二甲双胍抗肿瘤与 K－ras 突变的相关性

近年来,越来越多的研究表明,二甲双胍除了作为一种常用的降糖药物,还具有抗肿瘤作用。二甲双胍抗肿瘤作用机制包括：激活 AMPK 途径,促使细胞周期停滞,降低循环中胰岛素和 IGFs,自噬抗肿瘤,抑制肿瘤新生血管生成,杀灭肿瘤干细胞等。然而,二甲双胍抗肿瘤与基因突变是否相关还尚未明确。有研究证实,二甲双胍通过诱导细胞凋亡和抑制体内肿瘤细胞增殖的途径,能够有效地抑制 K －ras 突变型肿瘤细胞的生长,但并不抑制 K －ras 野生型肿瘤细胞的生长。因此,我们推论二甲双胍可作为 K －ras 突变型肿瘤的一个潜在的靶向药物。     

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。     

二甲双胍抗肿瘤机制的研究进展

二甲双胍通过减少肝脏葡萄糖的合成及肠道葡萄糖的吸收达到降低糖尿病患者空腹及餐后血糖的目的，主要用于 肥胖型2型糖尿病。而近年来的研究发现，二甲双胍还可抑制肿瘤细胞的增殖、迁移和侵袭、抑制肿瘤血管生成、干扰肿瘤细 胞周期并诱导细胞凋亡、诱导细胞分化等发挥抗肿瘤作用。它主要通过单磷酸腺苷蛋白激酶（AMPK）依赖性和非AMPK依赖 性机制，其中二甲双胍激活AMPK的途径又分为直接途径和间接途径两种。两种机制可单独发挥作用也可交叉发挥作用，通 过影响肿瘤细胞和免疫细胞的信号转导通路和能量代谢，参与改善乏氧和免疫抑制的肿瘤免疫微环境，以及通过调节肠道菌 群改善机体代谢和免疫功能，发挥抗肿瘤作用，抑制肿瘤发生、发展，以达到治疗肿瘤的目的。目前已有若干临床试验采取不 同的治疗方式与二甲双胍联用，并取得了一定的成绩。现就二甲双胍对肿瘤细胞、肿瘤微环境、肠道菌群的影响及其抗肿瘤的 相关临床试验四个方面展开综述。     

二甲双胍的放疗增敏机制及临床应用前景分析

二甲双胍是2型糖尿病的基础用药。越来越多研究显示二甲双胍具有抗肿瘤作用,同时其放射增敏作用也逐渐被发现。二甲双胍可通过改善乏氧、增加活性氧、抑制DNA损伤修复、诱导细胞周期阻滞、调节免疫微环境等机制增加肿瘤细胞的放射敏感性。但近期公布的几项随机对照研究却未证实二甲双胍能增加放化疗疗效。本文梳理了二甲双胍的放疗增敏机制和临床结果,二甲双胍的剂量是未来开展基础和临床研究的重要考量因素。     

二甲双胍的放疗增敏机制及临床应用前景分析北大核心CSCD

二甲双胍是2型糖尿病的基础用药。越来越多研究显示二甲双胍具有抗肿瘤作用,同时其放射增敏作用也逐渐被发现。二甲双胍可通过改善乏氧、增加活性氧、抑制DNA损伤修复、诱导细胞周期阻滞、调节免疫微环境等机制增加肿瘤细胞的放射敏感性。但近期公布的几项随机对照研究却未证实二甲双胍能增加放化疗疗效。本文梳理了二甲双胍的放疗增敏机制和临床结果,二甲双胍的剂量是未来开展基础和临床研究的重要考量因素。     

二甲双胍的抗肿瘤作用

二甲双胍作为一种廉价安全高效的糖尿病药物已应用多年,近年来研究显示其对各种肿瘤细胞都有不同程度的抑制作用。二甲双胍的抗肿瘤机制尚未完全明确,可能与糖代谢及蛋白激酶途径有关,也可能与炎症因子介导肿瘤杀伤有关。二甲双胍对不同肿瘤细胞杀伤效果不同,对其他抗肿瘤治疗也有一些辅助作用。     

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。      

二甲双胍相关性自噬与肿瘤的关系

二甲双胍是最广泛使用的双胍类抗糖尿病药物,其通过需肝激酶B1的机制降低肝葡萄糖,该酶为控制体内代谢的要点,二甲双胍通过该机制引起蛋白合成减少、细胞增殖减慢,这激发了人们研究其在肿瘤细胞增殖、自噬和凋亡调控方面作用的兴致,其中二甲双胍相关性自噬在不同的肿瘤及其肿瘤细胞的不同时期,对肿瘤发生发展的影响并不相同。目前,已有大量的实验致力于二甲双胍能否作为抗肿瘤药物应用于临床,二甲双胍有望成为新一代抗肿瘤药物或辅助用药。     

Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma

The antidiabetic drug metformin exerts antineoplastic effects in many types of malignancies, however the effect of metformin on cholangiocarcinoma (CCA) still remains unclear. In the present study, we investigated that metformin treatment was closely associated with the clinicopathologic characteristics and improved postoperative survival of CCA patients. Metformin inhibited CCA tumor growth by cell cycle arrest in vitro and in vivo. We explored that the expression of six miRNAs (mir124, 182, 27b, let7b, 221 and 181a), which could directly target cell-cycle-regulatory genes, was altered by metformin in vitro and in vivo. These miRNAs were dysregulated in cholangiocarcinoma and promoted the CCA genesis and metformin exactly modulated these carcinogenic miRNAs expression to arrest the cell cycle and inhibit the proliferation. Meanwhile, these miRNAs expression changes correlated with the tumor volume and postoperative survival of CCA patients and could be used to predict the prognosis. Further we confirmed that metformin upregulated Drosha to modulate these miRNAs expression. Our results elucidated that metformin inhibited CCA tumor growth via the regulation of Drosha-mediated multiple carcinogenic miRNAs expression and comprehensive evaluation of these miRNAs expression could be more efficient to predict the prognosis. Moreover, metformin might be a quite promising strategy for CCA prevention and treatment.     

二甲双胍与多发性骨髓瘤的研究进展

多发性骨髓瘤(Multiple myeloma,MM)是原发于骨髓的恶性克隆性浆细胞疾病,主要表现为单克隆免疫球蛋白增殖异常,老年人群多发。MM的治疗新药层出不穷,但仍是不可治愈的疾病。因此,采取新的治疗方案对改善MM病人的预后显得尤为重要。近些年,关于二甲双胍的抗肿瘤作用成为热点,在各种基础研究中,二甲双胍已显示出显著的抗癌活性,并能增强其他药物的抗肿瘤作用。根据二甲双胍抗肿瘤机制及MM的发病机制,本文就二甲双胍可能通过LKB1-AMPK-Akt/mTOR通路、IGF受体途径、IL-6信号通路发挥抗MM作用,及二甲双胍与硼替佐米、马法兰、地塞米松等药物联合使用可能增强其治疗效果做一综述,为MM的治疗提供新思路。     

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。     

二甲双胍抗肿瘤及调控HIF-1α的作用

研究发现二甲双胍对多种恶性肿瘤的增殖均有显著抑制作用,提示二甲双胍的抗肿瘤作用.二甲双胍可减少肿瘤细胞氧的消耗,经转录及转录后机制抑制缺氧诱导因子-1α(HIF-1α)的聚集,通过激活腺苷酸活化蛋白激酶(AMPK)抑制HIF-1α的表达.     

Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells

Metformin has emerged as a potential anticancer agent. Here, we demonstrate that metformin plays an anti-tumor role via repressing N-cadherin, independent of AMPK, in wild-type N-cadherin cancer cells. Ectopic-expression of N-cadherin develops metformin-resistant cancer cells, while suppression of N-cadherin sensitizes cancer to metformin. Manipulation of AMPK expression does not alter sensitivity of cancer to metformin. We show that NF-kappaB is a downstream molecule of N-cadherin and metformin regulates NF-kappaB signaling via suppressing N-cadherin. Moreover, we also suggest that TWIST1 is an upstream molecule of N-cadherin/NF-kappaB signaling and manipulation of TWIST1 expression changes the sensitivity of cancer cells to metformin. In contrast to the cells that express N-cadherin, in N-cadherin deficient cells, metformin plays an anti-tumor role via activation of AMPK. Ectopic expression of N-cadherin makes cancer more resistant to metformin. Therefore, we suggest that metformin''s anti-cancer therapeutic effect is mediated through different molecular mechanism in wild-type vs. deficient N-cadherin cancer cells. At last, we selected 49 out of 984 patients’ samples with prostatic cancer after radical prostatectomy (selection criteria: Gleason score ≥ 7 and all patients taking metformin) and showed levels of N-cadherin, p65 and AMPK could predict post-surgical recurrence in prostate cancer after treatment of metformin.     

Therapeutic Potential of an Anti-diabetic Drug,Metformin:Alteration of miRNA expression in Prostate Cancer Cells

Background and Aims: Prostate cancer is the most commonly diagnosed cancer in males in many populations.Metformin is the most widely used anti-diabetic drug in the world, and there is increasing evidence of a potentialefficacy of this agent as an anti-cancer drug. Metformin inhibits the proliferation of a range of cancer cellsincluding prostate, colon, breast, ovarian, and glioma lines. MicroRNAs (miRNAs) are a class of small, noncoding,single-stranded RNAs that downregulate gene expression. We aimed to evaluate the effects of metformintreatment on changes in miRNA expression in PC-3 cells, and possible associations with biological behaviour.Materials and Methods: Average cell viability and cytotoxic effects of metformin were investigated at 24 hourintervals for three days using the xCELLigence system. The IC50 dose of metformin in the PC-3 cells was foundto be 5 mM. RNA samples were used for analysis using custom multi-species microarrays containing 1209probes covering 1221 human mature microRNAs present in miRBase 16.0 database. Results: Among the humanmiRNAs investigated by the arrays, 10 miRNAs were up-regulated and 12 miRNAs were down-regulated in themetformin-treated group as compared to the control group. In conclusion, expression changes in miRNAs ofmiR-146a, miR-100, miR-425, miR-193a-3p and, miR-106b in metformin-treated cells may be important. Thisstudy may emphasize a new role of metformin on the regulation of miRNAs in prostate cancer.     

