Combination Strategy of Arsenic Trioxide and its Metabolite For Leukemia Treatment and Modulation of Endoplasmic Reticulum-mediated Hepatotoxicity.

BACKGROUND/AIM: 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.

MATERIALS AND

METHODS

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.

RESULTS

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.

CONCLUSION

The combination strategy of ATO and metabolite can provide valuable references for future reducing clinical dosage of ATO and enhancing medication safety.