The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells.
The pentacyclic triterpenoid, plectranthoic acid, a novel activator of AMPK induces apoptotic death in prostate cancer cells.
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DOI：
10.18632/oncotarget.6625
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Mukhtar H
中科院分区：
文献类型：
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作者：
Akhtar N;Syed DN;Khan MI;Adhami VM;Mirza B;Mukhtar H
流行病学研究表明，二甲双胍治疗的糖尿病患者癌症发病率低于服用其他抗糖尿病药物的患者。这导致了鉴定更安全和更有效的二甲双胍模拟化合物的努力激增。植物Ficus microcarpa在南亚的传统医学中广泛用于治疗2型糖尿病。我们从这种植物中获得提取物，并鉴定出一种小分子，plectranthoic acid（PA），其有效的5′ AMP激活激酶（AMPK）激活特性远远上级二甲双胍。AMPK是代谢调节的中心枢纽，也是代谢综合征、2型糖尿病和癌症的充分研究的治疗靶点。我们观察到，PA治疗前列腺癌（PCa）细胞的增殖抑制和诱导G 0/G1期细胞周期阻滞，这与细胞周期蛋白激酶抑制剂p21/CIP 1和p27/KIP 1的上调。PA处理抑制mTOR/S6 K信号传导，并以AMPK依赖的方式诱导PCa细胞凋亡。有趣的是，PA诱导的自噬在PCa细胞被发现是独立的AMPK激活。PA和二甲双胍的联合研究表明，二甲双胍对PA诱导的AMPK活化具有抑制作用，并抑制PA介导的细胞凋亡。鉴于PA在癌症中的抗增殖作用及其有效的抗高血糖活性，我们建议应进一步探索PA作为AMPK的新型激活剂，以最终用于预防癌症和治疗2型糖尿病。
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.