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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
- Source :
- Chemico-Biological Interactions. 260:1-12
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- Subjects :
- Male
0301 basic medicine
Mice, Nude
Apoptosis
Antimitotic Agents
Quinolones
Pharmacology
Biology
Toxicology
Microtubules
Polymerization
Microtubule polymerization
03 medical and health sciences
0302 clinical medicine
Tubulin
Cell Line, Tumor
LNCaP
Animals
Humans
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Sirolimus
Mice, Inbred BALB C
TOR Serine-Threonine Kinases
RPTOR
Prostatic Neoplasms
Cell Cycle Checkpoints
General Medicine
Cell cycle
Up-Regulation
030104 developmental biology
030220 oncology & carcinogenesis
Cancer cell
Antimitotic Agent
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 00092797
- Volume :
- 260
- Database :
- OpenAIRE
- Journal :
- Chemico-Biological Interactions
- Accession number :
- edsair.doi.dedup.....6cb8ebd19055047669428431c778e22e