Arsenic trioxide (ATO) shows limited efficacy against solid tumours, largely because it induces protective autophagy that attenuates its pro-apoptotic activity. Our previous studies established that nanodiamonds (NDs) function as nanoparticle autophagy inhibitors (NAPIs) when delivered systemically, markedly enhancing ATO efficacy in orthotopic liver tumour models by blocking NUPR1-mediated autolysosomal clearance. However, systemic administration remains inefficient in modulating the local autophagic microenvironment within tumours. Here we developed an interventional strategy based on intratumoral injection to assess the feasibility and biosafety of locally blocking autophagic flux while substantially reducing the required ATO dosage, thereby maximising the synergistic anti-tumour effects of NDs and ATO. In HepG2 hepatocellular carcinoma cells, NDs markedly blocked the late stage of autophagic flux, thereby significantly amplifying ATO-induced apoptosis. In a subcutaneous xenograft liver cancer mouse model, intratumoral co-administration of NDs with low-dose ATO achieved ~91% tumour inhibition and effectively eliminated the systemic toxicity associated with high-dose ATO monotherapy. Notably, the synergistic antitumor effect was independent of increased intratumoral ATO accumulation and was driven instead by targeted modulation of the autophagic pathway. Collectively, this study demonstrates a mechanism of localised, nanomaterial-mediated autophagy regulation and offers an efficient, safe strategy for interventional therapy of advanced solid tumours.

Diarylhaloarsines (Ar2AsX; X = Cl, Br, I) are important intermediates in the synthesis of a wide range of organoarsenic compounds. However, previous methods have long been constrained by limited substrate scope and complex procedures. Herein, we report a practical and general synthetic approach for Ar2AsX from arsenic trioxide (As2O3), an abundant and inexpensive arsenic source. The reaction of aryl Grignard reagents with As2O3 affords diarylarsinous acids or diarsine oxides, depending on the steric demand of the aryl substituents. Subsequent halogenation with trimethylsilyl halides proceeds almost quantitatively under mild conditions to produce the corresponding Ar2AsX. The resulting Ar2AsX exhibit broad reactivity and can be used in the synthesis of BINAP-type arsenic ligands, reductive formation of diarsines, and nickel-catalyzed coupling reactions for direct aryl group incorporation. This method provides a convenient and scalable route to structurally diverse Ar2AsX and expands the applicability of these materials as versatile precursors for organoarsenic synthesis.

[This retracts the article DOI: 10.3892/etm.2017.4392.].

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia characterized by the presence of the promyelocytic leukemia-retinoic acid receptor alpha (PML::RARA) fusion gene. The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved outcomes in patients with APL. Isotretinoin (13-cis retinoic acid), a stereoisomer of ATRA commonly used for acne vulgaris, shares a similar mechanism of action and has demonstrated differentiation-inducing activity in vitro and in limited clinical reports. We present the case of a 38-year-old uninsured male with low-risk APL, defined by a presenting white blood cell count of ≤10,000/µL per the Sanz risk stratification system, who achieved hematologic complete remission following standard induction therapy with ATRA plus ATO but was transitioned to isotretinoin during consolidation because he was unable to obtain ATRA due to financial constraints. The patient achieved molecular complete remission within two months of initiating isotretinoin-based consolidation therapy and continues to have negative PML::RARA reverse transcriptase polymerase chain reaction (RT-PCR) results, with sustained remission at 18 months of follow-up with ongoing molecular monitoring every three months. Although the concurrent use of ATO and prior ATRA-based induction are important confounders, this case highlights the potential role of isotretinoin as a cost-effective alternative retinoid for consolidation therapy in APL when ATRA is inaccessible, although ATRA remains the recommended standard treatment.

All-trans retinoic acid (ATRA) is essential in treating acute promyelocytic leukemia (APL), but has been linked to adverse events such as differentiation syndrome and intracranial hypertension. Hearing impairment associated with intracranial hypertension is rare but clinically relevant. We report the case of a 6-year-old girl with APL who developed transient low-frequency sensorineural hearing impairment during ATRA/arsenic trioxide therapy. No headache or neurologic signs suggesting intracranial hypertension were observed, and both hearing symptoms and low-frequency audiometric changes resolved spontaneously without corticosteroids or treatment modification. This case suggests that ATRA-related hearing impairment may occur even without intracranial hypertension, and careful monitoring may enable continuation of therapy.

