二甲双胍在肿瘤免疫治疗中的进展和挑战

二甲双胍属于双胍类口服降糖药物,广泛应用于2型糖尿病的治疗。流行病学和临床研究表明,二甲双胍除了具有降血糖作用外,对肿瘤的预防、治疗和预后均有裨益。这使得二甲双胍可能成为癌症预防和治疗的候选药物。免疫检查点抑制剂(ICIs)已成为许多肿瘤的有效治疗手段。新近研究表明,二甲双胍用作ICIs辅助用药可以使某些肿瘤患者获益,这对研究新型免疫治疗模式,提高免疫治疗的疗效,以期取得更持久的生存获益意义重大。本文就二甲双胍改善免疫微环境的机制、二甲双胍辅助ICIs治疗的相关研究进展展开综述,并探讨联合用药的不良反应,以期指导临床用药。     

二甲双胍与肿瘤相关性的新观点与挑战

2型糖尿病（T2DM）是一种慢性疾病,在全球范围内迅速增长,它是各类癌症的重要风险因素。而二甲双胍是治疗T2DM最常用的处方药。通过流行病学和临床研究表明,使用二甲双胍可以降低T2DM患者的癌症风险,改善癌症患者的预后和生存率。此外,二甲双胍在癌症治疗中的临床试验正在扩大到非糖尿病人群。越来越多的研究者认为二甲双胍将会成为癌症预防和治疗的一个有吸引力的候选药物。在这里,我们总结了近年来二甲双胍在肿瘤预防与治疗中的流行病学证据与相关研究进展、二甲双胍的抗肿瘤机制,并探讨了提高二甲双胍对肿瘤的敏感性和预防肿瘤转移的可能性。     

二甲双胍在妇科肿瘤治疗中的研究进展

二甲双胍以其稳定的疗效、安全性及低廉的价格,多年来一直应用于糖尿病的临床治疗。近年来研究显示二甲双胍的应用可降低肿瘤的发病、复发及转移率,长期应用二甲双胍还可改善癌症患者预后,延长患者的生存时间。本文旨在总结二甲双胍在妇科肿瘤领域新近的研究成果,并探讨其对妇科肿瘤的防治作用和其分子机制。     

二甲双胍在乳腺癌中抗肿瘤作用研究进展

临床前研究表明降糖药二甲双胍对乳腺癌有抗肿瘤作用,能降低糖尿病患者乳腺癌发病风险和死亡风险,也能提高乳腺癌患者新辅助化疗后病理完全缓解率。体内外实验表明二甲双胍有效抑制各种乳腺癌细胞和移植瘤,并和化疗药物、HER2靶向药物、新型抗肿瘤药物有良好协同作用。主要分子机制包括全身性下调胰岛素及相关信号通路、肿瘤细胞内激活LKBl／AMPK、抑制下游mTOR通路等。目前各国开展了多个临床试验评估--sp双胍在乳腺癌防治中的应用价值。     

二甲双胍抗肿瘤机制研究进展

二甲双胍是目前Ⅱ型糖尿病的一线用药,主要通过抑制肝脏糖异生和胰岛素抵抗发挥降血糖作用。近年来随着对二甲双胍研究的深入,二甲双胍用于抗肿瘤治疗展现出了巨大的潜力。研究发现二甲双胍不仅能单独抑制肿瘤生长,能显著提升肿瘤放化疗和生物治疗等疗效。但目前关于二甲双胍发挥抗肿瘤作用的具体机制尚未达成共识。本文就近几年来二甲双胍在抗肿瘤领域的研究进展进行综述,主要从二甲双胍对肿瘤细胞的凋亡、自噬、上皮间质转化、肿瘤细胞代谢、联合用药等方面展开讨论,以期未来能够更深入和全面地理解二甲双胍的抗癌机制与临床应用范围,为临床肿瘤治疗提供新的思路。     

二甲双胍抑制肿瘤细胞转移的研究进展

二甲双胍以其稳定的有效性、安全性及低廉的价格,已成为治疗2型糖尿病的首选用药。研究显示二甲双胍的应用可降低肿瘤的发病、复发及转移率,长期应用二甲双胍也可改善癌症患者预后,并延长寿命。二甲双胍的多重优势,促进其成为治疗和预防癌症的新兴选择。因此,深入研究二甲双胍抑制肿瘤细胞转移的机制对抗肿瘤治疗具有一定的指导意义。      

