The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells

// Nosheen Akhtar 1, 2 , Deeba N. Syed 1 , Mohammad Imran Khan 1 , Vaqar M. Adhami 1 , Bushra Mirza 2 , Hasan Mukhtar 1 1 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA 2 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad 45320, Pakistan Correspondence to: Bushra Mirza, e-mail: bushramirza@qau.edu.com Hasan Mukhtar, e-mail: hmukhtar@dermatology.wisc.edu Keywords: 5′AMP-activated kinase (AMPK), plectranthoic acid, prostate cancer (PCa) Received: September 15, 2015      Accepted: November 28, 2015      Published: December 16, 2015 ABSTRACT 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.