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

Abstract

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.

• Authors: Hong Sang Moon, Haeyoung Lim, Sangik Moon, Ha Lim Oh, Young-Tae Kim, Min Kyoung Kim, Chul-Hoon Lee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 3 Pg. 742-4 (Feb 01 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19119006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• Antineoplastic Agents
• Octanols
• benzyldihydroxyoctenone
• Prostate-Specific Antigen

Topics

• Androgens (metabolism)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis
• Cell Line, Tumor
• Chemistry, Pharmaceutical (methods)
• DNA Fragmentation
• Gene Expression Regulation, Neoplastic
• Humans
• In Situ Nick-End Labeling
• Male
• Mitochondria (metabolism)
• Models, Chemical
• Octanols (chemical synthesis, pharmacology)
• Prostate-Specific Antigen (biosynthesis)
• Prostatic Neoplasms (drug therapy)