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

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...

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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
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.12802