Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis.
Chemotherapeutic drugs are usually designed to induce cancer cell death via cell cycle arrest and/or apoptosis pathways. In this study, we used the chemical drug 15,16-dihydrotanshinone I (DHTS) to inhibit breast cancer cell proliferation and tumor growth, and investigate the underlying molecular mechanisms. Human breast cancer cell lines MCF-7 and MDA-MB-231 were both used in this study, and DHTS was found to significantly decrease cell proliferation by a dose-dependent manner in both cells. Flow cytometry indicated that DHTS induced G1 phase arrest in synchronous MCF-7 and MDA-MB-231 cells. When analyzing the expression of cell cycle-related proteins, we found that DHTS reduced cyclin D1, cyclin D3, cyclin E, and CDK4 expression, and increased CDK inhibitor p27 expression in a dose-dependent manner. In addition, DHTS inhibited the kinase activities of CDK2 and CDK4 by an immunocomplex kinase assay. In addition, DHTS also induced apoptosis in both cells through mainly mitochondrial apoptosis pathways. We found that DHTS decreased the anti-apoptotic protein Bcl-xL level and increased the loss of mitochondria membrane potential and the amount of cytochrome c released. Moreover, DHTS activated caspase-9, caspase-3, and caspase-7 and caused cell apoptosis. The fact that DHTS-induced apoptosis could be blocked by pretreating cells with pan-caspase inhibitor confirmed that it is mediated through activation of the caspase-3-dependent pathway. In a nude mice xenograft experiment, DHTS significantly inhibited the tumor growth of MDA-MB-231 cells. Taken together, these results suggest that DHTS can inhibit human breast cancer cell proliferation and tumor growth, and might have potential chemotherapeutic applications.
Tsai
Sun-Lung
SL
Liver Research Unit, Department of Medical Research, Chi-Mei Medical Center, Yung-Kang City, Tainan, Taiwan.
Suk
Fat-Moon
FM
Wang
Chun-I
CI
Liu
Der-Zen
DZ
Hou
Wen-Chi
WC
Lin
Pei-Jung
PJ
Hung
Ling-Fang
LF
Liang
Yu-Chih
YC
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005663:Furans; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011809:Quinones; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D005663:Furans; D010616:Phenanthrenes; D011809:Quinones; D051020:bcl-X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000713095:dihydrotanshinone I; D045304:Cytochromes c; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D053453:Caspase 9