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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme

Author(s): Mehdi Sanati, Samaneh Aminyavari, Hamid Mollazadeh, Ali Motamed-Sanaye, Bahram Bibak, Elmira Mohtashami, Yong Teng, Amir R. Afshari* and Amirhossein Sahebkar*

Volume 30, Issue 7, 2023

Published on: 19 September, 2022

Page: [857 - 877] Pages: 21

DOI: 10.2174/0929867329666220707103525

Price: $65


In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.

Keywords: Glioblastoma multiforme, metformin, anticancer, AMPK, proliferation, cancer.

Sanati, M.; Aminyavari, S.; Afshari, A.R.; Sahebkar, A. Mechanistic insight into the role of metformin in Alzheimer’s disease. Life Sci., 2022, 291, 120299.
[] [PMID: 34999113]
Vieira, I.H.; Barros, L.M.; Baptista, C.F.; Rodrigues, D.M.; Paiva, I.M. Recommendations for practical use of metformin, a central pharmacological therapy in type 2 diabetes. Clin. Diabetes, 2022, 40(1), 97-107.
[] [PMID: 35221479]
Agius, L.; Ford, B.E.; Chachra, S.S. The metformin mechanism on gluconeogenesis and AMPK activation: the metabolite perspective. Int. J. Mol. Sci., 2020, 21(9), 3240.
[] [PMID: 32375255]
Chaudhari, K.; Reynolds, C.D.; Yang, S-H. Metformin and cognition from the perspectives of sex, age, and disease. Geroscience, 2020, 42(1), 97-116.
[] [PMID: 31897861]
Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia, 2017, 60(9), 1577-1585.
[] [PMID: 28776086]
Łabuzek, K.; Suchy, D.; Gabryel, B.; Bielecka, A.; Liber, S.; Okopień, B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep., 2010, 62(5), 956-965.
[] [PMID: 21098880]
Lutz, T.A.; Estermann, A.; Haag, S.; Scharrer, E. Depolarization of the liver cell membrane by metformin. Biochim. Biophys. Acta Biomembr., 2001, 1513(2), 176-184.
Tucker, G.T.; Casey, C.; Phillips, P.J.; Connor, H.; Ward, J.D.; Woods, H.F. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br. J. Clin. Pharmacol., 1981, 12(2), 235-246.
[] [PMID: 7306436]
Wang, Z.; Wang, N.; Liu, P.; Xie, X. AMPK and cancer. Exp. Suppl., 2016, 203-226.
Singh-Makkar, S.; Pandav, K.; Hathaway, D., III; Paul, T.; Youssef, P. Multidimensional mechanisms of metformin in cancer treatment. Tumori J., 2021, 2021, 03008916211023548.
Dowling, R.J.; Niraula, S.; Stambolic, V.; Goodwin, P.J. Metformin in cancer: Translational challenges. J. Mol. Endocrinol., 2012, 48(3), R31-R43.
[] [PMID: 22355097]
Algire, C.; Amrein, L.; Zakikhani, M.; Panasci, L.; Pollak, M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr. Relat. Cancer, 2010, 17(2), 351-360.
[] [PMID: 20228137]
Colquhoun, A.J.; Venier, N.A.; Vandersluis, A.D.; Besla, R.; Sugar, L.M.; Kiss, A.; Fleshner, N.E.; Pollak, M.; Klotz, L.H.; Venkateswaran, V. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis., 2012, 15(4), 346-352.
[] [PMID: 22614062]
Li, L.; Han, R.; Xiao, H.; Lin, C.; Wang, Y.; Liu, H.; Li, K.; Chen, H.; Sun, F.; Yang, Z.; Jiang, J.; He, Y. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin. Cancer Res., 2014, 20(10), 2714-2726.
[] [PMID: 24644001]
Niehr, F.; von Euw, E.; Attar, N.; Guo, D.; Matsunaga, D.; Sazegar, H.; Ng, C.; Glaspy, J.A.; Recio, J.A.; Lo, R.S.; Mischel, P.S.; Comin-Anduix, B.; Ribas, A. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J. Transl. Med., 2011, 9(1), 76.
[] [PMID: 21609436]
Xu, Y.; Lu, S. Metformin inhibits esophagus cancer proliferation through upregulation of USP7. Cell. Physiol. Biochem., 2013, 32(5), 1178-1186.
[] [PMID: 24335168]
Han, G.; Gong, H.; Wang, Y.; Guo, S.; Liu, K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol. Ther., 2015, 16(1), 77-87.
[] [PMID: 25456211]
Zi, F-M.; He, J-S.; Li, Y.; Wu, C.; Yang, L.; Yang, Y.; Wang, L.J.; He, D.H.; Zhao, Y.; Wu, W.J.; Zheng, G.F.; Han, X.Y.; Huang, H.; Yi, Q.; Cai, Z. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett., 2015, 356(2 Pt B), 443-453.
[] [PMID: 25305450]
Zhao, D.; Long, X.D.; Lu, T.F.; Wang, T.; Zhang, W.W.; Liu, Y.X.; Cui, X.L.; Dai, H.J.; Xue, F.; Xia, Q. Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma. Int. J. Cancer, 2015, 136(11), 2556-2565.
[] [PMID: 25370454]
Lengyel, E.; Litchfield, L.M.; Mitra, A.K.; Nieman, K.M.; Mukherjee, A.; Zhang, Y. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am. J. Obstetr. Gynecol., 2015, 212(4), 479.
Uehara, T.; Mitsuhashi, A.; Tsuruoka, N.; Shozu, M. Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro. Oncol. Rep., 2015, 33(2), 744-750.
[] [PMID: 25421433]
Nangia-Makker, P.; Yu, Y.; Vasudevan, A.; Farhana, L.; Rajendra, S.G.; Levi, E.; Majumdar, A.P. Metformin: A potential therapeutic agent for recurrent colon cancer. PLoS One, 2014, 9(1), e84369.
[] [PMID: 24465408]
Barrière, G; Tartary, M; Rigaud, M. Metformin: A rising star to fight the epithelial mesenchymal transition in oncology. Anti-Cancer Agents Med. Chem., 2013, 13(2), 333-40.
Afshari, A.R.; Mollazadeh, H.; Mohtashami, E.; Soltani, A.; Soukhtanloo, M.; Hosseini, A.; Jalili-Nik, M.; Vahedi, M.M.; Roshan, M.K.; Sahebkar, A. Protective role of natural products in glioblastoma multiforme: A focus on nitric oxide pathway. Curr. Med. Chem., 2021, 28(2), 377-400.
[] [PMID: 32000638]
Jalili-Nik, M.; Sabri, H.; Zamiri, E.; Soukhtanloo, M.; Roshan, M.K.; Hosseini, A.; Mollazadeh, H.; Vahedi, M.M.; Afshari, A.R.; Mousavi, S.H. Cytotoxic effects of Ferula latisecta on human glioma U87 cells. Drug Res. (Stuttg.), 2019, 69(12), 665-670.
[] [PMID: 31499542]
Mohtashami, E.; Shafaei-Bajestani, N.; Mollazadeh, H.; Mousavi, S.H.; Jalili-Nik, M.; Sahebkar, A.; Afshari, A.R. The current state of potential therapeutic modalities for glioblastoma multiforme: A clinical review. Curr. Drug Metab., 2020, 21(8), 564-578.
