The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells
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Nosheen Akhtar1,2, Deeba N. Syed1, Mohammad Imran Khan1, Vaqar M. Adhami1, Bushra Mirza2, Hasan Mukhtar1
1Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA
2Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad 45320, Pakistan
Bushra Mirza, e-mail: [email protected]
Hasan Mukhtar, e-mail: [email protected]
Keywords: 5′AMP-activated kinase (AMPK), plectranthoic acid, prostate cancer (PCa)
Received: September 15, 2015 Accepted: November 28, 2015 Published: December 16, 2015
Epidemiologic studies indicated that diabetics treated with metformin had a lower incidence of cancer than those taking other anti-diabetes drugs. This led to a surge in the efforts for identification of safer and more effective metformin mimetic compounds. The plant Ficus microcarpa is widely used for the treatment of type 2 diabetes in traditional medicine in South Asia. We obtained extracts from this plant and identified a small molecule, plectranthoic acid (PA), with potent 5′AMP-activated kinase (AMPK) activating properties far superior than metformin. AMPK is the central hub of metabolic regulation and a well-studied therapeutic target for metabolic syndrome, type-2 diabetes and cancer. We observed that treatment of prostate cancer (PCa) cells with PA inhibited proliferation and induced G0/G1 phase cell cycle arrest that was associated with up-regulation of cyclin kinase inhibitors p21/CIP1 and p27/KIP1. PA treatment suppressed mTOR/S6K signaling and induced apoptosis in PCa cells in an AMPK-dependent manner. Interestingly, PA-induced autophagy in PCa cells was found to be independent of AMPK activation. Combination studies of PA and metformin demonstrated that metformin had an inhibitory effect on PA-induced AMPK activation and suppressed PA-mediated apoptosis. Given the anti-proliferative role of PA in cancer and its potent anti-hyperglycemic activity, we suggest that PA should be explored further as a novel activator of AMPK for its ultimate use for the prevention of cancers and treatment of type 2 diabetes.
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