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。     

二甲双胍诱导自噬的研究进展

近年来,越来越多的学者证实二甲双胍具有多种抗肿瘤作用,如启动LKB1/ AMPK 通路、调控胰岛素/ IGF -1轴、上调或诱导microRNA 的表达、活化Caspase 分子、诱导细胞周期停止或凋亡,其中对于启动LKB1/ AMPK 通路的认识相对全面,AMPK 是机体重要的“能量感应器”,是mTOR 上游重要的抑制剂, mTOR 的抑制和对于自噬的诱导是必不可少的。这些信号联系提示二甲双胍在发挥抗肿瘤作用的同时,与自噬有着千丝万缕的联系;现在,自噬在肿瘤发生、发展中的重要作用也越来越多被重视;本文总结两者的信号交汇,叙述二甲双胍在抗肿瘤中的重要机制,以期为其今后作为抗肿瘤药物应用于临床带来帮助。     

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。     

二甲双胍在乳腺癌进展和治疗中作用及其机制的研究进展

随着乳腺癌患者生存期的延长,肿瘤耐药性成为治疗过程的严峻挑战之一,临床通常将细胞死亡标志物的增加作为预测乳腺肿瘤患者生存率提高的标准。通过刺激肿瘤细胞死亡途径来提高抗肿瘤药物治疗的效果,使用某些佐剂是一种可行的方法。研究表明,二甲双胍（Met）是治疗Ⅱ型糖尿病的一线药物,同时具有抗肿瘤特性,其能增强细胞死亡机制,尤其是促进肿瘤细胞自噬、凋亡和铁死亡。同时证明,Met对免疫系统的刺激作用在诱导肿瘤细胞死亡方面发挥作用,其诱导不同细胞死亡机制在增敏抗肿瘤药物治疗中起着关键作用。本文论述了Met对乳腺癌肿瘤微环境（TME）的调控作用机制及其在抗肿瘤药物治疗中的增敏作用,对Met在临床前和临床免疫治疗中的研究方向提出建议。     

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。      

二甲双胍抑制结直肠肿瘤的相关机制研究进展*

结直肠癌（colorectal cancer ,CRC ）是世界上发病率和死亡率均较高的恶性肿瘤,近年来我国结直肠癌发病率和死亡率有增长趋势。二甲双胍作为降糖药物,广泛应用于临床,其抗结直肠肿瘤的研究已广泛开展,作用机制主要与抑制mTOR 信号通路、抑制p53缺乏细胞癌变、抑制STAT3 作用、降低脂肪酸合成、抑制细胞周期、诱导细胞自噬及凋亡、减弱胰岛素和胰岛素受体作用、与化疗药物协同等有关。因此,二甲双胍作为抗肿瘤药物或辅助化疗药物仍需进一步深入研究,为其更好地应用于临床提供理论依据。本文就二甲双胍抗结直肠肿瘤的流行病学研究及相关机制进行综述。      

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。     

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells

Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit‐8 (CCK‐8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth‐suppressive effects on these cell lines via inhibition of p‐Akt activity and the Bcl‐2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.     

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)‐mediated oncogenesis. Unfortunately, a growing number of HPV‐positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well‐tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first‐line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well‐tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+???? ???and HPV‐negative (?) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV? HNSCC cell lines. The curcumin effects appear more pronounced in the HPV? cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.     

Metformin inhibits prostate cancer cell proliferation,migration, and tumor growth through upregulation of PEDF expression

Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose- and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.     

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.     

Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells,via inhibition of CLIC1-mediated ion current

Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown.Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity.The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin''s antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.     

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.     

Cation‐selective transporters are critical to the AMPK‐mediated antiproliferative effects of metformin in human breast cancer cells

The antidiabetic drug metformin exerts antineoplastic effects against breast cancer and other cancers. One mechanism by which metformin is believed to exert its anticancer effect involves activation of its intracellular target, adenosine monophosphate‐activated protein kinase (AMPK), which is also implicated in the antidiabetic effect of metformin. It is proposed that in cancer cells, AMPK activation leads to inhibition of the mammalian target of rapamycin (mTOR) and the downstream pS6K that regulates cell proliferation. Due to its hydrophilic and cationic nature, metformin requires cation‐selective transporters to enter cells and activate AMPK. This study demonstrates that expression levels of cation‐selective transporters correlate with the antiproliferative and antitumor efficacy of metformin in breast cancer. Metformin uptake and antiproliferative activity were compared between a cation‐selective transporter‐deficient human breast cancer cell line, BT‐20, and a BT‐20 cell line that was engineered to overexpress organic cation transporter 3 (OCT3), a representative of cation‐selective transporters and a predominant transporter in human breast tumors. Metformin uptake was minimal in BT‐20 cells, but increased by >13‐fold in OCT3‐BT20 cells, and its antiproliferative potency was >4‐fold in OCT3‐BT20 versus BT‐20 cells. This increase in antiproliferative activity was associated with greater AMPK phosphorylation and decreased pS6K phosphorylation in OCT3‐BT20 cells. In vitro data were corroborated by in vivo observations of significantly greater antitumor efficacy of metformin in xenograft mice bearing OCT3‐overexpressing tumors versus low transporter‐expressing wildtype tumors. Collectively, these findings establish a clear relationship between cation‐selective transporter expression, the AMPK‐mTOR‐pS6K signaling cascade, and the antiproliferative activity of metformin in breast cancer.