[] [PMID: 32664839]
Mollazadeh, H.; Mohtashami, E.; Mousavi, S.H.; Soukhtanloo, M.; Vahedi, M.M.; Hosseini, A.; Afshari, A.R.; Sahebkar, A. Deciphering the role of glutamate signaling in glioblastoma multiforme: Current therapeutic modalities and future directions. Curr. Pharm. Des., 2020, 26(37), 4777-4788.
[] [PMID: 32493186]
Maghrouni, A.; Givari, M.; Jalili-Nik, M.; Mollazadeh, H.; Bibak, B.; Sadeghi, M.M.; Afshari, A.R.; Johnston, T.P.; Sahebkar, A. Targeting the PD-1/PD-L1 pathway in glioblastoma multiforme: Preclinical evidence and clinical interventions. Int. Immunopharmacol., 2021, 93, 107403.
[] [PMID: 33581502]
Jalili-Nik, M.; Afshari, A.R.; Sabri, H.; Bibak, B.; Mollazadeh, H.; Sahebkar, A. Zerumbone, a ginger sesquiterpene, inhibits migration, invasion, and metastatic behavior of human malignant glioblastoma multiforme in vitro. Biofactors, 2021, 47(5), 729-739.
[] [PMID: 34046952]
Somasuntharam, I.; Yehl, K.; Carroll, S.L.; Maxwell, J.T.; Martinez, M.D.; Che, P-L.; Brown, M.E.; Salaita, K.; Davis, M.E. Knockdown of TNF-α by DNAzyme gold nanoparticles as an anti-inflammatory therapy for myocardial infarction. Biomaterials, 2016, 83, 12-22.
[] [PMID: 26773660]
Ucbek, A.; Ozünal, Z.G.; Uzun, O.; Gepdıremen, A. Effect of metformin on the human T98G glioblastoma multiforme cell line. Exp. Ther. Med., 2014, 7(5), 1285-1290.
[] [PMID: 24940426]
Afshari, A.R.; Jalili-Nik, M.; Abbasinezhad-Moud, F.; Javid, H.; Karimi, M.; Mollazadeh, H.; Jamialahmadi, T.; Sathyapalan, T.; Sahebkar, A. Anti-tumor effects of curcuminoids in glioblastoma multiforme: An updated literature review. Curr. Med. Chem., 2021, 28(39), 8116-8138.
[] [PMID: 33176632]
Afshari, A.R.; Mollazadeh, H.; Henney, N.C.; Jamialahmad, T.; Sahebkar, A. Effects of statins on brain tumors: A review. Semin. Cancer Biol., 2021, 73, 116-133.
[] [PMID: 32814114]
Afshari, A.R.; Sanati, M.; Aminyavari, S.; Shakeri, F.; Bibak, B.; Keshavarzi, Z.; Soukhtanloo, M.; Jalili-Nik, M.; Sadeghi, M.M.; Mollazadeh, H.; Johnston, T.P.; Sahebkar, A. Advantages and drawbacks of dexamethasone in glioblastoma multiforme. Crit. Rev. Oncol. Hematol., 2022, 172, 103625.
[] [PMID: 35158070]
Liu, Y-J.; Chern, Y. AMPK-mediated regulation of neuronal metabolism and function in brain diseases. J. Neurogenet., 2015, 29(2-3), 50-58.
[] [PMID: 26119401]
Hashimoto, T.; Urushihara, Y.; Murata, Y.; Fujishima, Y.; Hosoi, Y. AMPK increases expression of ATM through transcriptional factor Sp1 and induces radioresistance under severe hypoxia in glioblastoma cell lines. Biochem. Biophys. Res. Commun., 2022, 590, 82-88.
[] [PMID: 34973534]
Lin, Y-C.; Hung, C-M.; Tsai, J-C.; Lee, J-C.; Chen, Y-L.S.; Wei, C-W.; Kao, J.Y.; Way, T.D. Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK). J. Agric. Food Chem., 2010, 58(17), 9511-9517.
[] [PMID: 20698539]
Würth, R.; Pattarozzi, A.; Gatti, M.; Bajetto, A.; Corsaro, A.; Parodi, A.; Sirito, R.; Massollo, M.; Marini, C.; Zona, G.; Fenoglio, D.; Sambuceti, G.; Filaci, G.; Daga, A.; Barbieri, F.; Florio, T. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle, 2013, 12(1), 145-156.
[] [PMID: 23255107]
Sesen, J.; Dahan, P.; Scotland, S.J.; Saland, E.; Dang, V-T.; Lemarié, A.; Tyler, B.M.; Brem, H.; Toulas, C.; Cohen-Jonathan Moyal, E.; Sarry, J.E.; Skuli, N. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One, 2015, 10(4), e0123721.
[] [PMID: 25867026]
Al Hassan, M.; Fakhoury, I.; El Masri, Z.; Ghazale, N.; Dennaoui, R.; El Atat, O. Metformin treatment inhibits motility and invasion of glioblastoma cancer cells. Anal. Cell. Pathol., 2018, 2018, 5917470.
Seliger, C.; Luber, C.; Gerken, M.; Schaertl, J.; Proescholdt, M.; Riemenschneider, M.J.; Meier, C.R.; Bogdahn, U.; Leitzmann, M.F.; Klinkhammer-Schalke, M.; Hau, P. Use of metformin and survival of patients with high-grade glioma. Int. J. Cancer, 2019, 144(2), 273-280.
[] [PMID: 30091464]
Rattan, R; Fehmi, R.A.; Munkarah, A. Metformin: An emerging new therapeutic option for targeting cancer stem cells and metastasis. J. Oncol., 2012, 2012, 928127.
Lei, Y.; Yi, Y.; Liu, Y.; Liu, X.; Keller, E.T.; Qian, C-N.; Zhang, J.; Lu, Y. Metformin targets multiple signaling pathways in cancer. Chin. J. Cancer, 2017, 36(1), 17.
[] [PMID: 28126011]
Leclerc, G.M.; Leclerc, G.J.; Kuznetsov, J.N.; DeSalvo, J.; Barredo, J.C. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One, 2013, 8(8), e74420.
[] [PMID: 24009772]
Yang, X.; Kord-Varkaneh, H.; Talaei, S.; Clark, C.C.T.; Zanghelini, F.; Tan, S.C.; Zarezadeh, M.; Mousavi, S.M.; Rahmani, J.; Zhang, Y. The influence of metformin on IGF-1 levels in humans: A systematic review and meta-analysis. Pharmacol. Res., 2020, 151, 104588.
[] [PMID: 31816435]
Zhao, Y.; Sun, H.; Feng, M.; Zhao, J.; Zhao, X.; Wan, Q.; Cai, D. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol. Endocrinol., 2018, 34(5), 428-432.
[] [PMID: 29182407]
Kim, H.G.; Hien, T.T.; Han, E.H.; Hwang, Y.P.; Choi, J.H.; Kang, K.W.; Kwon, K.I.; Kim, B.H.; Kim, S.K.; Song, G.Y.; Jeong, T.C.; Jeong, H.G. Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation. Br. J. Pharmacol., 2011, 162(5), 1096-1108.
[] [PMID: 21054339]
Wang, J.; Li, G.; Wang, Y.; Tang, S.; Sun, X.; Feng, X.; Li, Y.; Bao, G.; Li, P.; Mao, X.; Wang, M.; Liu, P. Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis. Oncotarget, 2015, 6(42), 44579-44592.
