The Mitochondrial Ca2+ Overload via Voltage-Gated Ca2+ Entry Contributes to an Anti-Melanoma Effect of Diallyl Trisulfide

Abstract

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 (Ca2+) in different cancer cell types, the role of Ca2+ in the anticancer effect is obscure. In the present study, we investigated the Ca2+ pathways involved in the anti-melanoma effect. We used melittin, the bee venom that can activate a store-operated Ca2+ entry (SOCE) and apoptosis, as a reference. DATS increased apoptosis in human melanoma cell lines in a Ca2+-dependent manner. It also induced mitochondrial Ca2+ (Ca2+mit) overload through intracellular and extracellular Ca2+ fluxes independently of SOCE. Strikingly, acidification augmented Ca2+mit overload, and Ca2+ channel blockers reduced the effect more significantly under acidic pH conditions. On the contrary, acidification mitigated SOCE and Ca2+mit overload caused by melittin. Finally, Ca2+ channel blockers entirely inhibited the anti-melanoma effect of DATS. Our findings suggest that DATS explicitly evokes Ca2+mit overload via a non-SOCE, thereby displaying the anti-melanoma effect.

Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry

“…Notably, we observed that the removal of Ca 2+ augmented the anti-melanoma effect of aspirin (Figure 4). The findings were similar to those obtained with two different apoptosis inducers, TRAIL, and the organosulfur compound diallyl trisulfide (DATS) [38,39]. Ca 2+ removal affected cell death only when cells were exposed to these pro-death stimuli, suggesting that specific Ca 2+ signals may be activated to protect cells from stress.…”

“…Because depolarization activates different types of VGCCs depending on its magnitude and duration, they may play a role in mediating the biological effect of aspirin. Consistent with this view, Ca 2+ channel blockers such as nifedipine and verapamil, inhibited the anti-melanoma effect (Figure 4), similar to the case for DATS [39]. Because LTCCs are the primary targets for these compounds, we further investigated their role.…”

Garlic‐derived compounds: Epigenetic modulators and their antitumor effects

“…DATS induced the apoptosis of human melanoma cells in a Ca 2+ ‐dependent manner. Studies investigated that DATS definitely causes Ca 2+ mit overload through non‐SOCE, thus showing the antitumor effect (Nakagawa et al, 2020). Treatment of osteosarcoma U2OS cells with different concentrations of DATS suggested that DATS induced apoptosis and arrested G0/G1 cell cycle.…”

The Role of Calcium Signaling in Melanoma

“…Calcium channel dynamics are implicated in melanoma treatment targeting mitochondria/ER stress. Although SOCE-mediated Ca 2+ responses are critical for melanoma proliferation and apoptosis [108], drugs with anti-melanoma effects, such as diallyl trisul-fide [109], to induce mitochondrial Ca 2+ overload, ROS production, and caspase activation are mediated not by SOCEs but VDCCs. Rouaud et al reported ER stress in melanoma induced by a NADPH analog, NS1, relying on TRPM2 and Ca 2+ -activated K + channels [110].…”