nitrophenols and clitocine

ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT-737. At the present study, we observed that clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of clitocine and ABT-737. Finally, clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Biphenyl Compounds; Caco-2 Cells; Cell Line, Tumor; Cell Membrane Permeability; Colonic Neoplasms; HCT116 Cells; Humans; Mice; Mice, Nude; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidine Nucleosides; Random Allocation; Sulfonamides; Xenograft Model Antitumor Assays