[] [PMID: 26625311]
Xu, J-N.; Zeng, C.; Zhou, Y.; Peng, C.; Zhou, Y-F.; Xue, Q. Metformin inhibits StAR expression in human endometriotic stromal cells via AMPK-mediated disruption of CREB-CRTC2 complex formation. J. Clin. Endocrinol. Metab., 2014, 99(8), 2795-2803.
[] [PMID: 24823468]
Tseng, S-C.; Huang, Y-C.; Chen, H-J.; Chiu, H-C.; Huang, Y-J.; Wo, T-Y.; Weng, S.H.; Lin, Y.W. Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem. Pharmacol., 2013, 85(4), 583-594.
[] [PMID: 23228696]
Faubert, B.; Vincent, E.E.; Poffenberger, M.C.; Jones, R.G. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett., 2015, 356(2 Pt A), 165-170.
[] [PMID: 24486219]
Shaw, R.J.; Lamia, K.A.; Vasquez, D.; Koo, S-H.; Bardeesy, N.; Depinho, R.A.; Montminy, M.; Cantley, L.C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005, 310(5754), 1642-1646.
[] [PMID: 16308421]
Hardie, D.G. AMP-activated/SNF1 protein kinases: Conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol., 2007, 8(10), 774-785.
[] [PMID: 17712357]
Barbato, D.L.; Vegliante, R.; Desideri, E.; Ciriolo, M.R. Managing lipid metabolism in proliferating cells: New perspective for metformin usage in cancer therapy. Biochim. Biophys. Acta, 2014, 1845(2), 317-324.
Jia, Y.; Ma, Z.; Liu, X.; Zhou, W.; He, S.; Xu, X.; Ren, G.; Xu, G.; Tian, K. Metformin prevents DMH-induced colorectal cancer in diabetic rats by reversing the warburg effect. Cancer Med., 2015, 4(11), 1730-1741.
[] [PMID: 26376762]
Zhang, Y.; Li, M-X.; Wang, H.; Zeng, Z.; Li, X-M. Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R. Asian Pac. J. Cancer Prev., 2015, 16(1), 221-225.
[] [PMID: 25640355]
Viollet, B.; Guigas, B.; Sanz Garcia, N.; Leclerc, J.; Foretz, M.; Andreelli, F. Cellular and molecular mechanisms of metformin: An overview. Clin. Sci. (Lond.), 2012, 122(6), 253-270.
[] [PMID: 22117616]
Fendt, S-M.; Bell, E.L.; Keibler, M.A.; Davidson, S.M.; Wirth, G.J.; Fiske, B.; Mayers, J.R.; Schwab, M.; Bellinger, G.; Csibi, A.; Patnaik, A.; Blouin, M.J.; Cantley, L.C.; Guarente, L.; Blenis, J.; Pollak, M.N.; Olumi, A.F.; Vander Heiden, M.G.; Stephanopoulos, G. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res., 2013, 73(14), 4429-4438.
[] [PMID: 23687346]
Marini, C.; Salani, B.; Massollo, M.; Amaro, A.; Esposito, A.I.; Orengo, A.M.; Capitanio, S.; Emionite, L.; Riondato, M.; Bottoni, G.; Massara, C.; Boccardo, S.; Fabbi, M.; Campi, C.; Ravera, S.; Angelini, G.; Morbelli, S.; Cilli, M.; Cordera, R.; Truini, M.; Maggi, D.; Pfeffer, U.; Sambuceti, G. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle, 2013, 12(22), 3490-3499.
[] [PMID: 24240433]
Dowling, R.J.; Zakikhani, M.; Fantus, I.G.; Pollak, M.; Sonenberg, N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res., 2007, 67(22), 10804-10812.
[] [PMID: 18006825]
Hsu, I.R.; Kim, S.P.; Kabir, M.; Bergman, R.N. Metabolic syndrome, hyperinsulinemia, and cancer. Am. J. Clin. Nutr., 2007, 86(3), s867-s871.
[] [PMID: 18265480]
Lopez, T.; Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell, 2002, 1(4), 339-353.
[] [PMID: 12086849]
Saxton, R.A.; Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6), 960-976.
[] [PMID: 28283069]
Fürstenberger, G.; Senn, H-J. Insulin-like growth factors and cancer. Lancet Oncol., 2002, 3(5), 298-302.
[] [PMID: 12067807]
Memmott, R.M.; Mercado, J.R.; Maier, C.R.; Kawabata, S.; Fox, S.D.; Dennis, P.A. Metformin prevents tobacco carcinogen induced lung tumorigenesis. Cancer Prev. Res. (Phila.), 2010, 3(9), 1066-1076.
[] [PMID: 20810672]
Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer, 2008, 8(12), 915-928.
[] [PMID: 19029956]
Xue, L.; Chen, F.; Yue, F.; Camacho, L.; Kothapalli, S.; Wei, G.; Huang, S.; Mo, Q.; Ma, F.; Li, Y.; Jiralerspong, S. Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer. Breast Cancer Res. Treat., 2021, 185(1), 73-84.
[] [PMID: 32940848]
Malaguarnera, R.; Sacco, A.; Morcavallo, A.; Squatrito, S.; Migliaccio, A.; Morrione, A.; Maggiolini, M.; Belfiore, A. Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling. Endocrinology, 2014, 155(4), 1207-1221.
[] [PMID: 24437490]
Conciatori, F.; Ciuffreda, L.; Bazzichetto, C.; Falcone, I.; Pilotto, S.; Bria, E.; Cognetti, F.; Milella, M. mTOR cross-talk in cancer and potential for combination therapy. Cancers (Basel), 2018, 10(1), 23.
[] [PMID: 29351204]
Shi, W.; Xiao, D.; Wang, L.; Dong, L.; Yan, Z.; Shen, Z. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis., 2012, 3(3), e275.
Mohammed, A.; Janakiram, N.B.; Brewer, M.; Ritchie, R.L.; Marya, A.; Lightfoot, S.; Steele, V.E.; Rao, C.V. Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl. Oncol., 2013, 6(6), 649-659.
[] [PMID: 24466367]
Han, B.; Cui, H.; Kang, L.; Zhang, X.; Jin, Z.; Lu, L.; Fan, Z. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumour Biol., 2015, 36(8), 6295-6304.
[] [PMID: 25854169]
Inoki, K.; Zhu, T.; Guan, K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell, 2003, 115(5), 577-590.
[] [PMID: 14651849]
Zakikhani, M.; Blouin, M-J.; Piura, E.; Pollak, M.N. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res. Treat., 2010, 123(1), 271-279.
[] [PMID: 20135346]
Ning, J.; Clemmons, D.R. AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol. Endocrinol., 2010, 24(6), 1218-1229.
[] [PMID: 20363874]
Karnevi, E.; Said, K.; Andersson, R.; Rosendahl, A.H. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer, 2013, 13(1), 235.
[] [PMID: 23663483]
Rozengurt, E.; Sinnett-Smith, J.; Kisfalvi, K. Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: A novel target for the antidiabetic drug metformin in pancreatic cancer. Clin. Cancer Res., 2010, 16(9), 2505-2511.
[] [PMID: 20388847]
Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell, 2008, 30(2), 214-226.
