Anti-cancer effect of bio-reductive drug β-lapachon is enhanced by activating NQO1 with heat shock

Abstract

Purpose: Bio-reduction/activation of anti-cancer drug β-lapachone (β-lap) is mediated by NAD(P)H: Quinone oxidoreductase (NQO1). We investigated the feasibility of using mild temperature hyperthermia to increase the anti-cancer effect of β-lap by up-regulating NQO1 expression.Methods: NQO1 expression in FSaII fibrosarcoma of C3H mice and A549 human lung cancer cells was evaluated with Western blot analysis and immunostaining of cells at different times after water-bath heating. Clonogenic cell survival method was used to determine the sensitivity of cells to heating, β-lap, and in combination. The growth of FSaII tumors in the right hind legs of C3H mice was studied after heating the tumors at 42°C for 1 h with water bath, an i.p. injection of β-lap to host mice or an i.p. injection of β-lap 24 h after heating the tumors.Results: Heating at 42°C for 1 h significantly increased the expression of NQO1 in the cancer cells with a maximum increase occurring 8–24 h after heating. The sensitivity of cancer cells to β-lap treatment progressively increased until 24 h after heating most likely due to the increase in NQO1 expression. Heating the FSaII tumors at 42°C for 1 h and treating the host mice with an i.p. injection of 50 mg/kg β-lap 24 h after the tumor heating was far more effective than heating alone or β-lap treatment alone to suppress the tumor growth.Conclusion: Mild temperature heat shock elevates the NQO1 expression in cancer cells, which in turn markedly increases the sensitivity of the cells to the bioreductive drug β-lap in vitro and in vivo.