midostaurin and Colorectal-Neoplasms

Midostaurin is an FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor that provides renewed hope for treating acute myeloid leukaemia (AML). The limited efficacy of this compound as a monotherapy contrasts with that of its synergistic combination with standard cytarabine and daunorubicin (Dau), suggesting a therapeutic benefit that is not driven only by FLT3 inhibition. In an AML context, the activity of the enzyme aldo-keto reductase 1C3 (AKR1C3) is a crucial factor in chemotherapy resistance, as it mediates the intracellular transformation of anthracyclines to less active hydroxy metabolites. Here, we report that midostaurin is a potent inhibitor of Dau inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in a transfected cell model. Likewise, in the FLT3

Topics: Aldo-Keto Reductase Family 1 Member C3; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Colorectal Neoplasms; Daunorubicin; Drug Synergism; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; HCT116 Cells; Humans; Leukemia, Myeloid, Acute; Staurosporine

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.

Topics: Animals; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Staurosporine; Xenograft Model Antitumor Assays