Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells.
We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity.
Department of Medicine, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007.
G J
GJ
Berchem
M
M
Bosseler
L Y
LY
Sugars
H J
HJ
Voeller
S
S
Zeitlin
E P
EP
Gelmann
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013196:Dihydrotestosterone; D005047:Etoposide