Metformin impairs Rho GTPase signaling to induce apoptosis in neuroblastoma cells and inhibits growth of tumors in the xenograft mouse model of neuroblastoma

Metformin has been shown to inhibit tumor growth in xenograft rodent models of adult cancers, and various human clinical trials are in progress. However, the precise molecular mechanisms of metformin action are largely unknown. In the present study we examined the anti-tumor activity of metformin against neuroblastoma, and determined the underlying signaling mechanisms. Using human neuroblastoma xenograft mice, we demonstrated that oral administration of metformin (100 and 250 mg/kg body weight) significantly inhibited the growth of tumors. The interference of metformin in spheroid formation further confirmed the anti-tumor activity of metformin. In tumors, the activation of Rac1 (GTP-Rac1) and Cdc42 (GTP-Cdc42) was increased while RhoA activation (GTP-RhoA) was decreased by metformin. It also induced phosphorylation of JNK and inhibited the phosphorylation of ERK1/2 without affecting p38 MAP Kinase. Infection of cells by adenoviruses expressing dominant negative Rac1 (Rac1-N17), Cdc42 (Cdc42-N17) or constitutively active RhoA (RhoA-V14), or incubation of cells with pharmacological inhibitors of Rac1 (NSC23766) or Cdc42 (ML141) significantly protected neuroblastoma cells from metformin-induced apoptosis. Additionally, inhibition of JNK activity along with Rac1 or Cdc42 attenuated cytotoxic effects of metformin. These studies demonstrated that metformin impairs Rho GTPases signaling to induce apoptosis via JNK pathway.     

二甲双胍与乳腺癌关系的研究进展

糖尿病增加乳腺癌的发病风险, 并影响乳腺癌患者的预后。二甲双胍作为一种降糖药除了能降低血糖外, 尚有抑制多种癌症的作用, 并对乳腺癌有独特的作用, 体内和体外实验均被证实能抑制乳腺癌细胞, 甚至对表皮生长因子受体-2(HER-2)阳性且曲妥株单抗耐药的乳腺癌细胞、乳腺癌干细胞、三阴性乳腺癌细胞也能发挥抗肿瘤作用。二甲双胍尚能减低糖尿病患者的乳腺癌发病风险、降低乳腺癌组织学级别、增加雌激素受体(ER)及孕激素受体(PR)表达, 对乳腺癌新辅助化疗也有一定的作用。本文将从基础及临床研究方面阐明二甲双胍对乳腺癌的抑制机制。      

低糖增强肿瘤对二甲双胍的敏感度

目的 观察不同浓度葡萄糖对二甲双胍抗肿瘤作用的影响并探讨其作用机制。方法 在含不同浓度葡萄糖的培养基中加入二甲双胍培养细胞24 h后,检测细胞增殖情况及ATP水平。构建裸鼠皮下移植瘤,随机分成四组：正常饮食（SD）组、SD+二甲双胍（Met）组、生酮饮食（KD）组、KD+Met组,实验干预8周后,检测瘤体体积、重量以及裸鼠血糖水平。结果 培养基中葡萄糖水平≥10 mmol/L时,二甲双胍对胰腺癌细胞增殖抑制不明显,但在低糖培养基（≤5 mmol/L）中, 10mmol/L二甲双胍能明显抑制胰腺癌细胞增殖。同时,低糖培养基中各细胞ATP水平显著降低（P<0.01）。体内实验中,KD组血糖水平明显降低（P<0.01）,肿瘤生长受到显著抑制（P<0.01）。与KD组相比,KD+Met组可进一步抑制移植瘤生长（P<0.05）。结论 低糖增强肿瘤对二甲双胍的敏感度,其机制可能与减少机体ATP生成有关。     

Metformin inhibits salivary adenocarcinoma growth through cell cycle arrest and apoptosis

The inhibitory effects of metformin have been observed in many types of cancer. However, its effect on human salivary gland carcinoma is unknown. The effect of metformin alone or in combination with pp242 (an mTOR inhibitor) on salivary adenocarcinoma cells growth were determined in vitro and in vivo. We found that metformin suppressed HSY cell growth in vitro in a time and dose dependent manner associated with a reduced expression of MYC onco-protein, and the same inhibitory effect of metformin was also confirmed in HSG cells. In association with the reduction of MYC onco-protein, metformin significantly restored p53 tumor suppressor gene expression. The distinctive effects of metformin and PP242 on MYC reduction and P53 restoration suggested that metformin inhibited cell growth through a different pathway from PP242 in salivary carcinoma cells. Furthermore, the anti-tumor efficacy of metformin was confirmed in vivo as indicated by the increases of tumor necrosis and reduced proliferation in xenograft tumors from metformin treated group. For the first time, the inhibitory effect of metformin on human salivary gland tumor cells was documented. Moreover, metformin inhibitory effects were enhanced by mTOR inhibitor suggesting that metformin and mTOR inhibitor utilize distinctive signaling pathways to suppress salivary tumor growth.