Benzyldihydroxyoctenone, a novel anticancer agent, induces apoptosis via mitochondrial-mediated pathway in androgen-sensitive LNCaP prostate cancer cells

초록

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-G1 phase in the flow cytometric analysis using propidium iodide staining. Moreover, the typical apoptotic DNA fragmentation of the LNCaP cells treated with 30 mu M 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. (C) 2008 Elsevier Ltd. All rights reserved.

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