As excretion organs, the kidneys and liver are exposed to high concentrations of potentially toxic substances. While animal models remain the gold standard for organ-specific toxicity testing, meaningful alternative ex vivo approaches are essential in order to align with the 3R principles (refinement, reduction, replacement). Precision-cut tissue slices (PCTS) retain native tissue architecture, cellular heterogeneity, the interplay of different cell types, and metabolic capacity, offering a promising link between in vitro and in vivo models. Here, we aimed to establish an optimized protocol for preparation and cultivation of precision-cut kidney and liver slices (PCKS and PCLS) from mice for use in substance-oriented toxicity testing. Key parameters - including slice thickness, media composition and oxygenation, glucose levels, and incubation time - were refined to preserve tissue viability and metabolic function. Five known prototypical toxins - acetaminophen, cyclosporin A, cisplatin, arsenic trioxide, and aristolochic acid I - were tested. While PCKS showed comparable sensitivity to established kidney cell lines, PCLS achieved IC50 values closely matching in vivo toxicity data. High reproducibility across different experimenters was achieved, highlighting the robustness of the model. In conclusion, the optimization of this ex vivo system makes this valuable, reproducible, and ethically approved platform for testing nephrotoxicity and hepatotoxicity accessible to more laboratories, for example for dose finding or compound prioritisation, thereby supporting 3R-conform preclinical drug screening as well as hazard identification and potentially reducing reliance on animal experiments.

Arsenic trioxide (ATO) is both a life-saving therapy for acute promyelocytic leukemia and a systemic toxicant whose hepatic effects remain incompletely defined. This study examined how a single clinically relevant ATO dose (8 mg/kg, i.p.) acutely remodels hepatic xenobiotic-metabolizing enzymes, arsenic transporters, and pro-inflammatory mediators in male and female C57Bl/6 mice. Mice were treated with ATO or saline and livers were collected at 6 and 24 h for integrated mRNA and protein profiling of major Cytochrome P450 (CYP) families, aquaglyceroporins (Aqp3/7/9), ATP-binding cassette (Abcb1, Abcc1-6) transporters, and cytokines (Tnf-α, Il-1β, Il-6). ATO induced highly sex-, time-, and isoform-specific reprogramming. Females exhibited a wider and earlier decline in several female-predominant CYP2, CYP3, and CYP4 isoforms, including a more pronounced reduction in hepatic CYP3A, CYP4A, and CYP4F protein abundance. In contrast, males showed mainly transcriptional induction of specific genes (Cyp1a1, Cyp2a, Cyp3a13, and Cyp4a), accompanied by comparatively modest decreases in overall CYP protein levels. Aqp and Abc transporters were differentially modulated, with males displaying early, relatively monotonic upregulation of Abcb1/Abcc efflux systems, while females exhibited higher basal Abc expression but more complex, biphasic regulation of both influx (Aqp7/9) and efflux pathways. These transcriptional changes paralleled a transient inflammatory response, including early Tnf-α induction and female-specific Il-6 elevation. Collectively, these findings highlight sex-dependent modulation of hepatic ATO handling and drug metabolizing capacity, with important implications for risk assessment and individualized ATO containing regimens.

Astragaloside IV (AS-IV), a compound extracted from Radix Astragali, has been shown to have beneficial effects on cardiovascular disease. However, the role of AS-IV in cardiac toxicity caused by arsenic trioxide (ATO) is unknown. The current experiment aimed to explore the protective effects and molecular mechanisms of AS-IV against ATO-induced cardiac toxicity. Rats were administered AS-IV intragastrically (40, 80 mg/kg) concurrently with ATO (5 mg/kg) infused intraperitoneally over 7 days. Electrocardiography, cardiac weight index, and heart morphology changes were observed. Histopathological and cardiac function indices showed that ATO caused severe cardiac damage. It increased MDA levels while reducing SOD and GSH-Px, indicating oxidative damage. Inflammatory markers, including IL-1β and TNF-α, were markedly upregulated. Apoptosis, marked by upregulated Bax and decreased Bcl-2, was enhanced. However, AS-IV treatment significantly suppressed these changes. Moreover, AS-IV treatment resulted in a significant decrease in the protein expression levels of p38MAPK and NF-κB. The findings revealed that AS-IV may inhibit the inflammation, apoptosis, and oxidative stress to exert protective effects on ATO-induced cardiac toxicity in rats through inhibiting the p38MAPK/NF-κB signaling pathway.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia defined by the t(15;17)(q24;q21)-derived PML::RARA fusion. However, a small subset of patients harbor cryptic or atypical RARA rearrangements that escape detection by routine real-time quantitative RT-PCR (qRT-PCR). We report a 34-year-old man presenting typical APL in whom repeated testing for the canonical long, short, and variant PML::RARA transcripts yielded negative results. RNA sequencing subsequently identified a previously unreported in-frame fusion linking PML exon 8 to a 58-base pair-deleted RARA exon 3. The resulting chimeric transcript retained the PML coiled-coil domain as well as the DNA- and ligand-binding domains of RARA, suggesting preserved sensitivity to retinoid-based therapy. Consistent with this prediction, induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resulted in achievement of complete molecular remission. Molecular relapse occurred three months after premature discontinuation of maintenance therapy, underscoring the leukemogenic potential of this novel fusion. This observation expands the molecular spectrum of APL and highlights the potential value of incorporating RNA sequencing into the diagnostic workflow for morphologically suspected but PCR-negative APL.

