title: 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.
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 IC50about 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.
authors: Department of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, I-Shou University, Kaohsiung, Taiwan.
authors: Chao-Ming
authors: CM
authors: Hung
authors: Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan; Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors: Ying-Chao
authors: YC
authors: Lin
authors: Department of Surgery, China Medical University Hospital, Taichung, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
authors: Liang-Chih
authors: LC
authors: Liu
authors: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
authors: Chi-Tang
authors: CT
authors: Ho
authors: Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan. Electronic address: tdway@mail.cmu.edu.tw.
authors: Tzong-Der
authors: TD
authors: Way
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D058105:Polymerization; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050256:Antimitotic Agents; C000613786:CWF-145; D015363:Quinolones; D014404:Tubulin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Akt/mTOR; CWF-145; G2/M arrest; Prostate cancer; Rapamycin