Oncotarget

Research Papers:

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells

Jian-Ping Li, Zhi-Jun Huang, Xing-Sheng Lu, Yi-Chan Zhou, Yun Shao, Xiao-Pu He, Su-Rong Chen, Dong-Dong Wang, Li-Sen Qin and Wei-Hao Sun _

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Oncotarget. 2016; 7:77815-77824. https://doi.org/10.18632/oncotarget.12802

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Abstract

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

*Co-first authors

Correspondence to:

Wei-Hao Sun, email: swh@njmu.edu.cn, weihaosun@hotmail.com

Keywords: colorectal cancer (CRC), PKC412, AKT, Bcl-2, receptor tyrosine kinases

Received: July 29, 2016    Accepted: September 29, 2016    Published: October 21, 2016

ABSTRACT

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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