Acute promyelocytic leukemia (APML) is characterized by promyelocytic leukemia retinoic acid receptor alpha (PML-RARA) fusion gene resulting from at (15;17) translocation. The purpose of this study was to evaluate the clinical outcomes of patients with APML treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), as well as to assess the diagnostic utility of flow cytometry (FCM) in this setting.This retrospective study was conducted from April 2021 to March 2024. Patients of either sex, aged 10 to 67 years, with APML were included in study. Patient history, symptom progression and lab parameters such as hemoglobin (Hb), total leucocytes count (TLC), and platelets count were extracted from medical records. A total of 45 patients with median age 33 years, with majority of female (55.6%) were included in study. The PML-RARA isoforms were detected in 97.8% patients, positive trait for bcr type 1 observed in 47.7% patients. Majority of patients (57.8%) were low risk type of APML. Most of patients show positive immunophenotype for CD117 (100%), CD33 (100%), MPO (94.7%), CD13 (97.7%) and CD64 (89.5%). Post treatment, complete remission was observed in 90% patients. The Hb levels significantly increased from baseline to last follow-up (7.7g/dL vs. 13.6 g/dL; P < .0001). Similarly, platelet count significantly increased from baseline to last follow-up (0.3 × 109/L vs. 2.6 × 109/L; P < 0.001). While, TLC significantly decreased from baseline in high risk cases to last follow-up (24 × 109/L vs. 9 × 109/L; P = 0.016). Patients with APML can be successfully treated with a combination of ATO and ATRA.

Dysregulation of intracellular Ca2+ signaling is a critical determinant of cell fate; however the contribution of non-canonical Ca2+ reservoirs to cancer-selective apoptosis remains incompletely understood. In this study, realgar transforming solution (RTS), a microbially processed arsenical, was employed as a biologically informative perturbation to investigate the potential link between lysosomal pH dysregulation and a Ca2+-associated mitochondrial apoptotic program in triple-negative breast cancer (TNBC) cells. RTS displayed selective inhibitory activity compared with inorganic arsenic trioxide (ATO) and paclitaxel, leading to reduced viability of TNBC cells (MDA-MB-231, BT-549, and MDA-MB-468) while showing minimal impact on non-malignant MCF-10 A cells. RTS-induced cell death was linked to a Ca2+-mediated mitochondrial program-marked by cytochrome c release and caspase-9 activation-while showing limited correlation with reactive oxygen species (ROS) accumulation or p53 signaling. Mechanistically, RTS triggered sustained cytosolic and mitochondrial Ca2+ overload derived primarily from lysosomal mobilization rather than extracellular influx or endoplasmic reticulum depletion. Time-course profiling observed lysosomal acidic intensification as an early event, preceding TRPML1-mediated Ca2+ efflux and subsequent lysosomal membrane permeabilization (LMP). Consistently, pharmacological neutralization of the acidic shift (BafA1) or TRPML1 inhibition (ML-SI1) significantly attenuated the cytosolic Ca2+ elevation observed at the measured intervals. Collectively, these in vitro findings highlight a potential"lysosome-mitochondria" signaling axis in which early pH perturbation may represent a vulnerability in TNBC. While the multicomponent nature of RTS requires further characterization, this study provides preliminary insights into targeting organelle-specific Ca2+ hubs as a possible complementary strategy for refractory solid tumors.

Statins and arsenic trioxide (ATO) are known for their significant anti-neoplastic properties; however, limited research has investigated their potential synergistic effects. This study explores the individual and combined impact of ATO and atorvastatin on programmed cell death and proliferation in acute lymphoblastic leukemia (ALL) cell model. The ALL cell line was exposed to different doses of atorvastatin and ATO, both individually and in combination, to evaluate their respective IC50 values and identify the most effective concentrations. The proportions of apoptotic cells were quantified using Annexin V/PI staining, while Ki-67 expression, a well-established marker of cell proliferation, was assessed through flow cytometry. The findings revealed that atorvastatin and ATO, at concentrations of 12.4 µM and 3.34 µM, respectively, significantly enhanced apoptosis in ALL cells. Moreover, the combination therapy resulted in a marked increase in anti-proliferative effects. These findings provide new insights into the potential use of ATO and atorvastatin as a combined therapeutic strategy, highlighting their promise as a novel approach in the treatment of ALL.