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。     

二甲双胍治疗乳腺癌的分子机制与临床研究进展

乳腺癌已成为严重影响妇女身心健康甚至危及生命的最常见的恶性肿瘤。糖尿病增加了乳腺癌的发病率,并对乳腺癌的预后产生重要的影响。二甲双胍作为Ⅱ型糖尿病一线的降糖药,不仅能够降低血糖,增强胰岛素的敏感性,还能够促进乳腺癌细胞的凋亡,降低乳腺癌患者死亡率。在体内体外的实验中均已证实二甲双胍能诱导细胞周期停滞,抑制乳腺癌细胞的增殖,促进其凋亡,甚至对ErbB2过度表达的乳腺癌细胞、乳腺癌干细胞、三阴性乳腺癌也能发挥抗肿瘤作用。二甲双胍还能预防线粒体功能障碍,下调丙酮酸激酶表达,抑制Ki-67表达,起到抑制乳腺癌细胞的作用。这对乳腺癌新辅助化疗及放射治疗起到一定的协同作用。因此,本文拟对二甲双胍治疗乳腺癌的分子机制与临床研究进行综述。     

二甲双胍对人肺腺癌A549细胞增殖和凋亡的调控

背景与目的:二甲双胍作为一种胰岛素增敏剂被用于Ⅱ型糖尿病的一线治疗。近来的临床研究发现二甲双胍可降低糖尿病患者的肿瘤发生率,提示它可能具有抗肿瘤的作用。本研究观察二甲双胍对人肺腺癌A549细胞增殖及凋亡的影响,并探讨其可能的机制。方法:二甲双胍干预人肺腺癌A549细胞48h后,采用MTT法检测其对细胞增殖的影响,流式细胞术检测细胞凋亡,实时PCR法检测p53、Bcl-2和Bax mRNA的转录情况。结果:经二甲双胍干预48h后,人肺腺癌A549细胞的增殖受到明显抑制,且该抑制作用呈药物浓度依赖性增加。当二甲双胍浓度为0.5、2和8mmol/L时对细胞生长的抑制率分别为(29±5)%、(68±3)%和(84.1±2.6)%。流式细胞术检测提示中、高浓度(2、8mmol/L)二甲双胍可促进A549细胞凋亡;其中,药物作用48h后,8mmol/L组细胞的早期凋亡率为(2.1±0.5)%,中、晚期凋亡率为(9±4)%,均显著高于对照组。二甲双胍干预后细胞凋亡相关基因p53、Bcl-2和BaxmRNA表达均上调,且Bcl-2/Bax比值下调。结论:二甲双胍能显著抑制人肺腺癌A549细胞增殖,促进细胞凋亡增加;其机制可能与上调细胞凋亡相关基因p53的表达及Bcl-2/Bax比值下降有关。     

二甲双胍与2型糖尿病患者结直肠肿瘤发病风险的Meta分析

目的 系统评价二甲双胍与2型糖尿病患者结直肠肿瘤(腺瘤和癌)发病风险之间的相关性。方法 计算机检索建库以来至2023年5月PubMed、Embase、Cochrane Library、ISI Web of Science、万方和中国知网等数据库,按照纳入和排除标准筛选所有关于2型糖尿病患者服用二甲双胍与结直肠肿瘤发病风险之间相关性的研究,进行Meta分析。结果 在评价文献质量的基础上共纳入了符合标准的17项研究,其中包括队列研究12项、病例对照研究5项。Meta分析结果显示：服用二甲双胍者较未服用二甲双胍者结直肠腺瘤发病风险降低38%(n=9,OR=0.62, 95%CI:0.54～0.70),结直肠癌发病风险降低了23%(n=7,OR=0.77, 95%CI:0.58～0.97)。结论 二甲双胍的使用可能降低2型糖尿病患者结直肠肿瘤的发病风险。     

二甲双胍与不同分子亚型乳腺癌的关系

二甲双胍做为糖尿病治疗的一线用药,不仅可以降低血糖,还能促使乳腺癌细胞凋亡。体内外实验证实了二甲双胍对各型乳腺癌的抑制作用,而且二甲双胍还能在新辅助化疗以及放疗中协同治疗乳腺癌。本文将对二甲双胍在乳腺癌治疗中的研究进展做一综述。     

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。     

二甲双胍与结直肠癌

二甲双胍是治疗2型糖尿病的一线用药,除发挥降糖作用外,还具有抑制结直肠癌等肿瘤细胞增殖的作用。近年来大量证据表明二甲双胍能降低结直肠癌等肿瘤的发病风险及死亡率,其机制主要包括激活单磷酸腺苷活化的蛋白激酶通路,干扰细胞周期,改善胰岛素抵抗,抑制炎症反应,杀伤结直肠癌干细胞等。     

降糖药物二甲双胍在癌症防治方面的新用途

二甲双胍是世界上应用最广范的抗糖尿病药物,而现在越来越多的证据证明这种药物具有潜在的抗癌功能。流行病学调查显示,使用二甲双胍治疗的糖尿病癌症患者发病率会降低。而且,二甲双胍能活化细胞能量感受器腺苷酸活化蛋白激酶(AMPK)途径,后者可以作为治疗癌症的最新靶点。最后,多项研究指出,二甲双胍能直接抑制癌细胞生长,具有抗肿瘤功能。     

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。     

Metformin: Taking away the candy for cancer?

Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin’s anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.     

Metformin increases survival in hormone receptor-positive,HER2-positive breast cancer patients with diabetes

Introduction

Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment.

