Enhancement of arsenic trioxide cytotoxicity by dietary isothiocyanates in human leukemic cells via a reactive oxygen species-dependent mechanism.
Although clearly effective in acute promyelocytic leukemia (APL), arsenic trioxide (ATO) demonstrates little clinical benefit as a single agent in the treatment of non-APL hematological malignancies. We screened a library of 2000 marketed drugs and naturally occurring compounds to identify agents that potentiate the cytotoxic effects of ATO in leukemic cells. Here, we report the identification of three isothiocyanates (sulforaphane, erysolin and erucin) found in cruciferous vegetables as enhancers of ATO cytotoxicity. Both erysolin and sulforaphane significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of leukemic cell lines; erucin activity was variable among cell types. Cellular exposure to sulforaphane in combination with ATO resulted in a dramatic increase in levels of reactive oxygen species (ROS) compared to treatment with either agent alone. Sulforaphane, alone or with ATO, decreased intracellular glutathione (GSH) content. Furthermore, addition of the free radical scavenger N-acetyl-l-cysteine (NAC) rescued cells from ATO/isothiocyanate-mediated cytotoxicity. Our data suggest that isothiocyanates enhance the cytotoxic effects of ATO through a ROS-dependent mechanism. Combinatorial treatment with isothiocyanates and ATO might provide a promising therapeutic approach for a variety of myeloid malignancies.
Doudican
Nicole A
NA
NYU School of Medicine, Departments of Dermatology and Cell Biology, New York, NY 10016, United States.
Bowling
Benjamin
B
Orlow
Seth J
SJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014675:Vegetables / Q000737:chemistry
D001152:Arsenicals; D017879:Isothiocyanates; D010087:Oxides; D017382:Reactive Oxygen Species; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D013861:Thiocyanates; C073538:erysolin; C073539:erucin; C016766:sulforaphane; D000077237:Arsenic Trioxide