Abstract

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.

Original languageEnglish
Pages (from-to)1575-1586
Number of pages12
JournalBiochemical Pharmacology
Volume74
Issue number11
DOIs
Publication statusPublished - Dec 1 2007

Fingerprint

Tumors
Adenocarcinoma
Breast
Apoptosis
Cell proliferation
Cells
Neoplasms
Caspase 3
Cell Proliferation
Breast Neoplasms
Phosphotransferases
Cyclin D3
Cyclin-Dependent Kinase Inhibitor p27
Caspase 7
Growth
Cyclin E
Apoptosis Regulatory Proteins
Mitochondria
Caspase Inhibitors
Flow cytometry

Keywords

  • 15,16-Dihydrotanshinone I
  • Apoptosis
  • Breast cancer
  • Caspase
  • Cell cycle
  • G1 arrest

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis. / Tsai, Sun Lung; Suk, Fat Moon; Wang, Chun I.; Liu, Der Zen; Hou, Wen Chi; Lin, Pei Jung; Hung, Ling Fang; Liang, Yu Chih.

In: Biochemical Pharmacology, Vol. 74, No. 11, 01.12.2007, p. 1575-1586.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Tsai, Sun Lung

AU - Suk, Fat Moon

AU - Wang, Chun I.

AU - Liu, Der Zen

AU - Hou, Wen Chi

AU - Lin, Pei Jung

AU - Hung, Ling Fang

AU - Liang, Yu Chih

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