[] [PMID: 18439900]
Vakana, E.; Altman, J.K.; Glaser, H.; Donato, N.J.; Platanias, L.C. Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood, 2011, 118(24), 6399-6402.
[] [PMID: 22021366]
Malumbres, M. Cyclin-dependent kinases. Genome Biol., 2014, 15(6), 122.
[] [PMID: 25180339]
Jones, R.G.; Plas, D.R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M.J.; Thompson, C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 2005, 18(3), 283-293.
[] [PMID: 15866171]
Feng, Z.; Zhang, H.; Levine, A.J.; Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA, 2005, 102(23), 8204-8209.
[] [PMID: 15928081]
Kalender, A.; Selvaraj, A.; Kim, S.Y.; Gulati, P.; Brûlé, S.; Viollet, B.; Kemp, B.E.; Bardeesy, N.; Dennis, P.; Schlager, J.J.; Marette, A.; Kozma, S.C.; Thomas, G. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab., 2010, 11(5), 390-401.
[] [PMID: 20444419]
Yuan, J.; Dong, X.; Yap, J.; Hu, J. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J. Hematol. Oncol., 2020, 13(1), 113.
[] [PMID: 32807225]
Hwang, Y.P.; Jeong, H.G. Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase-9 activation through a calcium and protein kinase Calpha-dependent pathway: Phorbol-12-myristate-13-acetate-induced/extracellular signal-regulated kinase/activator protein-1. Br. J. Pharmacol., 2010, 160(5), 1195-1211.
[] [PMID: 20590612]
Alimova, I.N.; Liu, B.; Fan, Z.; Edgerton, S.M.; Dillon, T.; Lind, S.E.; Thor, A.D. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle, 2009, 8(6), 909-915.
[] [PMID: 19221498]
Monteagudo, S.; Pérez-Martínez, F.C.; Pérez-Carrión, M.D.; Guerra, J.; Merino, S.; Sánchez-Verdú, M.P.; Ceña, V. Inhibition of p42 MAPK using a nonviral vector-delivered siRNA potentiates the anti-tumor effect of metformin in prostate cancer cells. Nanomedicine (Lond.), 2012, 7(4), 493-506.
[] [PMID: 21995500]
Zhang, Q.; Celestino, J.; Schmandt, R.; McCampbell, A.S.; Urbauer, D.L.; Meyer, L.A. Chemopreventive effects of metformin on obesity-associated endometrial proliferation. Am. J. Obstetr. Gynecol., 2013, 209(1), 1-12.
Xie, Y.; Peng, Z.; Shi, M.; Ji, M.; Guo, H.; Shi, H. Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatin-resistant ovarian cancer. Mol. Med. Rep., 2014, 10(5), 2346-2350.
[] [PMID: 25118792]
Bi, T.; Zhu, A.; Yang, X.; Qiao, H.; Tang, J.; Liu, Y.; Lv, R. Metformin synergistically enhances antitumor activity of cisplatin in gall bladder cancer via the PI3K/AKT/ERK pathway. Cytotechnology, 2018, 70(1), 439-448.
[] [PMID: 29110119]
Martin-Castillo, B.; Vazquez-Martin, A.; Oliveras-Ferraros, C.; Menendez, J.A. Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle, 2010, 9(6), 1057-1064.
[] [PMID: 20305377]
Dhillon, S.S.; Groman, A.; Meagher, A.; Demmy, T.; Warren, G.W.; Yendamuri, S. Metformin and not diabetes influences the survival of resected early stage NSCLC patients. J. Cancer Sci. Ther., 2014, 6(7), 217-222.
[PMID: 26457130]
Sayed, R.; Saad, A.S.; El Wakeel, L.; Elkholy, E.; Badary, O. Metformin addition to chemotherapy in stage IV non-small cell lung cancer: An open label randomized controlled study. Asian Pac. J. Cancer Prev., 2015, 16(15), 6621-6626.
[] [PMID: 26434885]
Alcusky, M.; Keith, S.W.; Karagiannis, T.; Rabinowitz, C.; Louis, D.Z.; Maio, V. Metformin exposure and survival in head and neck cancer: A large population-based cohort study. J. Clin. Pharm. Ther., 2019, 44(4), 588-594.
[] [PMID: 31293011]
Dhanasekaran, D.N.; Johnson, G.L. MAPKs: Function, regulation, role in cancer and therapeutic targeting. Oncogene, 2007, 26(22), 3097-3099.
[] [PMID: 17496908]
Xia, W.; Qi, X.; Li, M.; Wu, Y.; Sun, L.; Fan, X.; Yuan, Y.; Li, J. Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner. OncoImmunology, 2021, 10(1), 1995999.
[] [PMID: 34745769]
Chen, Y-H.; Wu, J-X.; Yang, S-F.; Chen, M-L.; Chen, T-H.; Hsiao, Y-H. Metformin potentiates the anticancer effect of everolimus on cervical cancer in vitro and in vivo. Cancers (Basel), 2021, 13(18), 4612.
[] [PMID: 34572837]
Li, B.; Zhou, P.; Xu, K.; Chen, T.; Jiao, J.; Wei, H.; Yang, X.; Xu, W.; Wan, W.; Xiao, J. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int. J. Biol. Sci., 2020, 16(1), 74-84.
[] [PMID: 31892847]
Wu, N.; Gu, C.; Gu, H.; Hu, H.; Han, Y.; Li, Q. Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153. Neoplasma, 2011, 58(6), 482-490.
[] [PMID: 21895401]
Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer, 2013, 12(1), 86.
[] [PMID: 23915189]
Escárcega, R.O.; Fuentes-Alexandro, S.; García-Carrasco, M.; Gatica, A.; Zamora, A. The transcription factor nuclear factor-kappa B and cancer. Clin. Oncol. (R. Coll. Radiol.), 2007, 19(2), 154-161.
[] [PMID: 17355113]
Zheng, L.; Yang, W.; Wu, F.; Wang, C.; Yu, L.; Tang, L.; Qiu, B.; Li, Y.; Guo, L.; Wu, M.; Feng, G.; Zou, D.; Wang, H. Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin. Cancer Res., 2013, 19(19), 5372-5380.
[] [PMID: 23942093]
Chaudhary, S.C.; Kurundkar, D.; Elmets, C.A.; Kopelovich, L.; Athar, M. Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem. Photobiol., 2012, 88(5), 1149-1156.
[] [PMID: 22540890]
Donath, M.Y.; Shoelson, S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol., 2011, 11(2), 98-107.
[] [PMID: 21233852]
Kern, P.A.; Ranganathan, S.; Li, C.; Wood, L.; Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab., 2001, 280(5), E745-E751.
[] [PMID: 11287357]
Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer, 2009, 9(5), 361-371.
[] [PMID: 19343034]
Neurath, M.F.; Finotto, S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev., 2011, 22(2), 83-89.
[] [PMID: 21377916]
Takemura, Y.; Osuga, Y.; Yoshino, O.; Hasegawa, A.; Hirata, T.; Hirota, Y.; Nose, E.; Morimoto, C.; Harada, M.; Koga, K.; Tajima, T.; Yano, T.; Taketani, Y. Metformin suppresses interleukin (IL)-1β-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells. J. Clin. Endocrinol. Metab., 2007, 92(8), 3213-3218.
