Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells

Abstract

Abstract. Although ascorbate (Vitamin C) has been shown to inhibit cell growth and induce cell death in variety of cancer cells, results reported in other studies are inconsistent with this conclusion. It was previously reported that ascorbate induces apoptosis in human breast cancer cells. However, the molecular mechanism for this is not clear. In this study, we demonstrate that ascorbate induces cell death through the apoptosis-inducing factor (AIF) in the human breast cancer cell lines, SK-BR3 and Hs578T, but not in a normal breast cell line, Hs578. Ascorbate treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in healthy cells, but caspase cleavage is not induced. Moreover, MG132, an inhibitor of AIF release from mitochondria, blocked the induction of cell death. Furthermore, cells that had been treated with human AIF-specific siRNA resisted cell death induced by ascorbate, implying that the translocation of AIF from mitochondria to the nucleus is responsible for ascorbate-mediated cell death. Therefore, these results suggest that ascorbate activates a caspase-independent and AIFmediated cell death pathway in human breast cancer cells, SK-BR3, and Hs578T.

The unpaved journey of vitamin C in cancer treatment

“…However, it has been difficult to generalize a molecular mechanism in all types of susceptible cancer cells, because H 2 O 2 and ROS have promiscuous targets in the cell Levine et al 2011). Some studies indicated that ascorbate induced apoptosis in some types of cancer cells (Carosio et al 2007;Hong et al 2007;Lin et al 2006), while others showed that the ascorbateinduced cell death was caspase independent, and apoptosis was not the main type of cell death induced by ascorbate (Chen et al 2005;Kang et al 2003;Ohtani et al 2007;Verrax et al 2004;Verrax et al 2005). Autophagy was also suggested to be causing death when cells were treated with ascorbate (Cullen 2010;Du et al 2010).…”

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

“…In contrast, ascorbate-mediated cytotoxicity in breast cancer cell lines, SK-BR3 and Hs578T, involved nuclear translocation of the mitochondrial apoptosis-inducing factor (AIF) protein (36). Inhibition of mitochondrial AIF release only partially inhibited cell death.…”

Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

“…In detail, pro-apoptotic effects of ascorbate were observed in epithelial tumor cells derived from different cancers such as hepatocellular carcinoma [11,37], esophageal cancer [38], breast cancer [39], non-small cell lung cancer [40] and gastric cancer [41]. Ascorbate seems to have a preferential toxicity toward melanoma cells [42].…”