Metformin: multi-faceted protection against cancer.
Metformin: multi-faceted protection against cancer.
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DOI：
10.18632/oncotarget.387
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Menendez JA
中科院分区：
文献类型：
--
作者：
Del Barco S;Vazquez-Martin A;Cufí S;Oliveras-Ferraros C;Bosch-Barrera J;Joven J;Martin-Castillo B;Menendez JA
双胍二甲双胍是一种广泛用于治疗2型糖尿病的药物，可通过抑制引发癌变的转化和过度增殖过程来发挥癌症化学预防作用。癌细胞中的代谢物分子靶点（例如，mTOR、HER 2）类似于目前用于定向癌症治疗的那些。然而，二甲双胍是无毒的，可能是非常有用的，以提高治疗效果的机制为基础的和生物靶向药物。在这里，我们首先回顾了过去5年的流行病学、临床前和临床证据，这些证据表明二甲双胍是一种有前途的肿瘤治疗候选药物。其次，二甲双胍的直接（胰岛素非依赖性）和间接（胰岛素依赖性）机制的抗癌作用进行了讨论，二甲双胍靶向过程和肿瘤干细胞（CSC）的个体发生，包括上皮间充质转化（EMT）和microRNA调节的CSC去分化。最后，我们提出的初步证据表明，二甲双胍可以调节细胞衰老，对细胞永生化的先天保障。有两条主要的证据表明二甲双胍的主要靶点是肿瘤发生过程中的永生化步骤。首先，二甲双胍激活细胞内DNA损伤反应检查点。其次，二甲双胍减弱ATP生成糖酵解代谢型的抗衰老作用-瓦尔堡效应，这是CSC自我更新和增殖所必需的。如果二甲双胍治疗通过降低应激诱导衰老的阈值而呈现针对肿瘤发生的内在屏障，则二甲双胍治疗策略可能是癌症治疗干预的关键。目前和未来的临床试验将阐明二甲双胍是否有潜力作为目前癌症治疗的辅助药物用于预防和治疗。
The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
3.9
作者：
Anisimov, VN;Berstein, LM;Franceschi, C
通讯作者：
Franceschi, C
DOI：
10.1186/bcr2358
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Behbod F;Kittrell FS;LaMarca H;Edwards D;Kerbawy S;Heestand JC;Young E;Mukhopadhyay P;Yeh HW;Allred DC;Hu M;Polyak K;Rosen JM;Medina D
通讯作者：
Medina D
影响因子：
0.7
作者：
Anisimov, VN;Egormin, PA;Semenchenko, AV
通讯作者：
Semenchenko, AV