The Mitochondrial Ca(2+) Overload via Voltage-Gated Ca(2+) Entry Contributes to an Anti-Melanoma Effect of Diallyl Trisulfide

Allium vegetables such as garlic (Allium sativum L.) are rich in organosulfur compounds that prevent human chronic diseases, including cancer. Of these, diallyl trisulfide (DATS) exhibits anticancer effects against a variety of tumors, including malignant melanoma. Although previous studies have shown that DATS increases intracellular calcium (Ca(2+)) in different cancer cell types, the role of Ca(2+) in the anticancer effect is obscure. In the present study, we investigated the Ca(2+) pathways involved in the anti-melanoma effect. We used melittin, the bee venom that can activate a store-operated Ca(2+) entry (SOCE) and apoptosis, as a reference. DATS increased apoptosis in human melanoma cell lines in a Ca(2+)-dependent manner. It also induced mitochondrial Ca(2+) (Ca(2+)(mit)) overload through intracellular and extracellular Ca(2+) fluxes independently of SOCE. Strikingly, acidification augmented Ca(2+)(mit) overload, and Ca(2+) channel blockers reduced the effect more significantly under acidic pH conditions. On the contrary, acidification mitigated SOCE and Ca(2+)(mit) overload caused by melittin. Finally, Ca(2+) channel blockers entirely inhibited the anti-melanoma effect of DATS. Our findings suggest that DATS explicitly evokes Ca(2+)(mit) overload via a non-SOCE, thereby displaying the anti-melanoma effect.