Furanonaphthoquinones cause apoptosis of cancer cells by inducing the production of reactive oxygen species by the mitochondrial voltage-dependent anion channel

Abstract

The mitochondrial production of reactive oxygen species has been implicated in the anticancer activity of furanonaphthoquinone. However, the mechanism of the activation remains elusive. In the current study, we found that treatment of HeLa cells with 2-methyl-5(or -8)-hydroxy-furanonaphthoquinone (FNQ13) induces mitochondrial swelling, followed by apoptosis. This toxic effect of FNQ13 was reduced by the radical scavengers alpha-tocopherol and trolox. Cytochemical experiments in isolated mitochondria showed that a combination of FNQ13 and NADH induces the production of H(2)O(2) at the exterior mitochondrial membrane surface. This production of H(2)O(2) was reduced by an antibody to the voltage-dependent anion channel (VDAC). Overexpression of the VDAC by transfection with vdac1 cDNA increased the production of H(2)O(2) by HeLa cells, whereas transfection with a small interfering RNA to VDAC reduced FNQ13-induced H(2)O(2) production and cell death due to an almost complete knockdown of VDAC expression. We also found significant correlations between the expression of VDAC and the induction of H(2)O(2) production and cell death by FNQ13 in 11 human cancer cell lines. These results indicate that the anticancer activity of furanonaphthoquinones depends on the production of reactive oxygen species by mitochondrial permeability transition pores including the VDAC.

Outer membrane VDAC1 controls permeability transition of the inner mitochondrial membrane in cellulo during stress-induced apoptosis

“…Consistent with this finding, VDAC1-siRNAs lower the ROS as well as cell death induced by FNQ13 [61], and downregulation of VDAC1 reduces apoptosis induced by cisplatin [67]. Conversely, VDAC1 downregulation does not affect cellular responsiveness to inducers of physiological apoptosis like STS.…”

“…In general, VDACs have often been considered as mediators of apoptosis induced by ROS [37,[57][58][59][60]. Recently, Simamura et al [61] demonstrated that the anti-cancer activity of the furanophtoquinone FNQ13 was potentiated by overexpression of VDAC1 and the mitochondrial production of ROS. This finding confirms a previous report from our lab where it was demonstrated that plasma membrane VDAC may act as a transmembrane oxidoreductase using the cytoplasmic NADH as the reducing species [62].…”

Swapping of the N‐terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti‐aging features to the cell

“…Unfortunately these authors did not consider that in the outer mitochondrial membrane there are three different VDACs. Since dextran sulfate acts as a kind of clog upon the pore and since the VDAC isoforms are structurally very similar, it is very probable that the overall effect measured for example in [41] was not specific of VDAC1 but possibly the sum of the effect of the isoforms. In the literature there are systemic surveys of ROS-dependent chemical modifications of the yeast proteome and it was shown that VDAC was usually involved.…”

Proteomic analysis reveals overexpression of moesin and cytokeratin 17 proteins in colorectal carcinoma

“…It adjusts cell oxidation-reduction reactions and participates in apoptosis through regulating the permeability of mitochondrial membrane under the influence of proapoptotic Bax and Bak proteins or antiapoptotic Bcl-xL protein (91,92). VDAC1 has been reported to be overexpressed in several cancer cells (93,94), however, the suggested roles of this molecules have been inconsistent in several studies. For example, in studies by Simamura et al, overexpression of VDAC1 in cancer cells was reported to increase the sensitivity of cancer cells to quinine antitumor drugs (93)(94)(95).…”

“…VDAC1 has been reported to be overexpressed in several cancer cells (93,94), however, the suggested roles of this molecules have been inconsistent in several studies. For example, in studies by Simamura et al, overexpression of VDAC1 in cancer cells was reported to increase the sensitivity of cancer cells to quinine antitumor drugs (93)(94)(95). On the other hand, Pan et al reported that VDAC1 was consistently increased at both the protein and the RNA levels in caboplatinand paclitaxel-resistant ovarian cancer (96).…”