Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells
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Jian-Ping Li1,2,*, Zhi-Jun Huang3,4,*, Xing-Sheng Lu5,*, Yi-Chan Zhou1, Yun Shao1, Xiao-Pu He1, Su-Rong Chen2, Dong-Dong Wang2, Li-Sen Qin6, Wei-Hao Sun1
1Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Department of Oncology, Yancheng Fist People’s Hospital, Yancheng, China
3Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
4Department of Surgery, Yancheng Fist People’s Hospital, Yancheng, China
5Department of Hepatobiliary Surgery, Suzhou Municipal Hospital, Suzhou, China
6Department of Neurosurgery, Yancheng Pavilion Lake District People’s Hospital, Yancheng, China
Wei-Hao Sun, email: [email protected], [email protected]
Keywords: colorectal cancer (CRC), PKC412, AKT, Bcl-2, receptor tyrosine kinases
Received: July 29, 2016 Accepted: September 29, 2016 Published: October 21, 2016
The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412’s cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412’s lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412’s cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.
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