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.