[] [PMID: 17504902]
(a) Canonici, A.; Gijsen, M.; Mullooly, M.; Bennett, R.; ouguern, N.; Pedersen, K.; O’Brien, N.A.; Roxanis, I.; Li, J.L.; Bridge, E.; Finn, R.; Siamon, D.; McGowan, P.; Duffy, M.J.; O’Donovan, N.; Crown, J.; Kong, A. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget, 2013, 4(10), 1592-1605.
[] [PMID: 24009064];
(b) Al-Ostoot, F.H.; Salah, S.; Khamees, H.A.; Khanum, S.A. Tumor angiogenesis: Current challenges and therapeutic opportunities. Cancer Treat. Res. Commun., 2021, 28, 100422.
[] [PMID: 34147821]
(a) Desroches-Castan, A.; Quélard, D.; Demeunynck, M.; Constant, J-F.; Dong, C.; Keramidas, M.; Coll, J.L.; Barette, C.; Lafanechère, L.; Feige, J.J. A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras. Oncotarget, 2015, 6(7), 5382-5411.
[] [PMID: 25742784];
(b) Sanati, M.; Afshari, A.R.; Amini, J.; Mollazadeh, H.; Jamialahmadi, T.; Sahebkar, A. Targeting angiogenesis in gliomas: Potential role of phytochemicals. (2022) J. Func. Foods, 2022, 96, 105192.
Vazquez-Martin, A.; Oliveras-Ferraros, C.; Menendez, J.A. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle, 2009, 8(1), 88-96.
[] [PMID: 19106626]
Vazquez-Martin, A.; Oliveras-Ferraros, C.; Del Barco, S.; Martin-Castillo, B.; Menendez, J.A. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res. Treat., 2011, 126(2), 355-364.
[] [PMID: 20458531]
Kim, H.J.; Kwon, H.; Lee, J.W.; Kim, H.J.; Lee, S.B.; Park, H.S.; Sohn, G.; Lee, Y.; Koh, B.S.; Yu, J.H.; Son, B.H.; Ahn, S.H. Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes. Breast Cancer Res., 2015, 17(1), 64.
[] [PMID: 25935404]
Ye, J.; Chen, K.; Qi, L.; Li, R.; Tang, H.; Zhou, C.; Zhai, W. Metformin suppresses hypoxia-induced migration via the HIF-1α/VEGF pathway in gallbladder cancer in vitro and in vivo. Oncol. Rep., 2018, 40(6), 3501-3510.
[] [PMID: 30272364]
Meireles, C.G.; Lourenço de Lima, C.; Martins de Paula Oliveira, M.; Abe da Rocha Miranda, R.; Romano, L.; Yo-Stella Brashaw, T.; Neves da Silva Guerra, E.; de Assis Rocha Neves, F.; Chapple, J.P.; Simeoni, L.A.; Lofrano- Porto, A. Antiproliferative effects of metformin in cellular models of pheochromocytoma. Mol. Cell. Endocrinol., 2022, 539, 111484.
[] [PMID: 34637881]
Hirsch, H.A.; Iliopoulos, D.; Tsichlis, P.N.; Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res., 2009, 69(19), 7507-7511.
[] [PMID: 19752085]
Ben Sahra, I.; Regazzetti, C.; Robert, G.; Laurent, K.; Le Marchand-Brustel, Y.; Auberger, P.; Tanti, J.F.; Giorgetti-Peraldi, S.; Bost, F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res., 2011, 71(13), 4366-4372.
[] [PMID: 21540236]
Kalogirou, C.; Schäfer, D.; Krebs, M.; Kurz, F.; Schneider, A.; Riedmiller, H.; Kneitz, B.; Vergho, D. Metformin-derived growth inhibition in renal cell carcinoma depends on miR-21-mediated PTEN expression. Urol. Int., 2016, 96(1), 106-115.
[] [PMID: 26496641]
Wu, L.; Zhou, B.; Oshiro-Rapley, N.; Li, M.; Paulo, J.A.; Webster, C.M. An ancient, unified mechanism for metformin growth inhibition in C. elegans and cancer. Cell, 2016, 167(7), 1705-1718.
Cufí, S.; Vazquez-Martin, A.; Oliveras-Ferraros, C.; Martin-Castillo, B.; Joven, J.; Menendez, J.A. Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis. Cell Cycle, 2010, 9(22), 4461-4468.
[] [PMID: 21088486]
Wang, L-W.; Li, Z-S.; Zou, D-W.; Jin, Z-D.; Gao, J.; Xu, G-M. Metformin induces apoptosis of pancreatic cancer cells. World J. Gastroenterol., 2008, 14(47), 7192-7198.
[] [PMID: 19084933]
Blandino, G.; Valerio, M.; Cioce, M.; Mori, F.; Casadei, L.; Pulito, C.; Sacconi, A.; Biagioni, F.; Cortese, G.; Galanti, S.; Manetti, C.; Citro, G.; Muti, P.; Strano, S. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat. Commun., 2012, 3(1), 865.
[] [PMID: 22643892]
Gui, D.Y.; Sullivan, L.B.; Luengo, A.; Hosios, A.M.; Bush, L.N.; Gitego, N.; Davidson, S.M.; Freinkman, E.; Thomas, C.J.; Heiden, M.G.V. Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin. Cell Metab., 2016, 24(5), 716-727.
[] [PMID: 27746050]
Liu, X.; Romero, I.L.; Litchfield, L.M.; Lengyel, E.; Locasale, J.W. Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab., 2016, 24(5), 728-739.
[] [PMID: 27746051]
Cheng, T.; Wang, C.; Lu, Q.; Cao, Y.; Yu, W.; Li, W.; Liu, B.; Gao, X.; Lü, J.; Pan, X. Metformin inhibits the tumor-promoting effect of low-dose resveratrol, and enhances the anti-tumor activity of high-dose resveratrol by increasing its reducibility in triple negative breast cancer. Free Radic. Biol. Med., 2022, 180, 108-120.
[] [PMID: 35038549]
Abdelhamid, A.M.; Saber, S.; Youssef, M.E.; Gaafar, A.G.A.; Eissa, H.; Abd-Eldayem, M.A.; Alqarni, M.; Batiha, G.E.; Obaidullah, A.J.; Shahien, M.A.; El-Ahwany, E.; Amin, N.A.; Etman, M.A.; Kaddah, M.M.Y.; Abd El-Fattah, E.E. Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application. Biomed. Pharmacother., 2022, 145, 112455.
[] [PMID: 34844106]
Feng, J.; Lu, H.; Ma, W.; Tian, W.; Lu, Z.; Yang, H.; Cai, Y.; Cai, P.; Sun, Y.; Zhou, Z.; Feng, J.; Deng, J.; Shu, Y.; Qu, K.; Jia, W.; Gao, P.; Zhang, H. Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer. Protein Cell, 2022. [Epub ahead of print].
[] [PMID: 35217990]
Yu, Y.; Feng, C.; Kuang, J.; Guo, L.; Guan, H. Metformin exerts an antitumoral effect on papillary thyroid cancer cells through altered cell energy metabolism and sensitized by BACH1 depletion. Endocrine, 2022, 76(1), 116-131.
[] [PMID: 35050486]
Zhu, D.; Xia, J.; Liu, C.; Fang, C. Numb/Notch/PLK1 signaling pathway mediated hyperglycemic memory in pancreatic cancer cell radioresistance and the therapeutic effects of metformin. Cell. Signal., 2022, 93, 110268.