二甲双胍辅助治疗合并2型糖尿病的恶性肿瘤患者的专家共识（2022年版）

恶性肿瘤是近年来慢性非传染性疾病死亡的主要原因,也是影响人类预期寿命的最重要原因,其治疗效果差,预后不良。二甲双胍为2型糖尿病首选的降糖药物,其抗肿瘤的作用得到越来越多同行的认可。然而,目前国内外缺乏独立的临床指南、共识及大型前瞻性临床试验。本共识旨在为二甲双胍在抗肿瘤方面的临床应用提供参考。对于大多数合并2型糖尿病的恶性肿瘤患者,推荐联合使用二甲双胍治疗,可以辅助抗肿瘤及增强化疗药物敏感性,降低多种恶性肿瘤的发病率、转移率,从而降低死亡率;对于少部分合并2型糖尿病的恶性肿瘤患者,不推荐也不反对使用二甲双胍,如雌激素受体（estrogen receptor,ER）阴性或三阴性乳腺癌;对于大部分不合并糖尿病的恶性肿瘤患者,不推荐使用二甲双胍,如肺癌、结直肠癌、前列腺癌等;而对于极少部分不合并糖尿病的恶性肿瘤患者,在充分知情同意的情况下,可使用二甲双胍。     

二甲双胍辅助化疗治疗对卵巢癌患者术后外周血相关因子水平的影响

目的探讨二甲双胍辅助化疗治疗对卵巢癌患者术后外周血D-二聚体、溶血磷脂酸(LPA)和白细胞介素-6 (IL-6)水平的影响。方法选取2017年1月至2018年6月间昆明医科大学附属肿瘤医院收治的100例卵巢癌术后患者,按照不同治疗方法分为顺铂组和联合组,每组50例。顺铂组患者采用顺铂联合紫杉醇(TC方案)化疗治疗,联合组患者采用二甲双胍辅助化疗方案治疗,比较两组患者的临床疗效和外周血D-二聚体、LPA及IL-6水平。结果顺铂组患者治疗有效率和控制率分别为28. 0%和68. 0%,联合组患者分别为46. 0%和80. 0%,联合组均高于顺铂组患者,差异均有统计学意义(均P <0. 05)。治疗后,联合组患者外周血D-二聚体、LPA和IL-6水平均优于顺铂组,差异均有统计学意义(均P <0. 05)。结论二甲双胍辅助顺铂对卵巢癌患者术后的预后作用积极,可提高临床疗效,改善外周血D-二聚体、LPA和IL-6水平,值得临床推行。     

二甲双胍抗肿瘤机制的研究进展

近年来,很多研究发现糖尿病能增加癌症的发生率和死亡率。目前,二甲双胍是临床治疗糖尿病的最常用药物之一。大量研究表明二甲双胍除具有降糖作用外,还有抑制肿瘤细胞生长的作用,因此可以降低2型糖尿病患者恶性肿瘤的发生率和死亡率。二甲双胍能激活腺苷活化蛋白激酶（AMPK）途径、阻滞细胞周期、调节胰岛素/IGF-1轴、调节肿瘤细胞的自噬效应、抑制肿瘤血管生成、激活体内免疫系统、增加化疗药物敏感性及杀伤肿瘤干细胞,从而杀灭肿瘤细胞,抑制肿瘤生长。二甲双胍具有安全、低毒的特性,将其应用于肿瘤的辅助治疗,可能会明显减轻化疗药物的毒副作用,提高患者的耐受性,并有望成为一种新型抗肿瘤药物。目前,二甲双胍的抗肿瘤机制仍处于实验及流行病学研究阶段,并未进入临床实验阶段,但其抗肿瘤作用是确切的。     

