Chamaecypanone C, a novel skeleton microtubule inhibitor, with anticancer activity by trigger caspase 8-Fas/FasL dependent apoptotic pathway in human cancer cells.
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 IC(50) values in nanomolar ranges. Flow cytometric analysis revealed that chamaecypanone C treated human KB cancer cells were arrested in G(2)-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.
Hsieh
Cheng-Chih
CC
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Kuo
Yueh-Hsiung
YH
Kuo
Ching-Chuan
CC
Chen
Li-Tzong
LT
Cheung
Chun-Hei Antonio
CH
Chao
Tsu-Yi
TY
Lin
Chi-Hung
CH
Pan
Wen-Yu
WY
Chang
Chi-Yen
CY
Chien
Shih-Chang
SC
Chen
Tung-Wei
TW
Lung
Chia-Chi
CC
Chang
Jang-Yang
JY
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; C491901:FAS protein, human; D053222:Fas Ligand Protein; C539295:chamaecypanone C; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8