Kalyanaraman Balaraman, Cheng Gang, Hardy Micael, Ouari Olivier, Sikora Adam, Zielonka Jacek, Dwinell Michael B
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
CNRS, Institut de Chimie Radicalaire (ICR), Aix-Marseille Univ, UMR 7273, Marseille, 13013, France.
Cell Biochem Biophys. 2017 Dec;75(3-4):311-317. doi: 10.1007/s12013-017-0796-3. Epub 2017 Apr 21.
Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells. Results indicate that the lead compound, mito-metformin, was nearly 1000-fold more potent than metformin in inhibiting mitochondrial complex I activity, inducing reactive oxygen species (superoxide and hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate kinase and inhibition of proliferation of pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in tumor regression in response to metformin and mito-metformins in the in vivo setting is discussed.
二甲双胍是世界上处方最广泛的抗糖尿病药物之一，目前正被重新用作癌症治疗的潜在药物。流行病学研究表明，二甲双胍对患有胰腺癌的糖尿病患者具有抗癌作用。然而，在典型的抗糖尿病剂量下，二甲双胍的生物利用度可能过低，无法发挥抗肿瘤作用。因此，需要更有效的二甲双胍类似物来提高其抗癌功效。为此，合成了一类新的含带正电荷亲脂性三苯基鏻基团的线粒体靶向二甲双胍类似物（或线粒体二甲双胍），并测试了它们对胰腺癌细胞的抗肿瘤功效。结果表明，先导化合物线粒体二甲双胍在抑制线粒体复合体I活性方面比二甲双胍强近1000倍，能诱导活性氧（超氧化物和过氧化氢），刺激氧化还原信号机制，包括激活单磷酸腺苷激酶和抑制胰腺癌细胞增殖。本文还讨论了低温电子顺磁共振技术在评估包括复合体I在内的线粒体复合体在体内环境中对二甲双胍和线粒体二甲双胍反应的肿瘤消退中的作用的潜在用途。