Methods

Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status.

Results

In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P <0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95 % CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95 % CI, 1.88 to 15.28) on the hormone receptor-positive and HER2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for disease free survival 2.14; 95 % CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments.

Conclusion

Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients.     

二甲双胍在肿瘤治疗基础研究中的进展

二甲双胍是治疗2型糖尿病的一线药物。临床流行病学研究发现在2型糖尿病患者中, 相较于胰岛素及其他口服降糖药物治疗组, 二甲双胍治疗组的恶性肿瘤发病率和死亡率均显著降低。同时, 基础研究证实在体外培养细胞及体内动物模型中二甲双胍可抑制多种恶性肿瘤细胞的生长。其可能的机制为调节体内胰岛素/IGF-1轴间接抑制肿瘤生长; 直接作用于肿瘤细胞并抑制其生长。这些结果提示二甲双胍具有抗肿瘤的作用, 可能成为恶性肿瘤辅助治疗的新手段之一。      

Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes

Whether metformin therapy affects breast cancer risk in Asian patients with type 2 diabetes mellitus (T2DM) has not been investigated. The reimbursement databases of Taiwanese female patients with a new diagnosis of T2DM between 1998 and 2002 (n = 476,282) were retrieved from the National Health Insurance for follow-up of breast cancer until the end of 2009. Metformin was treated as a time-dependent variable; and of these patients, 285,087 were never-users and 191,195 were ever-users. A time-dependent approach was used to calculate breast cancer incidence and estimate hazard ratios by Cox regression for ever-users, never-users, and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). During follow-up, 2,412 (1.26 %) metformin ever-users and 9,322 (2.10 %) never-users developed breast cancer, representing an incidence of 201.08 and 535.88 per 100,000 person-years, respectively. The overall multivariable-adjusted hazard ratio (95 % confidence intervals) for ever- versus never-users was 0.630 (0.597–0.665). The multivariable-adjusted hazard ratios for the first, second, and third tertiles of cumulative duration of metformin therapy were 1.122 (1.043–1.207), 0.754 (0.692–0.820), and 0.280 (0.253–0.310), respectively, (P-trend <0.0001); and 1.099 (1.021–1.182), 0.664 (0.611–0.723), and 0.311 (0.281–0.344), respectively, (P-trend <0.0001), for cumulative dose of metformin. Metformin use is associated with a decreased risk of breast cancer.     

Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis

Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched.     

二甲双胍抗肿瘤作用机制的研究进展

二甲双胍作为Ⅱ型糖尿病患者的口服治疗药物已有50多年的历史。近年来多项研究发现并证实了二甲双胍在抗肿瘤方面的作用。研究发现二甲双胍能通过调控多种信号通路抑制肿瘤细胞的生长,为肿瘤治疗提供了新的思路。全文对近年来二甲双胍抗肿瘤的作用机制进行综述,希望能为肿瘤患者的治疗带来新的方向。     

Antidiabetic drug metformin induces apoptosis in human MCF breast cancer via targeting ERK signaling

Metformin is the most widely used antidiabetic drug for type II diabetes in the world. Recent studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. This observation led us to hypothesize that metformin might inhibit human breast cancer cells (MCF-7) growth. Here, we report that metformin induced apoptosis in human breast carcinoma cell lines MCF-7 cells via novel signaling pathway. Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2. Inhibitors of signaling proteins were used to study the mechanism(s) of metformin function. Receptor inhibitor studies indicated that p53 activation was mediated through insulin receptor (IR), not insulin-like growth factor-1 receptor (IGF-IR). Furthermore, MEK inhibitor significantly suppressed metformin-induced p53 and Bax elevation while ERK inhibitor generated a slight reduction in p53 levels. In contrast, PI3K inhibitor did not produce any effect on the metformin-elevated p53 levels. Finally, SAPK/JNK, known to be involved in apoptosis, was activated in cells treated with metformin and the activation appeared to occur downstream of ERK. All these results suggested that metformin activated p53, Bax, and induced tumor cell apoptosis through the ERK signaling pathway. This pathway has not been previously described for IR, p53, Bax activation, or apoptosis. Metformin, a novel inducer of apoptosis, and its analogs may offer a novel strategy for the treatment of cancer cells.     

Association between Metformin Therapy and Breast Cancer Incidence and Mortality: Evidence from a Meta-Analysis

Purpose

Metformin may be associated with a decreased risk of breast cancer. We performed a meta-analysis to assess the effect of metformin intake on breast cancer risk and mortality.

Methods

We performed a PubMed and EMbase search for all available studies that described the risk of breast cancer and all-cause mortality in relation to the use of metformin among patients with type 2 diabetes mellitus. Pooled relative risks (RRs) were determined using a random effects model to assess the strength of association between metformin and the risk of breast cancer.

Results

Fifteen articles from PubMed satisfied the inclusion criteria, including a total of 838,333 participants. Compared with the control group, metformin use was not related to a reduced incidence of breast cancer (RR, 0.964; 95% confidence interval [CI], 0.761-1.221; p=0.761). However, metformin therapy was associated with decreased all-cause mortality (RR, 0.652; 95% CI, 0.488-0.873; p=0.004). No obvious publication bias was detected (incidence: p_Begg=0.755, p_Egger=0.008; mortality: p_Begg=0.072, p_Egger=0.185).

Conclusion

The present study suggested that metformin therapy may decrease the all-cause mortality of patients affected by breast cancer. However, this finding should be considered carefully and confirmed with further studies.