[] [PMID: 35143930]
Chen, J.; Qin, C.; Zhou, Y.; Chen, Y.; Mao, M.; Yang, J. Metformin may induce ferroptosis by inhibiting autophagy via lncRNA H19 in breast cancer. FEBS Open Bio, 2022, 12(1), 146-153.
[] [PMID: 34644456]
You, R.; Wang, B.; Chen, P.; Zheng, X.; Hou, D.; Wang, X.; Zhang, B.; Chen, L.; Li, D.; Lin, X.; Huang, H. Metformin sensitizes AML cells to chemotherapy through blocking mitochondrial transfer from stromal cells to AML cells. Cancer Lett., 2022, 532, 215582.
[] [PMID: 35122876]
Allende-Vega, N.; Marco Brualla, J.; Falvo, P.; Alexia, C.; Constantinides, M.; de Maudave, A.F.; Coenon, L.; Gitenay, D.; Mitola, G.; Massa, P.; Orecchioni, S.; Bertolini, F.; Marzo, I.; Anel, A.; Villalba, M. Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1). Sci. Rep., 2022, 12(1), 1341.
[] [PMID: 35079096]
Zhuang, A.; Chai, P.; Wang, S.; Zuo, S.; Yu, J.; Jia, S.; Ge, S.; Jia, R.; Zhou, Y.; Shi, W.; Xu, X.; Ruan, J.; Fan, X. Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma. Clin. Transl. Med., 2022, 12(1), e660.
[] [PMID: 35075807]
Zhu, M.; Zhang, Q.; Wang, X.; Kang, L.; Yang, Y.; Liu, Y.; Yang, L.; Li, J.; Yang, L.; Liu, J.; Li, Y.; Zu, L.; Shen, Y.; Qi, Z. Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway. Oncotarget, 2016, 7(51), 84190-84200.
[] [PMID: 27705937]
Jalili-Nik, M.; Sadeghi, M.M.; Mohtashami, E.; Mollazadeh, H.; Afshari, A.R.; Sahebkar, A. Zerumbone promotes cytotoxicity in human malignant glioblastoma cells through reactive oxygen species (ROS) generation. Oxid. Med. Cell. Longev., 2020, 2020, 3237983.
Afshari, A.R.; Motamed-Sanaye, A.; Sabri, H.; Soltani, A.; Karkon-Shayan, S.; Radvar, S.; Javid, H.; Mollazadeh, H.; Sathyapalan, T.; Sahebkar, A. Neurokinin-1 receptor (NK-1R) antagonists: Potential targets in the treatment of glioblastoma multiforme. Curr. Med. Chem., 2021, 28(24), 4877-4892.
[] [PMID: 33441062]
Tavana, E.; Mollazadeh, H.; Mohtashami, E.; Modaresi, S.M.S.; Hosseini, A.; Sabri, H.; Soltani, A.; Javid, H.; Afshari, A.R.; Sahebkar, A. Quercetin: A promising phytochemical for the treatment of glioblastoma multiforme. Biofactors, 2020, 46(3), 356-366.
[] [PMID: 31880372]
Adeberg, S.; Bernhardt, D.; Ben Harrabi, S.; Bostel, T.; Mohr, A.; Koelsche, C.; Diehl, C.; Rieken, S.; Debus, J. Metformin influences progression in diabetic glioblastoma patients. Strahlenther. Onkol., 2015, 191(12), 928-935.
[] [PMID: 26329695]
Adeberg, S.; Bernhardt, D.; Harrabi, S.B.; Nicolay, N.; Rieber, J.; Koenig, L. Metformin enhanced in vitro radiosensitivity associates with G2/M cell cycle arrest and elevated pAMPK levels in glioblastoma. Radiol. Oncol., 2017, 51(4), 42.
[] [PMID: 29333122]
Tseng, C-H. Metformin and risk of malignant brain tumors in patients with type 2 diabetes mellitus. Biomolecules, 2021, 11(8), 1226.
[] [PMID: 34439890]
Seliger, C.; Genbrugge, E.; Gorlia, T.; Chinot, O.; Stupp, R.; Nabors, B.; Weller, M.; Hau, P. Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. Int. J. Cancer, 2020, 146(3), 803-809.
[] [PMID: 30980539]
Saputra, E.C.; Huang, L.; Chen, Y.; Tucker-Kellogg, L. Combination therapy and the evolution of resistance: The theoretical merits of synergism and antagonism in cancer. Cancer Res., 2018, 78(9), 2419-2431.
[] [PMID: 29686021]
Saini, N.; Yang, X. Metformin as an anti-cancer agent: Actions and mechanisms targeting cancer stem cells. Acta Biochim. Biophys. Sin. (Shanghai), 2018, 50(2), 133-143.
[] [PMID: 29342230]
Li, M.; Li, X.; Zhang, H.; Lu, Y. Molecular mechanisms of metformin for diabetes and cancer treatment. Front. Physiol., 2018, 9, 1039.
[] [PMID: 30108523]
Tang, Z; Tang, N; Jiang, S; Bai, Y; Guan, C; Zhang, W The chemosensitizing role of metformin in anti-cancer therapy. Anti-Cancer Agents Med. Chem., 2021, 21(8), 949-62.
Samsuri, N.A.B.; Leech, M.; Marignol, L. Metformin and improved treatment outcomes in radiation therapy - A review. Cancer Treat. Rev., 2017, 55, 150-162.
[] [PMID: 28399491]
Yang, S.H.; Li, S.; Lu, G.; Xue, H.; Kim, D.H.; Zhu, J-J.; Liu, Y. Metformin treatment reduces temozolomide resistance of glioblastoma cells. Oncotarget, 2016, 7(48), 78787-78803.
[] [PMID: 27791206]
Yu, Z.; Zhao, G.; Xie, G.; Zhao, L.; Chen, Y.; Yu, H.; Zhang, Z.; Li, C.; Li, Y. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget, 2015, 6(32), 32930-32943.
[] [PMID: 26431379]
Yu, Z.; Zhao, G.; Li, P.; Li, Y.; Zhou, G.; Chen, Y.; Xie, G. Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells. Oncol. Lett., 2016, 11(4), 2792-2800.
[] [PMID: 27073554]
Soritau, O.; Tomuleasa, C.; Aldea, M.; Petrushev, B.; Susman, S.; Gheban, D.; Ioani, H.; Cosis, A.; Brie, I.; Irimie, A.; Kacso, G.; Florian, I.S. Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas. J. BUON, 2011, 16(2), 282-289.
[PMID: 21766499]
Valtorta, S.; Lo Dico, A.; Raccagni, I.; Gaglio, D.; Belloli, S.; Politi, L.S.; Martelli, C.; Diceglie, C.; Bonanomi, M.; Ercoli, G.; Vaira, V.; Ottobrini, L.; Moresco, R.M. Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models. Oncotarget, 2017, 8(68), 113090-113104.
[] [PMID: 29348889]
Valtorta, S.; Lo Dico, A.; Raccagni, I.; Martelli, C.; Pieri, V.; Rainone, P.; Todde, S.; Zinnhardt, B.; De Bernardi, E.; Coliva, A.; Politi, L.S.; Viel, T.; Jacobs, A.H.; Galli, R.; Ottobrini, L.; Vaira, V.; Moresco, R.M. Imaging metformin efficacy as add-on therapy in cells and mouse models of human EGFR glioblastoma. Front. Oncol., 2021, 11, 664149.
