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Chamaecypanone C, a novel skeleton microtubule inhibitor, with anticancer activity by trigger caspase 8-Fas/FasL dependent apoptotic pathway in human cancer cells |
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| Authors: | Cheng-Chih Hsieh Yueh-Hsiung Kuo Ching-Chuan Kuo Chun-Hei Antonio Cheung Chi-Hung Lin Wen-Yu Pan Shih-Chang Chien Chia-Chi Lung |
| Institution: | a Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC b Department of Pharmacy Practice, Tri-service General Hospital, Taipei, Taiwan, ROC c Tsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC d Department of Chemistry, National Taiwan University, Taipei, Taiwan, ROC e Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC f National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC g Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC h Division of Hematology/Oncology, Department of Internal Medicine, Tri-service General Hospital, Taipei, Taiwan, ROC i Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC j Institute of Biophotonics Engineering, National Yang-Ming University, Taipei, Taiwan, ROC k School of Chinese Medicine Resources, China Medical University, Taichung, Taiwan, ROC |
| Abstract: | Microtubule is a popular target for anticancer drugs. Chamaecypanone C, is a natural occurring novel skeleton compound isolated from the heartwood of Chamaecyparis obtusa var. formosana. The present study demonstrates that chamaecypanone C induced mitotic arrest through binding to the colchicine-binding site of tubulin, thus preventing tubulin polymerization. In addition, cytotoxic activity of chamaecypanone C in a variety of human tumor cell lines has been ascertained, with IC50 values in nanomolar ranges. Flow cytometric analysis revealed that chamaecypanone C treated human KB cancer cells were arrested in G2-M phases in a time-dependent manner before cell death occurred. Additional studies indicated that the effect of Chamaecypanone C on cell cycle arrest was associated with an increase in cyclin B1 levels and a mobility shift of Cdc2/Cdc25C. The changes in Cdc2 and Cdc25C coincided with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Interestingly, this compound induced apoptotic cell death through caspase 8-Fas/FasL dependent pathway, instead of mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug resistant cancer cell lines overexpressing P-gp170/MDR and MRP were sensitive to Chamaecypanone C. Taken together, these findings indicated that Chamaecypanone C is a promising anticancer compound that has potential for management of various malignancies, particularly for patients with drug resistance. |
| Keywords: | CA-4 combretastatin A-4 CCD charge-coupled device DIC differential interference contrast DMSO dimethyl sulfoxide FITC fluorescent isothiocyanate GFP green fluorescent protein HRP horseradish peroxidase MAP Microtubule-associated protein MDR multidrug resistance MRP multidrug resistance-associated proteins PI propidium iodide SPA scintillation proximity assay VP16 etoposide |
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