CWF-145, a novel synthetic quinolone derivative exerts potent antimitotic activity against human prostate cancer: Rapamycin enhances antimitotic drug-induced apoptosis through the inhibition of Akt/mTOR pathway. (25th December 2016)

• Record Type: Journal Article
• Authors: Hung, Chao-Ming; Lin, Ying-Chao; Liu, Liang-Chih; Kuo, Sheng-Chu; Ho, Chi-Tang; Way, Tzong-Der
• Is Part Of: Chemico-biological interactions. Volume 260(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12-25
• Subjects: CWF-145 -- Prostate cancer -- G2/M arrest -- Akt/mTOR -- Rapamycin; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.10.014
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU-145 and LNCap. It had a very low IC50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin at the colchicine-binding site then disrupted microtubule polymerization. Furthermore, the damaged microtubule affected the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our data showed that CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. The increased cyclin B1 and securin arrested cell cycle at G2/M phase. Moreover, we showed that Akt activation markedly increased resistance to microtubule-directed agents, including CWF-145, colchicine, and paclitaxel. Interestingly, rapamycin inhibited Akt-mediated therapeutic resistance, indicating that these effects were dependent on mTOR. Taken together, these observations suggest that activation of the Akt/mTOR signaling pathway can promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data may provide insight into potentially synergistic combinations of anticancer therapies. Highlights: CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin. CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. Akt activation markedly increased resistance to microtubule-directed agents. Rapamycin inhibited Akt-mediated therapeutic resistance.