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.

Protective effects of Fraxinus xanthoxyloides (Wall.) leaves against CCl4 induced hepatic toxicity in rat

“…Nummularic acid and plectranthoic acid are the triterpenoids, a class of phyto-chemicals. Use of plectranthoic acid during in vitro studies has 5'AMP-activated kinase (AMPK) activity that is considered to be a metabolic hub for the treatment of type-2 diabetes and cancer [55]. Further GC-MS analysis of the FXM indicated the presence of various compounds belonging to 15 major classes of which; three were terpenoids (26.61 %), four lactam (16.47 %), three esters (15.81 %), three phenols (8.37 %), two steroid (6.91 %), three alcohols (5.02 %), three ketones (4.49 %), one aldehyde (3.89 %), two fatty acid glycerol (3.01 %), one nitrile (2.64 %), two lactones (2.31 %), one silyl-ether (2.25 %), one alkene (1.31 %) and one alkyne (0.89 %) [35].…”

Targeting epithelial to mesenchymal transition in prostate cancer by a novel compound, plectranthoic acid, isolated from Ficus microcarpa

“…We isolated a pure compound from Ficus microcarpa , that is Plectranthoic acid (PA), and studied its antiproliferative activity against cancer cells. We previously reported that PA induced apoptosis and suppressed mTOR/S6K signaling in PCa cells, in an AMPK‐dependent manner . The aim of the current study was to evaluate the effect of PA on EMT program in PCa cells and gain an understanding of the underlying molecular mechanisms.…”

Ser‐486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration‐resistance in prostate cancer: A retrospective clinical study

“…In post-sprint muscle, high glycolytic rate, marked lactate accumulation, and hypoxia were associated with increased p-Ser-486/491 AMPKα1/α2 [8]; a similar environment can be found within the prostate tumor and is associated with metastasis and poor prognosis [9]. Chemical agents that activate AMPKα lead to death of prostate cancer cells [10, 11]. Elevated fatty acid and cholesterol biomarkers were identified in the serum of prostate cancer patients who progressed to castration-resistant prostate cancer (CRPC) within one year of endocrine therapy, compared to those who did not progress [12].…”