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.
Highlights
Surgical resection of early-defined tumors and chemotherapies are applied for colorectal cancer (CRC) treatment, yet they have failed to significantly improve patients’ prognosis [1,2,3]
MTT assay was applied to test cell viability, and results in Figure 1A demonstrated that PKC412 inhibited HT-29 cell survival in time- and dose-dependent manners
The primary human colon epithelial cells were resistant to the same PKC412 treatment (Figure 1F). We repeated these experiments in two other primary colon epithelial cell lines, and similar results were obtained (Data not shown). These results show that PKC412 inhibits CRC cell survival and proliferation
Summary
Surgical resection of early-defined tumors and chemotherapies are applied for colorectal cancer (CRC) treatment, yet they have failed to significantly improve patients’ prognosis [1,2,3]. Considerable efforts have been spent to explore novel chemo-preventive agents against CRC [4, 5]. It has been our research focus in recent years [6]. PKC412 (N-benzoylstaurosporine) was originally developed as a small-molecular inhibitor of protein kinase C (PKC) [7]. Considering that most of these kinases were dysregulated and/or over-activated in CRC [5, 9], we here tested the anti-cancer activity of this multi-kinase inhibitor in preclinical CRC models [6]
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