二甲双胍联合醋酸甲地孕酮治疗子宫内膜癌的效果及对患者肿瘤标志物的影响

目的 探讨二甲双胍联合醋酸甲地孕酮治疗子宫内膜癌的效果及对患者肿瘤标志物的影响.方法 依据治疗方式的不同将65例子宫内膜癌患者分为二甲双胍组(n=33,给予二甲双胍治疗)及联合治疗组(n=32,给予二甲双胍联合醋酸甲地孕酮治疗).比较两组患者的临床疗效、血清肿瘤标志物[结缔组织生长因子(CT-GF)、血管生成素-2(Ang-2)、糖类抗原(CA)125、血管内皮生长因子(VEGF)、CA19-9、基质金属蛋白酶9(MMP9)]水平和不良反应发生情况.结果 联合治疗组患者治疗总有效率为96.88％,明显高于二甲双胍组患者的84.85％(P<0.01).治疗后,两组患者CTGF、Ang-2、CA125、CA19-9、VEGF、MMP9水平均明显低于本组治疗前(P<0.01),且联合治疗组患者CTGF、Ang-2、CA125、CA19-9、VEGF、MMP9水平均明显低于二甲双胍组(P<0.01).联合治疗组患者不良反应总发生率为6.25％,低于二甲双胍组患者的27.27％(P<0.05).结论 二甲双胍联合醋酸甲地孕酮治疗子宫内膜癌效果显著,可降低肿瘤标志物水平和不良反应发生率.     

Metformin and cancer: new applications for an old drug

Metformin, one of most widely prescribed oral hypoglycemic agents, has recently received increased attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. Several potential mechanisms have been suggested for the ability of metformin to suppress cancer growth in vitro and vivo: (1) activation of LKB1/AMPK pathway, (2) induction of cell cycle arrest and/or apoptosis, (3) inhibition of protein synthesis, (4) reduction in circulating insulin levels, (5) inhibition of the unfolded protein response (UPR), (6) activation of the immune system, and (7) eradication of cancer stem cells. There is also a growing number of evidence, mostly in the form of retrospective clinical studies that suggest that metformin may be associated with a decreased risk of developing cancer and with a better response to chemotherapy. There are currently several ongoing randomized clinical trials that incorporate metformin as an adjuvant to classic chemotherapy and aim to evaluate its potential benefits in this setting. This review highlights basic aspects of the molecular biology of metformin and summarizes new advances in basic science as well as intriguing results from recent clinical studies.     

二甲双胍抑制膀胱癌相关分子机制的研究进展

二甲双胍应用于临床已有50多年的历史,是目前全球应用最广泛的口服降糖药之一。近年来,研究表明二甲双胍对膀胱癌有抑制作用,可以改善膀胱癌患者的预后。研究表明二甲双胍通过以下分子机制发挥抗癌作用:激活AMPK/mTOR信号通路;抑制STAT3信号通路;抑制c-FLIPL/TRAIL/Procaspase信号通路。另外,二甲双胍联合吉非替尼、吡柔比星、顺铂、维生素D3、帕比司他均可增强抑癌作用。     

Metformin: multi-faceted protection against cancer

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.     

Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic,oncogenic/tumorsuppresing and immunity context

Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin’s role in cancer immunity. Insight in these complex molecular networks, will simplify application of metformin in clinical trials and contribute to improvement of anti-cancer therapy.     

Type II Diabetes,Metformin Use,and Colorectal Neoplasia: Mechanisms of Action and Implications for Future Research

Type 2 diabetes mellitus has been associated with increased colorectal cancer incidence and mortality. Recently, metformin, a drug used widely for treatment of type 2 diabetes mellitus, has gained much attention because of its anticancer effect. Several observational and preclinical studies reported that metformin was associated with decreased risk of colorectal cancer and improved colorectal cancer survival. Although the exact mechanisms underlying the anticancer effect of metformin are not known, several mechanisms have been proposed, including AMP-activated protein kinase mediated inhibition of mammalian target of the rapamycin, decreasing insulin-like growth factor 1 levels, anti-inflammatory activity, cell cycle arrest, and cancer stem cell inhibition. In addition, in patients with colorectal cancer, metformin may have potential as a chemopreventive agent and adjuvant drug. Large-scale, well-designed, long-term, and randomized controlled trials are needed to confirm the potential benefit of metformin for both the diabetic population and the nondiabetic population.     

The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development

Metformin has been used for nearly a century to treat type 2 diabetes mellitus. Epidemiologic studies first identified the association between metformin and reduced risk of several cancers. The anticancer mechanisms of metformin involve both indirect or insulin-dependent pathways and direct or insulin-independent pathways. Preclinical studies have demonstrated metformin’s broad anticancer activity across a spectrum of malignancies. Prospective clinical trials involving metformin in the chemoprevention and treatment of cancer now number in the hundreds. We provide an update on the anticancer mechanisms of metformin and review the results thus far available from prospective clinical trials investigating metformin’s efficacy in cancer.

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Metformin in breast cancer: preclinical and clinical evidence

Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.     

Metformin: A promising drug for human cancers

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo, and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.