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

• Published in: Oncotarget 2016-11, Vol.7 (47), p.77815-77824
• Main Authors: Li, Jian-Ping, Huang, Zhi-Jun, Lu, Xing-Sheng, Zhou, Yi-Chan, Shao, Yun, He, Xiao-Pu, Chen, Su-Rong, Wang, Dong-Dong, Qin, Li-Sen, Sun, Wei-Hao
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, Nude; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Staurosporine - administration & dosage; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12802

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.