Open AccessNovel anticancer agent, benzyldihydroxyoctenone, isolated from Streptomyces sp. causes G 1 cell cycle arrest and induces apoptosis of HeLa cells
Author(s) -
Lee ChulHoon,
Lim Haeyoung,
Moon Sangik,
Shin Choonshik,
Kim Seunghyun,
Kim BumJoon,
Lim Yoongho
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00473.x
Subject(s) - hela , apoptosis , cell cycle , dna fragmentation , microbiology and biotechnology , cyclin d1 , cell cycle checkpoint , fragmentation (computing) , retinoblastoma protein , poly adp ribose polymerase , cell growth , cyclin dependent kinase 1 , biology , cell culture , kinase , chemistry , programmed cell death , cell , biochemistry , dna , polymerase , genetics , ecology
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 IC 50 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 p21 WAF1/CIP1 increased. Taken together, these findings show that F3‐2‐5 inhibits proliferation of HeLa cells by inducing G 1 phase arrest as a consequence of inhibition of pRb phosphorylation following up‐regulation of p21 WAF1/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)