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1.
二甲双胍不仅是最广泛使用的口服降糖药之一, 还表现出降血糖作用外的多种疗效, 如保护心脏作用、改善血脂作用及可能的抗癌作用。流行病学数据也显示服用二甲双胍的患者癌症发病率和死亡率均降低。随着研究的开展, 二甲双胍作为一种潜在辅助抗癌药物引起了广泛关注。围绕二甲双胍作用机制及疗效的临床试验在不同癌种中陆续开展, 随着更多临床试验的结果公布, 二甲双胍与化疗、放疗、分子靶向药物或免疫治疗等联合治疗的效果以及对治疗前后某些代谢分子的表达影响均获得验证, 为二甲双胍联合治疗癌症提供了更为明确的证据, 有助于促进二甲双胍作为辅助抗癌剂的临床应用。 相似文献
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Xiaowan Chen Chenli Li Tiantian He Jiating Mao Chunmei Li 《Cancer biology & therapy》2016,17(5):507-514
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. 相似文献
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Jun Gong Gauri Kelekar James Shen John Shen Sukhpreet Kaur Monica Mita 《Targeted oncology》2016,11(4):447-467
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, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 dia-betes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addi-tion, cutting-edge targeting of cancer stem cells by metformin is summarized. 相似文献
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Lack of Metformin Effects on Different Molecular Subtypes of Breast Cancer under Normoglycemic Conditions: An in vitro Study
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《Asian Pacific journal of cancer prevention》2014,15(5):2287-2290
Background: In the past few years, a considerable number of preclinical studies have been proposed metforminas a potential anticancer agent, but some of these studies suffer from a number of methodological limitationssuch as assessment of cytotoxicity in the presence of supraphysiological glucose concentrations or applyingsuprapharmacological levels of the drug. These objections have limited the translation of published preclinicaldata to the clinical setting. The present study aimed to investigate direct anticancer effects of metformin ondifferent molecular subtypes of breast cancer with pharmacological concentrations and under normoglycemicconditions in vitro. Materials and Methods: Breast cancer cell lines from luminal A, luminal B, ErbB2 andtriple-negative molecular subtypes were treated with a pharmacological concentration of metformin (2mM)at a glucose concentration of 5.5mM. Time-dependant cell viability was assessed by dye exclusion assay. MTTbasedcytotoxicity assays were also performed with metformin alone or in combination with paclitaxel. Results:Metformin did not show any growth inhibitory effects or time-dependant cytotoxicity on breast cancer cell linesin the presence of normal glucose concentrations at the therapeutic plasma level. No augmentation of the antineoplasticproperties of paclitaxel was apparent under the tested conditions. Conclusions: Metformin is probablyunable to exert cytotoxic or cytostatic effects on breast cancer subtypes at pharmacological concentrations andnormal plasma glucose levels. These results highlight the importance of establishing a higher steady-state plasmaconcentration of metformin in the clinical setting for assessment of anticancer effects i n normoglycemic patients. 相似文献
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Rongbin Ge Zongwei Wang Shulin Wu Yangjia Zhuo Aleksandar G. Otsetov Chao Cai Weide Zhong Chin-Lee Wu Aria F. Olumi 《Oncotarget》2015,6(30):28973-28987
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. 相似文献
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Mathilde Jalving Jourik A. Gietema Joop D. Lefrandt Steven de Jong Anna K.L. Reyners Rijk O.B. Gans Elisabeth G.E. de Vries 《European journal of cancer (Oxford, England : 1990)》2010,46(13):2369-2380
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. 相似文献
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《Current problems in cancer》2020,44(1):100488
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. 相似文献
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Metformin is an orally available, biguanide derivative that is widely used in the treatment of Type 2 diabetes. Recent preclinical data have demonstrated that it can also act as an anticancer agent by activation of AMPK and subsequent inhibition of mTOR. Metformin is currently being investigated in several Phase II/III clinical trials. This article will review the current evidence for its mechanism of action, efficacy in preclinical and clinical models, and toxicity. Ongoing and planned studies evaluating the impact of metformin on breast cancer outcomes are also discussed. 相似文献
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Ben Sahra I Regazzetti C Robert G Laurent K Le Marchand-Brustel Y Auberger P Tanti JF Giorgetti-Peraldi S Bost F 《Cancer research》2011,71(13):4366-4372
Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment. 相似文献
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Guangxia Chen Wan Feng Shu Zhang Kangqi Bian Yan Yang Cheng Fang Min Chen Jun Yang Xiaoping Zou 《American journal of cancer research》2015,5(4):1423-1434
Recent evidence suggests that anti-diabetic drug metformin prevents cancer progression, but the mechanism by which metformin inhibits tumor growth remains elusive. In this study, we investigated the anticancer role of metformin in gastric cancer and explored the underlying mechanism. The expression of hypoxia inducible factor 1α (HIF1α) and pyruvate kinase M2 (PKM2) in different stages of gastric cancer tissues was detected by immunohistochemistry. Gastric cancer cell viability was evaluated by CCK-8 assay; apoptosis and cell cycle were analyzed by flow cytometry. The expression of PI3K, Akt, HIF1α, PARP, PKM2 and COX in gastric cancer cells was detected by immunofluorescence and Western blot analysis. We found that HIF1α and PKM2 protein expression levels were higher in advanced gastric cancer tissues than in gastritis tissues. Metformin reduced gastric cancer cell viability, invasion and migration. Metformin induced apoptosis and cell cycle arrest in part through inhibiting PARP expression. Metformin downregulated PI3K, Akt, HIF1α, PARP, PKM2 and COX expression. Moreover, overexpression of HIF1α increased gastric cancer cell viability, invasion and migration. In summary, metformin has profound antitumor effect for gastric cancer by inducing intrinsic apoptosis via the inhibition of HIF1α/PKM2 signaling pathway. 相似文献
13.
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。 相似文献
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Henna HakimeePilaiwanwadee HutamekalinSupita TanasawetPennapa ChonpathompikunlertVaromyalin TipmaneeWanida Sukketsiri 《Asian Pacific journal of cancer prevention》2019,20(12):3539-3545
Background: Metformin, an antidiabetic drug, has been previously reported to have anti-cancer activities. However, its role in the control of cancer cell migration remains elusive. Methods: To examine the possible effect of metformin on migration of cervical cancer cells. The related mechanisms were further determined by immunocytochemistry and Western’s blotting assay. Results: The results showed that metformin treatment substantially inhibited the migration ability of cervical cancer cells. Consistently, the filopodia and lamellipodia formation were depleted after exposure to metformin. The suppression of migration mediated through the regulatory proteins such as focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (Akt), Rac1 and RhoA after metformin treatment. Conclusion: Metformin displays antimigration effects in cervical cancer cells by inhibiting filopodia and lamellipodia formation through the suppression of FAK, Akt and its downstream Rac1 and RhoA protein. We propose that metformin could be a novel potential candidate as an antimetastatic cancer drug in the cervical cancer management. 相似文献
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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。 相似文献
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Wen Yue Xi Zheng Yong Lin Chung S. Yang Qing Xu Darren Carpizo Huarong Huang Robert S. DiPaola Xiang-Lin Tan 《Oncotarget》2015,6(25):21208-21224
Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. 相似文献
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Hongnian Wu Dan Huang Hong Zhou Xueqin Sima Zhe Wu Yanling Sun Long Wang Ying Ruan Qian Wu Feng Wu Tonghui She Ying Chu Qizhi Huang Zhifeng Ning Hao Zhang 《Oncology Letters》2022,24(1)
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. 相似文献