[] [PMID: 34012924]
Pezzuto, A.; Carico, E. Role of HIF-1 in cancer progression: Novel insights. A review. Curr. Mol. Med., 2018, 18(6), 343-351.
[] [PMID: 30411685]
Lo Dico, A.; Valtorta, S.; Ottobrini, L.; Moresco, R.M. Role of metformin and AKT axis modulation in the reversion of hypoxia induced TMZ-resistance in glioma cells. Front. Oncol., 2019, 9, 463.
[] [PMID: 31214505]
Zając, A.; Sumorek-Wiadro, J.; Langner, E.; Wertel, I.; Maciejczyk, A.; Pawlikowska-Pawlęga, B.; Pawelec, J.; Wasiak, M.; Hułas-Stasiak, M.; Bądziul, D.; Rzeski, W.; Reichert, M.; Jakubowicz-Gil, J. Involvement of PI3K Pathway in glioma cell resistance to temozolomide treatment. Int. J. Mol. Sci., 2021, 22(10), 5155.
[] [PMID: 34068110]
Haas, B.; Klinger, V.; Keksel, C.; Bonigut, V.; Kiefer, D.; Caspers, J.; Walther, J.; Wos-Maganga, M.; Weickhardt, S.; Röhn, G.; Timmer, M.; Frötschl, R.; Eckstein, N. Inhibition of the PI3K but not the MEK/ERK pathway sensitizes human glioma cells to alkylating drugs. Cancer Cell Int., 2018, 18(1), 69.
[] [PMID: 29755294]
Adeberg, S.; Bernhardt, D.; Harrabi, S.B.; Nicolay, N.H.; Hörner-Rieber, J.; König, L.; Repka, M.; Mohr, A.; Abdollahi, A.; Weber, K.J.; Debus, J.; Rieken, S. Metformin enhanced in vitro radiosensitivity associates with G2/M cell cycle arrest and elevated adenosine-5′-monophosphate-activated protein kinase levels in glioblastoma. Radiol. Oncol., 2017, 51(4), 431-437.
[] [PMID: 29333122]
Kolesnik, D.L.; Pyaskovskaya, O.N.; Yurchenko, O.V.; Solyanik, G.I. Metformin enhances antitumor action of sodium dichloroacetate against glioma C6. Exp. Oncol., 2019, 41(2), 123-129.
[] [PMID: 31262158]
Ward, N.P.; Poff, A.M.; Koutnik, A.P.; D'Agostino, D.P. Metformin modulation of dichloroacetate‐induced oxidative stress and its impact on mitochondrial integrity in VM‐M3 glioblastoma cells. FASEB J., 2016, 30, 1099.17.
Aldea, M.D.; Petrushev, B.; Soritau, O.; Tomuleasa, C.I.; Berindan-Neagoe, I.; Filip, A.G.; Chereches, G.; Cenariu, M.; Craciun, L.; Tatomir, C.; Florian, I.S.; Crivii, C.B.; Kacso, G. Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells. J. BUON, 2014, 19(2), 502-511.
[PMID: 24965413]
Wang, Y.; Meng, Y.; Zhang, S.; Wu, H.; Yang, D.; Nie, C.; Hu, Q. Phenformin and metformin inhibit growth and migration of LN229 glioma cells in vitro and in vivo. OncoTargets Ther., 2018, 11, 6039-6048.
[] [PMID: 30275708]
Alhajala, H.S.; Markley, J.L.; Kim, J.H.; Al-Gizawiy, M.M.; Schmainda, K.M.; Kuo, J.S.; Chitambar, C.R. The cytotoxicity of gallium maltolate in glioblastoma cells is enhanced by metformin through combined action on mitochondrial complex 1. Oncotarget, 2020, 11(17), 1531-1544.
[] [PMID: 32391122]
Rezaei, N.; Neshasteh-Riz, A.; Mazaheri, Z.; Koosha, F.; Hoormand, M. The combination of metformin and disulfiram-Cu for effective radiosensitization on glioblastoma cells. Cell J., 2020, 22(3), 263-272.
[PMID: 31863651]
Korsakova, L; Krasko, JA; Stankevicius, E Metabolic-targeted combination therapy with dichloroacetate and metformin suppresses glioblastoma cell line growth in vitro and in vivo. In vivo, 2021, 35(1), 341-348.
Mouhieddine, T.H.; Nokkari, A.; Itani, M.M.; Chamaa, F.; Bahmad, H.; Monzer, A.; El-Merahbi, R.; Daoud, G.; Eid, A.; Kobeissy, F.H.; Abou-Kheir, W. Metformin and ara-a effectively suppress brain cancer by targeting cancer stem/progenitor cells. Front. Neurosci., 2015, 9, 442.
[] [PMID: 26635517]
Albayrak, G.; Konac, E.; Dere, U.A.; Emmez, H. Targeting cancer cell metabolism with metformin, dichloroacetate and memantine in glioblastoma (GBM). Turk Neurosurg., 2021, 31(2), 233-237.
[PMID: 33372258]
Gerthofer, V.; Kreutz, M.; Renner, K.; Jachnik, B.; Dettmer, K.; Oefner, P.; Riemenschneider, M.J.; Proescholdt, M.; Vollmann-Zwerenz, A.; Hau, P.; Seliger, C. Combined modulation of tumor metabolism by metformin and diclofenac in glioma. Int. J. Mol. Sci., 2018, 19(9), 2586.
[] [PMID: 30200299]
Leidgens, V.; Proske, J.; Rauer, L.; Moeckel, S.; Renner, K.; Bogdahn, U.; Riemenschneider, M.J.; Proescholdt, M.; Vollmann-Zwerenz, A.; Hau, P.; Seliger, C. Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation. Oncotarget, 2017, 8(5), 8250-8263.
[] [PMID: 28030813]
Caja, L.; Dadras, M.S.; Mezheyeuski, A.; Rodrigues-Junior, D.M.; Liu, S.; Webb, A.T.; Gomez-Puerto, M.C.; Ten Dijke, P.; Heldin, C.H.; Moustakas, A. The protein kinase LKB1 promotes self-renewal and blocks invasiveness in glioblastoma. J. Cell. Physiol., 2022, 237(1), 743-762.
[] [PMID: 34350982]
Kuduvalli, S.S.; Precilla, D.S.; Anandhan, V.; Sivasubramanian, A.T. Synergism of temozolomide, metformin, and epigallocatechin gallate promotes oxidative stress-induced apoptosis in glioma cells. Curr. Drug Ther., 2021, 16(3), 252-267.
Zhang, C. Enhanced tumor inhibitory effects by combining metformin with rosiglitazone in glioblastoma cells. Int. J. Radiat. Oncol. Biol. Phys., 2017, 99(2), S188-S9.
[] [PMID: 28872004]
Ferla, R.; Haspinger, E.; Surmacz, E. Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol. Lett., 2012, 4(5), 1077-1081
[] [PMID: 23162655]
Zhang, C.; Yan, S.; Wu, J.; Hei, T. Combination of metformin and a dual mTOR inhibitor shows enhanced inhibitory effects on cell proliferation of glioblastoma cells. Int. J. Radiat. Oncol. Biol. Phys., 2015, 93(3), E523.
