Novel anticancer agent, benzyldihydroxyoctenone, isolated from Streptomyces sp. causes G1 cell cycle arrest and induces apoptosis of HeLa cells

• Published in: Cancer science Vol. 98; no. 6; pp. 795 - 802
• Main Authors: Lee, Chul‐Hoon, Lim, Haeyoung, Moon, Sangik, Shin, Choonshik, Kim, Seunghyun, Kim, Bum‐Joon, Lim, Yoongho
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01.06.2007; Blackwell
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Cell Proliferation - drug effects; G1 Phase - drug effects; HeLa Cells; Humans; Medical sciences; Octanols - isolation & purification; Octanols - therapeutic use; Original; Phosphorylation; Retinoblastoma Protein - metabolism; Streptomyces - chemistry; Tumor Suppressor Protein p53 - metabolism; Tumors; Actinomycetales; Antineoplastic agent; G1 Phase; Streptomycetaceae; Cancerology; Cell death; Cell cycle; Streptomyces; Bacteria; Actinomycetes; Hela cell line; Apoptosis
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2007.00473.x

In the course of screening for anticancer agents, a novel active compound, F3‐2‐5, was isolated from culture broth of Streptomyces sp., KACC91015. Its structure was identified using nuclear magnetic resonance, mass spectrometry, and molecular modeling experiments, and confirmed by total synthesis. The growth of various human cancer cell lines was inhibited in a dose‐dependent manner by 0.06–0.48 mM F3‐2‐5 over 24 h. Its IC50 values were estimated at 37 µM on HeLa, 72 µM on A549, and 190 µM on HT‐29 cells. However, F3‐2‐5 had no antiproliferative effect on normal lymphocytes and normal fibroblasts used as controls. Moreover, it affected cell cycle regulation and caused apoptosis of the HeLa cells; chromatin condensation and DNA fragmentation were observed in cells exposed to 80 µM F3‐2‐5. Western blot analysis revealed that F3‐2‐5 inhibited phosphorylation of retinoblastoma protein (pRb) and reduced expression of cyclin‐dependent kinase‐4 and ‐6, and cyclin D1 and E, while levels of p53 and p21WAF1/CIP1 increased. Taken together, these findings show that F3‐2‐5 inhibits proliferation of HeLa cells by inducing G1 phase arrest as a consequence of inhibition of pRb phosphorylation following up‐regulation of p21WAF1/CIP1 and p53. Furthermore, apoptosis in HeLa cells treated with F3‐2‐5 was associated with an increase in Bax and p53, leading to release of cytochrome c, activation of caspase‐3, and ‐8, and cleavage of poly (ADP‐ribose) polymerase. (Cancer Sci 2007; 98: 795–802)