title: The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells.
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.
authors.affiliation: Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.|Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad 45320, Pakistan.
authors.forename: Nosheen
authors.initials: N
authors.lastname: Akhtar
authors.affiliation: Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.affiliation: Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Vaqar M
authors.initials: VM
authors.lastname: Adhami
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Islamabad 45320, Pakistan.
authors.forename: Bushra
authors.initials: B
authors.lastname: Mirza
authors.affiliation: Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D030681:Ficus / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D056004:Molecular Dynamics Simulation; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011487:Protein Conformation; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D014315:Triterpenes; C000611866:plectranthoic acid; D055372:AMP-Activated Protein Kinases
keywords: 5′AMP-activated kinase (AMPK); plectranthoic acid; prostate cancer (PCa)