beta-Lapachone-induced apoptosis in human prostate cancer cells: Involvement of NQO1/xip3

beta -Lapachone (beta -lap) induces apoptosis in various cancer cells, and its intracellular target has recently been elucidated in breast cancer cell s, Here we show that NAD(P)H:quinone oxidoreductase (NQO1/xip3) expression in human prostate cancer cells is a key determinant for apoptosis and letha lity after beta -lap exposures. beta -Lap-treated, NQO1-deficient LNCaP cel ls were significantly more resistant to apoptosis than NQO1-expressing DU-1 45 or PC-3 cells after drug exposures, Formation of an atypical 60-kDa PARP cleavage fragment in DU-145 or PC-3 cells was observed after 10 muM beta - lap treatment and correlated with apoptosis, In contrast, LNCaP cells requi red 25 muM beta -lap to induce similar responses. Atypical PARP cleavage in beta -lap-treated cells was not affected by 100 muM zVAD-fmk; however, coa dministration of dicoumarol, a specific inhibitor of NQO1, reduced beta -la p-mediated cytotoxicity, apoptosis, and atypical PARP cleavage in NQO1-expr essing cells. Dicoumarol did not affect the more beta -lap-resistant LNCaP cells, Stable transfection of LNCaP cells with NQO1 increased their sensiti vity to beta -lap, enhancing apoptosis compared to parental LNCaP cells or vector-alone transfectants. Dicoumarol increased survival of beta -lap-trea ted NQO1-expressing LNCaP transfectants, NQO1 activity, therefore, is a key determinant of beta -lap-mediated apoptosis and cytotoxicity in prostate c ancer cells. (C) 2001 Academic Press.