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Previous studies demonstrated a synergistic cytotoxic effect by ascorbate-menadione on various types of cancer cells. When used in combination, ascorbate and menadione are entering a redox cycle leading to hydrogen peroxide production, which seems to be the basis of this cytotoxicity. Recent studies suggest that oxidative stress generated by ascorbate/menadione affects Hsp90 leading to the degradation of some critical proteins and cell death. Moreover, this association leads to the appearance of an additional Hsp90 protein band of about 70 kDa, suggesting Hsp90 cleavage,in the K562 leukemia myelogenous chronic cells.ln this study, we first confirmed the presence of the additional Hsp90 protein band induced by ascorbate/menadione in murine hepatocarcinoma cells (Transplantable liver tumor).Secondly, by using two modulators of oxidative stress, N-acetylcysteine and 3-aminotriazole, we showed the implication of oxidative stress in the Hsp90 cleavage.Thirdly, by using two calcium chelating agents, namely Bapta-AM and EGTA, we showed that intracellular calcium may be implicated in this cleavage.Finally, by using some metabolic inhibitors of Hsp90, we founded that both the cleavage of Hsp90 and the cytotoxicity induced by ascorbate/menadione are not necessarily correlated. That means that Hsp90 cleavage is not the only expianation of cell death. As conclusion, given the key role played by Hsp90 in cancer cells stabilizing mutated proteins critical for their survival, we would like to propose ascorbate/menadione as a new non toxic adjuvant anticancer therapy, without presenting any supplementary risk for the patients.

Oxidative Stress --- HSP90 Heat-Shock Proteins --- Liver Neoplasms, Experimental --- Vitamin K 3 --- Ascorbic Acid --- Mice