide roaster waste (0.8 wt.%). A water treatment system for high As mine dewatering effluent has operated since the end of mine operations, with the intermediate storage area being the Northwest Tailings Containment Area (NW‐TCA). The tailings porewater contains elevated concentrations of dissolved As, Sb, Zn, and other metals. A multi‐year water balance supported by an examination of unsaturated and saturated flow conditions and based on isotope and geochemical analysis was conducted to understand the NW‐TCA hydrological system. Hydraulic gradients indicate persistent downward flow in the south end of NW‐TCA. Water balance calculations indicate an average of 384,000 m3 y−1 of water from the NW‐TCA entered the groundwater system during the study period (2017–2022). Stable water isotope and water chemistry measurements indicate porewater in areas of high‐water table is influenced by mine dewatering effluent. Isotope mass balance indicates 60% of the mine dewatering effluent, which contains high concentrations of As, is sourced from water cycled through the NW‐TCA. The impact of the mine dewatering effluent is minimal in areas with a deep vadose zone, containing lower concentrations of As. Hydrological simulations indicate groundwater flow rates into the deep groundwater flow system from the NW‐TCA would be modest in the absence of the mine dewater pond because the system is near net evaporative in the absence of mine dewatering effluent.

Over 90% of patients with acute promyelocytic leukemia (APL) harbor the typical translocation characterized by the dual fusion of PML::RARA and RARA::PML transcripts. Here, we report a case with a single fusion of PML::RARA formed on der(17), without the RARA::PML fusion, and the patient responded well to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. To our knowledge, this represents only the fourth reported case of this type. Our findings indicate that the PML::RARA fusion is the primary driver of APL leukemogenesis and the main therapeutic target for ATRA and ATO, suggesting that the RARA::PML transcript may not be essential for APL development.

Patients with acute promyelocytic leukemia (APL) who present with leukocytosis are considered high-risk due to lower relapse-free survival when treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. The discovery and incorporation of arsenic trioxide (ATO) in therapeutic regimens for high-risk patients have led to improved survival, but there is no consensus on the optimal treatment approach. This review addresses reduction in early death and explores questions of regimen selection, including the choice of induction, consolidation, and maintenance, as well as the use of prophylactic adjunctive therapies, while examining clinical trial and real-world evidence. ATRA-ATO combined with idarubicin (IDA) or gemtuzumab ozogamicin are highly effective compared to ATRA-IDA-based chemotherapy in clinical trials and real-world studies. Improved survival and early death reduction can be seen in the randomized controlled APOLLO study and in data from the recently published HARMONY and HERO analyses. ATRA-ATO-based combinations, including ATRA-ATO-IDA and ATRA-ATO-GO, are current standards of care in high-risk APL. Further studies should seek to clarify the choice between these and other regimens and to more clearly show the benefit of maintenance therapy and of additional therapies such as for differentiation syndrome and CNS prophylaxis with these highly effective induction/consolidation regimens.