Barrios-Bernal Pedro, Zatarain-Barrón Zyanya Lucia, Hernández-Pedro Norma, Orozco-Morales Mario, Olivera-Ramírez Alejandra, Ávila-Moreno Federico, Colín-González Ana Laura, Cardona Andrés F, Rosell Rafael, Arrieta Oscar
Personalized Medicine Laboratory, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico.
Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico.
Pharmaceuticals (Basel). 2022 Jun 24;15(7):786. doi: 10.3390/ph15070786.
Metformin has been under basic and clinical study as an oncological repurposing pharmacological agent for several years, stemming from observational studies which consistently evidenced that subjects who were treated with metformin had a reduced risk for development of cancer throughout their lives, as well as improved survival outcomes when diagnosed with neoplastic diseases. As a result, several basic science studies have attempted to dissect the relationship between metformin's metabolic mechanism of action and antineoplastic cellular signaling pathways. Evidence in this regard was compelling enough that a myriad of randomized clinical trials was planned and conducted in order to establish the effect of metformin treatment for patients with diverse neoplasms, including lung cancer. As with most novel antineoplastic agents, early results from these studies have been mostly discouraging, though a recent analysis that incorporated body mass index may provide significant information regarding which patient subgroups might derive the most benefit from the addition of metformin to their anticancer treatment. Much in line with the current pipeline for anticancer agents, it appears that the benefit of metformin may be circumscribed to a specific patient subgroup. If so, addition of metformin to antineoplastic agents could prove one of the most cost-effective interventions proposed in the context of precision oncology. Currently published reviews mostly rely on a widely questioned mechanism of action by metformin, which fails to consider the differential effects of the drug in lean vs. obese subjects. In this review, we analyze the pre-clinical and clinical information available to date regarding the use of metformin in various subtypes of lung cancer and, further, we present evidence as to the differential metabolic effects of metformin in lean and obese subjects where, paradoxically, the obese subjects have reported more benefit with the addition of metformin treatment. The novel mechanisms of action described for this biguanide may explain the different results observed in clinical trials published in the last decade. Lastly, we present novel hypothesis regarding potential biomarkers to identify who might reap benefit from this intervention, including the role of prolyl hydroxylase domain 3 ( expression to modify metabolic phenotypes in malignant diseases.
多年来，二甲双胍一直作为一种具有肿瘤治疗新用途的药物进行基础和临床研究，这源于一些观察性研究，这些研究一致表明，接受二甲双胍治疗的受试者一生中患癌症的风险降低，并且在被诊断患有肿瘤疾病时生存结果也有所改善。因此，一些基础科学研究试图剖析二甲双胍的代谢作用机制与抗肿瘤细胞信号通路之间的关系。这方面的证据非常有说服力，以至于人们计划并开展了大量随机临床试验，以确定二甲双胍治疗对包括肺癌在内的各种肿瘤患者的效果。与大多数新型抗肿瘤药物一样，这些研究的早期结果大多令人沮丧，不过最近一项纳入体重指数的分析可能会提供重要信息，说明哪些患者亚组可能从在抗癌治疗中添加二甲双胍中获益最多。与目前的抗癌药物研发流程非常一致的是，二甲双胍的益处似乎仅限于特定的患者亚组。如果是这样，在抗肿瘤药物中添加二甲双胍可能被证明是精准肿瘤学背景下提出的最具成本效益的干预措施之一。目前发表的综述大多依赖于一种广受质疑的二甲双胍作用机制，该机制没有考虑到药物在瘦人与肥胖受试者中的不同作用。在本综述中，我们分析了迄今为止有关二甲双胍在各种肺癌亚型中应用的临床前和临床信息，此外，我们还提供了证据，证明二甲双胍在瘦人和肥胖受试者中的代谢作用存在差异，矛盾的是，肥胖受试者在添加二甲双胍治疗后报告的获益更多。这种双胍类药物所描述的新作用机制可能解释了过去十年发表的临床试验中观察到的不同结果。最后，我们提出了关于潜在生物标志物的新假设，以确定谁可能从这种干预中获益，包括脯氨酰羟化酶结构域3（PHD3）在改变恶性疾病代谢表型中的作用。
