Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo.

Abstract

Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.

• Authors: Jian-Guo Sun, Hua Li, Xia Li, Xueli Zeng, Ping Wu, Kwok-Pui Fung, Fei-Yan Liu
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 5 Pg. 871-82 (May 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24563182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Pyrimidine Nucleosides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• clitocine

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Male
• Mice
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Protein Transport
• Pyrimidine Nucleosides (chemistry, pharmacology)
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-2-Associated X Protein (metabolism)