Ruthenium red, inhibitor of mitochondrial Ca2+ uniporter, inhibits curcumin-induced apoptosis via the prevention of intracellular Ca2+ depletion and cytochrome c release

The voltage-dependent anion channel-1 modulates apoptotic cell death

“…In the present report, we have shown that RuR and Ru360, which interact with purified VDAC and inhibit its channel activity as well as the opening of the PTP, 7,10,12 also inhibited apoptotic cell death induced by STS or by VDAC overexpression (Table 1, Figure 5). RuR was shown to protect against cell death induced by different stimuli including curcumin in U-937 cells, 20 ursolic acid in HL-60 cells 21 or microcystin in cultured rat hepatocytes. 22 Since RuR interacts with Ca 2 þ -binding proteins and inhibits their activities, 7,10,13-18 the inhibition by RuR of apoptotic cell death induced by the various stimuli in different cell types suggests that apoptosis is mediated by an intracellular Ca 2 þ signaling pathway.…”

“…Indeed, the RuRinsensitive E72Q-mutated VDAC provides an opportunity to verify the relationship between RuR interaction with VDAC and the ability of RuR to prevent apoptotic cell death. [20][21][22] RuR-mediated protection against nuclear fragmentation in U-937 cells appeared to abrogate apoptosis by modifying VDAC function. This concept is further strongly supported by the finding that the channel activity of E72Q-mutated VDAC was not inhibited by RuR or Ru360.…”

“…Apart from RuR ( Figure 2, Table 1 and Gincel et al, 7,12 Shoshan-Barmatz and Gincel, 10 Bae et al, 20 Baek et al, 21 and Ding et al 22 ), overexpression of mitochondrial HK-I 25 or HK-II 24 also reduces apoptosis induced by different stimuli. We have shown that HK-I and RuR directly interact with purified VDAC reconstituted into a PLB to induce channel closure.…”

“…[20][21][22] Such protection has been Figure 2 HK-I inhibits channel activity of native but not E72Q-mutated mVDAC1. (a) Purified recombinant native or E72Q-mutated mVDAC1 was reconstituted into a PLB in symmetrical solutions of 0.5 M NaCl as described under Materials and Methods.…”

“…7,10,12 RuR was further shown to inhibit cytochrome c release, activation of caspases-3-and curcumin-induced apoptosis in the U-937 cell line. 20 Finally, RuR also inhibits both ursolic acid-induced cell death in LH-60 21 cells and microcystininduced cell death in cultured rat hepatocytes. 22 However, the mechanism(s) underlying the protective action of RuR against apoptosis remains unknown.…”