Benzyldihydroxyoctenone, a novel anticancer agent, induces apoptosis via mitochondrial-mediated pathway in androgen-sensitive LNCaP prostate cancer cells.
This study was aimed to evaluate detailed mechanisms on the apoptotic induction of benzyldihydroxyoctenone, a novel compound isolated from Streptomyces sp. KACC91015, in androgen-sensitive LNCaP prostate cancer cells. Benzyldihydroxyoctenone, designated as F3-2-5 in the current study, caused accumulation of apoptotic sub-G(1) phase in the flow cytometric analysis using propidium iodide staining. Moreover, the typical apoptotic DNA fragmentation of the LNCaP cells treated with 30 microM of F3-2-5 was confirmed using the TUNEL assay. This apoptotic induction of F3-2-5 in the LNCaP cells was associated with the cytochrome c release from mitochondria to cytosol, and the activation of procaspase-8, -9, and -3, as well as the specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). In addition, F3-2-5 treatment caused the down-regulation of the antiapoptotic protein, such as Bcl-2 and Bcl-X(L), but the proapoptotic protein, such as Bax, was not influenced. To investigate whether apoptotic induction by F3-2-5 is also due to the down-regulation of androgen receptor (AR), Western blot analysis and quantitative RT-PCR were conducted in F3-2-5-treated LNCaP prostate cancer cells. We found that F3-2-5 significantly inhibited the expression levels of AR and prostate-specific antigen (PSA) proteins in a time-dependent manner, as well as F3-2-5 abrogated the up-regulation of AR and PSA genes with and without DHT. Therefore, F3-2-5 has been shown to be an androgen antagonist, suggesting that F3-2-5 could be a potent agent for the treatment of both androgen-dependent and hormone-refractory prostate cancer.
Moon
Hong Sang
HS
Department of Urology, College of Medicine, Hanyang University, Seoul 133-791, Republic of Korea.
Lim
Haeyoung
H
Moon
Sangik
S
Oh
Ha Lim
HL
Kim
Young-Tae
YT
Kim
Min Kyoung
MK
Lee
Chul-Hoon
CH
D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D053938:DNA Fragmentation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D000442:Octanols / Q000138:chemical synthesis* / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy*
D000728:Androgens; D000970:Antineoplastic Agents; D000442:Octanols; C521510:benzyldihydroxyoctenone; D017430:Prostate-Specific Antigen