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Silibinin inhibits human nonsmall cell lung cancer cell growth through cell‐cycle arrest by modulating expression and function of key cell‐cycle regulators

Recent studies show that silibinin possesses a strong antineoplastic potential against many cancers; however, its efficacy and underlying molecular mechanisms in nonsmall cell lung cancer (NSCLC) are not well defined. Herein, we assessed silibinin activity on prime endpoints and key molecular targets such as cell number, cell‐cycle progression, and cell‐cycle regulatory molecules in three cell lines representing different NSCLC subtypes, namely large cell carcinoma cells (H1299 and H460) and a bronchioalveolar carcinoma cell line (H322). Silibinin treatment (10–75 µM) inhibited cell growth and targeted cell‐cycle progressing causing a prominent G1 arrest in dose‐ and time‐dependent manner. In mechanistic studies, silibinin (50–75 µM) modulated the protein levels of cyclin‐dependent kinases (CDKs) (4, 6, and 2), cyclins (D1, D3, and E), CDKIs (p18/INK4C, p21/Cip1, and p27/Kip1) in a differential manner in these three cell lines. Consistent with these observations, silibinin caused a reduction in kinase activity of CDK4 and 2 in all cell lines except no effect on CDK4 kinase activity in H460 cells, and concomitantly reduced Rb phosphorylation. Together, for the first time, these results identify potential molecular targets and anticancer effects of silibinin in NSCLC cells representing different NSCLC subtypes. © 2009 Wiley‐Liss, Inc.