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

// Jian-Ping Li 1, 2, * , Zhi-Jun Huang 3, 4, * , Xing-Sheng Lu 5, * , Yi-Chan Zhou 1 , Yun Shao 1 , Xiao-Pu He 1 , Su-Rong Chen 2 , Dong-Dong Wang 2 , Li-Sen Qin 6 , Wei-Hao Sun 1 1 Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Department of Oncology, Yancheng Fist People’s Hospital, Yancheng, China 3 Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China 4 Department of Surgery, Yancheng Fist People’s Hospital, Yancheng, China 5 Department of Hepatobiliary Surgery, Suzhou Municipal Hospital, Suzhou, China 6 Department 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.