Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak.

Abstract

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.

• Authors: Jian-guo Sun, Jun Xiang, Xue-li Zeng, Xia Li, Ping Wu, Kwok Pui Fung, Fei-yan Liu
• Journal: Cancer letters (Cancer Lett) Vol. 355 Issue 2 Pg. 253-63 (Dec 28 2014) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25304383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ABT-737
• BAK1 protein, human
• Biphenyl Compounds
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidine Nucleosides
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• clitocine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (administration & dosage, pharmacology)
• Caco-2 Cells
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• HCT116 Cells
• Humans
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Nitrophenols (administration & dosage, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyrimidine Nucleosides (administration & dosage, pharmacology)
• Random Allocation
• Sulfonamides (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)