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.
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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)
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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
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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)
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