Targeting Wnt/β-Catenin Pathway by DNA Alkylating Pyrrole-Imidazole Polyamide in Colon Cancer.

Wnt/β-catenin pathway, which is under the control of T cell factor/lymphocyte enhancer factor (TCF/LEF) transcription factors, plays a pivotal role during carcinogenesis through the regulation of cancer cell proliferation and differentiation. Thus, it is likely that an inhibitor against this pro-oncogenic pathway might be a promising anti-cancer drug candidate. In the present study, we have synthesized a novel polyamide (WNT-Chb) composed of N-methylpyrrole, N-methylimidazole, and DNA alkylator chlorambucil, and examined its anti-cancer effect on colon cancer cells in vitro and in vivo. Based on our results, WNT-Chb preferentially bound to a consensus TCF/LEF-responsive element (5'-CCTTTGA-3'), and suppressed multiple Wnt-target gene expression. Consistent with these results, WNT-Chb attenuated in vitro proliferation and in vivo tumor growth of colon cancer cells with an aberrantly activated Wnt/β-catenin pathway. Together, these findings strongly suggest that the originally produced WNT-Chb might be a novel anti-cancer drug candidate against Wnt/β-catenin pathway-dependent colon cancers.