The potential utility of acetyltanshinone IIA in the treatment of HER2-overexpressed breast cancer: Induction of cancer cell death by targeting apoptotic and metabolic signaling pathways
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Mounia Guerram1, Zhen-Zhou Jiang1,2, Bashir Alsiddig Yousef1, Aida Mejda Hamdi1, Hozeifa Mohamed Hassan1, Zi-Qiao Yuan1, Hou-Wei Luo3, Xiong Zhu4, Lu-Yong Zhang1,5
1Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
2Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
3Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
4Medical and Chemical Institute, China Pharmaceutical University, Nanjing 210009, China
5State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Zhen-Zhou Jiang, e-mail: firstname.lastname@example.org
Lu-Yong Zhang, e-mail: email@example.com
Keywords: ATA, breast cancer, metabolism, HER2, signaling pathways
Received: February 15, 2015 Accepted: May 14, 2015 Published: May 28, 2015
Increased lipogenesis and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression and is under intense investigation as a potential antineoplastic target. Acetyltanshinone IIA (ATA) is a compound that was obtained from chemical modifications of tanshinone IIA (TIIA), a potent anticancer agent extracted from the dried roots of the Chinese herbal medicine Salvia miltiorrhiza Bunge. A previous investigation indicated that ATA is more effective in inhibiting the growth of breast cancer especially cells with HER2 overexpression. However, the molecular mechanism(s) mediating this cytotoxic effect on HER2-positive breast cancer remained undefined. Studies described here report that ATA induced G1/S phase arrest and apoptosis in the HER2-positive MDA-MB-453, SK-BR-3, and BT-474 breast cancer cell lines. Mechanistic investigations revealed that the ATA-induced apoptosis effect is associated with remarkably down-regulation of receptor tyrosine kinases (RTKs) EGFR/HER2 and inhibition of their downstream pro-survival signaling pathways. Interestingly, ATA was found to trigger oxidative and endoplasmic reticulum (ER) stresses and to activate AMP activated protein kinase (AMPK) leading to inactivation of key enzymes involved in lipid and protein biogenesis. Intraperitoneal administration of ATA significantly inhibited the growth of MDA-MB-453 xenografts in athymic mice without causing weight loss and any other side effects. Additionally, transwell migration, invasion, and wound healing assays revealed that ATA could suppress tumor angiogenesis in vitro. Taken together, our data suggest that ATA may have broad utility in the treatment of HER2-overexpressed breast cancers.
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