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 cells. Here we show that NAD(P)H:quinone oxidoreductase (NQO1/xip3) expression in human prostate cancer cells is a key determinant for apoptosis and lethality after beta-lap exposures. beta-Lap-treated, NQO1-deficient LNCaP cells were significantly more resistant to apoptosis than NQO1-expressing DU-145 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 microM beta-lap treatment and correlated with apoptosis. In contrast, LNCaP cells required 25 microM beta-lap to induce similar responses. Atypical PARP cleavage in beta-lap-treated cells was not affected by 100 microM zVAD-fmk; however, coadministration of dicoumarol, a specific inhibitor of NQO1, reduced beta-lap-mediated cytotoxicity, apoptosis, and atypical PARP cleavage in NQO1-expressing cells. Dicoumarol did not affect the more beta-lap-resistant LNCaP cells. Stable transfection of LNCaP cells with NQO1 increased their sensitivity to beta-lap, enhancing apoptosis compared to parental LNCaP cells or vector-alone transfectants. Dicoumarol increased survival of beta-lap-treated NQO1-expressing LNCaP transfectants. NQO1 activity, therefore, is a key determinant of beta-lap-mediated apoptosis and cytotoxicity in prostate cancer cells.
Planchon
S M
SM
Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106-4942, USA.
Pink
J J
JJ
Tagliarino
C
C
Bornmann
W G
WG
Varnes
M E
ME
Boothman
D A
DA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D016159:Tumor Suppressor Protein p53; C014638:beta-lapachone; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002166:Camptothecin