[] [PMID: 26460994]
Mollazadeh, H.; Afshari, A.R.; Hosseinzadeh, H. Review on the potential therapeutic roles of nigella sativa in the treatment of patients with cancer: Involvement of apoptosis: Black cumin and cancer. J. Pharmacopuncture, 2017, 20(3), 158-172.
[] [PMID: 30087792]
Steinbach, J.P.; Weller, M. Apoptosis in gliomas: Molecular mechanisms and therapeutic implications. J. Neurooncol., 2004, 70(2), 245-254.
[] [PMID: 15674481]
Valdés-Rives, S.A.; Casique-Aguirre, D.; Germán- Castelán, L.; Velasco-Velázquez, M.A.; González-Arenas, A. Apoptotic signaling pathways in glioblastoma and therapeutic implications. BioMed Res. Int., 2017, 2017, 7403747.
Isakovic, A.; Harhaji, L.; Stevanovic, D.; Markovic, Z.; Sumarac-Dumanovic, M.; Starcevic, V.; Micic, D.; Trajkovic, V. Dual antiglioma action of metformin: Cell cycle arrest and mitochondria-dependent apoptosis. Cell. Mol. Life Sci., 2007, 64(10), 1290-1302.
[] [PMID: 17447005]
Lee, J.E.; Lim, J.H.; Hong, Y.K.; Yang, S.H. High-dose metformin plus temozolomide shows increased anti-tumor effects in glioblastoma in vitro and in vivo compared with monotherapy. Cancer Res. Treat., 2018, 50(4), 1331.
Xiong, Z.S.; Gong, S.F.; Si, W.; Jiang, T.; Li, Q.L.; Wang, T.J.; Wang, W.J.; Wu, R.Y.; Jiang, K. Effect of metformin on cell proliferation, apoptosis, migration and invasion in A172 glioma cells and its mechanisms. Mol. Med. Rep., 2019, 20(2), 887-894.
[] [PMID: 31173255]
Levesley, J.; Steele, L.; Taylor, C.; Sinha, P.; Lawler, S.E. ABT-263 enhances sensitivity to metformin and 2-deoxyglucose in pediatric glioma by promoting apoptotic cell death. PLoS One, 2013, 8(5), e64051.
[] [PMID: 23691145]
Songthaveesin, C.; Sa-Nongdej, W.; Limboonreung, T.; Chongthammakun, S. Combination of metformin and 9-cis retinoic acid increases apoptosis in C6 glioma stem-like cells. Heliyon, 2018, 4(5), e00638.
[] [PMID: 29872770]
Karimi Roshan, M.; Soltani, A.; Soleimani, A.; Rezaie Kahkhaie, K.; Afshari, A.R.; Soukhtanloo, M. Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process. Biochimie, 2019, 165, 229-234.
[] [PMID: 31401189]
Gasior, K.; Wagner, N.J.; Cores, J.; Caspar, R.; Wilson, A.; Bhattacharya, S.; Hauck, M.L. The role of cellular contact and TGF-beta signaling in the activation of the epithelial mesenchymal transition (EMT). Cell Adhes. Migr., 2019, 13(1), 63-75.
[] [PMID: 30296203]
Song, Y.; Chen, Y.; Li, Y.; Lyu, X.; Cui, J.; Cheng, Y.; Zhao, L.; Zhao, G. Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway. Oncotarget, 2017, 9(6), 7023-7035.
[] [PMID: 29467947]
Seliger, C.; Meyer, A-L.; Renner, K.; Leidgens, V.; Moeckel, S.; Jachnik, B.; Dettmer, K.; Tischler, U.; Gerthofer, V.; Rauer, L.; Uhl, M.; Proescholdt, M.; Bogdahn, U.; Riemenschneider, M.J.; Oefner, P.J.; Kreutz, M.; Vollmann-Zwerenz, A.; Hau, P. Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2. Cell Cycle, 2016, 15(13), 1755-1766.
[] [PMID: 27163626]
Sanati, M.; Aminyavari, S.; Mollazadeh, H.; Bibak, B.; Mohtashami, E.; Afshari, A.R. How do phosphodiesterase-5 inhibitors affect cancer? A focus on glioblastoma multiforme. Pharmacol. Rep., 2022, 74(2), 323-339.
[] [PMID: 35050491]
Kim, E.H.; Lee, J-H.; Oh, Y.; Koh, I.; Shim, J-K.; Park, J.; Choi, J.; Yun, M.; Jeon, J.Y.; Huh, Y.M.; Chang, J.H.; Kim, S.H.; Kim, K.S.; Cheong, J.H.; Kim, P.; Kang, S.G. Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin. Neuro-oncol., 2017, 19(2), 197-207.
[PMID: 27571886]
Roh, T.H.; Lee, J-H.; Kim, S.J.; Shim, J-K.; Park, J.; Yoon, S-J.; Teo, W.Y.; Kim, S.H.; Chang, J.H.; Kang, S.G. A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres. J. Neurooncol., 2022, 156(1), 139-151.
[] [PMID: 34811601]
Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways. Semin Cancer Biol., 2022. [Epub ahead of print].
Taghizadehghalehjoughi, A.; Hacimuftuoglu, A.; Cetin, M.; Ugur, A.B.; Galateanu, B.; Mezhuev, Y.; Okkay, U.; Taspinar, N.; Taspinar, M.; Uyanik, A.; Gundogdu, B.; Mohammadzadeh, M.; Nalci, K.A.; Stivaktakis, P.; Tsatsakis, A.; Jung, T.W.; Jeong, J.H.; Abd El-Aty, A.M. Effect of metformin/irinotecan-loaded poly-lactic-co-glycolic acid nanoparticles on glioblastoma: In vitro and in vivo studies. Nanomedicine (Lond.), 2018, 13(13), 1595-1606.
[] [PMID: 30028222]
Maraka, S.; Groves, M.D.; Mammoser, A.G.; Melguizo- Gavilanes, I.; Conrad, C.A.; Tremont-Lukats, I.W.; Loghin, M.E.; O’Brien, B.J.; Puduvalli, V.K.; Sulman, E.P.; Hess, K.R.; Aldape, K.D.; Gilbert, M.R.; de Groot, J.F.; Alfred Yung, W.K.; Penas-Prado, M. Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer, 2019, 125(3), 424-433.
[] [PMID: 30359477]
Porper, K.; Shpatz, Y.; Plotkin, L.; Pechthold, R.G.; Talianski, A.; Champ, C.E.; Furman, O.; Shimoni-Sebag, A.; Symon, Z.; Amit, U.; Hemi, R.; Kanety, H.; Mardor, Y.; Cohen, Z.R.; Jan, E.; Genssin, H.; Anikster, Y.; Zach, L.; Lawrence, Y.R. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma. J. Neurooncol., 2021, 153(3), 487-496.
[] [PMID: 34152528]
Sui, X.; Xu, Y.; Yang, J.; Fang, Y.; Lou, H.; Han, W.; Zhang, M.; Chen, W.; Wang, K.; Li, D.; Jin, W.; Lou, F.; Zheng, Y.; Hu, H.; Gong, L.; Zhou, X.; Pan, Q.; Pan, H.; Wang, X.; He, C. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One, 2014, 9(5), e97781.
[] [PMID: 24849329]
Zhao, B.; Wang, X.; Zheng, J.; Wang, H.; Liu, J. Effects of metformin treatment on glioma-induced brain edema. Am. J. Transl. Res., 2016, 8(8), 3351-3363.
[PMID: 27648126]

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