Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Metformin displays in vitro and in vivo antitumor effect against osteosarcoma

  • Ko, Yunmi (Division of Clinical Translational Research, Korea Cancer Center Hospital) ;
  • Choi, Aery (Department of Pediatrics, Korea Cancer Center Hospital) ;
  • Lee, Minyoung (Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences) ;
  • Lee, Jun Ah (Division of Clinical Translational Research, Korea Cancer Center Hospital)
  • Received : 2016.06.08
  • Accepted : 2016.08.08
  • Published : 2016.09.10
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Abstract

Purpose: Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research. Methods: We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3-4 days for a period of 4 weeks. Results: Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects. Conclusion: Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.

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References

  1. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009;115:1531-43. https://doi.org/10.1002/cncr.24121
  2. Bacci G, Forni C, Ferrari S, Longhi A, Bertoni F, Mercuri M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol 2003;25:845-53. https://doi.org/10.1097/00043426-200311000-00006
  3. Eselgrim M, Grunert H, Kuhne T, Zoubek A, Kevric M, Burger H, et al. Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials. Pediatr Blood Cancer 2006;47:42-50. https://doi.org/10.1002/pbc.20608
  4. Kempf-Bielack B, Bielack SS, Jurgens H, Branscheid D, Berdel WE, Exner GU, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23:559-68. https://doi.org/10.1200/JCO.2005.04.063
  5. Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003;21:2011-8. https://doi.org/10.1200/JCO.2003.08.132
  6. Leone A, Di Gennaro E, Bruzzese F, Avallone A, Budillon A. New perspective for an old antidiabetic drug: metformin as anticancer agent. Cancer Treat Res 2014;159:355-76.
  7. Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 2013; 32:1475-87. https://doi.org/10.1038/onc.2012.181
  8. Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 2013;8:e71583. https://doi.org/10.1371/journal.pone.0071583
  9. Hernandez-Diaz S, Adami HO. Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia 2010;53:802-8. https://doi.org/10.1007/s00125-010-1675-2
  10. Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 2012;35:299-304. https://doi.org/10.2337/dc11-1313
  11. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 2010;33:322-6. https://doi.org/10.2337/dc09-1380
  12. Anisimov VN, Bartke A. The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol 2013; 87:201-23. https://doi.org/10.1016/j.critrevonc.2013.01.005
  13. Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat 2011;128:783-94. https://doi.org/10.1007/s10549-011-1612-1
  14. Choi YK, Park KG. Metabolic roles of AMPK and metformin in cancer cells. Mol Cells 2013;36:279-87. https://doi.org/10.1007/s10059-013-0169-8
  15. Perl A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad Sci 2015;1346:33-44. https://doi.org/10.1111/nyas.12756
  16. Garofalo C, Capristo M, Manara MC, Mancarella C, Landuzzi L, Belfiore A, et al. Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug. PLoS One 2013;8:e83832. https://doi.org/10.1371/journal.pone.0083832
  17. Issaq SH, Teicher BA, Monks A. Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors. Cell Cycle 2014;13:1152-61. https://doi.org/10.4161/cc.28010
  18. Duo J, Ma Y, Wang G, Han X, Zhang C. Metformin synergistically enhances antitumor activity of histone deacetylase inhibitor trichostatin a against osteosarcoma cell line. DNA Cell Biol 2013; 32:156-64. https://doi.org/10.1089/dna.2012.1926
  19. Quattrini I, Conti A, Pazzaglia L, Novello C, Ferrari S, Picci P, et al. Metformin inhibits growth and sensitizes osteosarcoma cell lines to cisplatin through cell cycle modulation. Oncol Rep 2014;31:370-5. https://doi.org/10.3892/or.2013.2862
  20. Chen X, Hu C, Zhang W, Shen Y, Wang J, Hu F, et al. Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro. Tumour Biol 2015; 36:9873-83. https://doi.org/10.1007/s13277-015-3751-1
  21. Perry JA, Kiezun A, Tonzi P, Van Allen EM, Carter SL, Baca SC, et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 2014;111:E5564-73. https://doi.org/10.1073/pnas.1419260111
  22. Han B, Cui H, Kang L, Zhang X, Jin Z, Lu L, et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumour Biol 2015;36:6295-304. https://doi.org/10.1007/s13277-015-3315-4
  23. Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008;27:3576-86. https://doi.org/10.1038/sj.onc.1211024
  24. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 2014;74:4783-95. https://doi.org/10.1158/0008-5472.CAN-14-0135
  25. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18:283-93. https://doi.org/10.1016/j.molcel.2005.03.027
  26. Muaddi H, Chowdhury S, Vellanki R, Zamiara P, Koritzinsky M. Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin. Radiother Oncol 2013; 108:446-50. https://doi.org/10.1016/j.radonc.2013.06.014
  27. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981;12:235-46. https://doi.org/10.1111/j.1365-2125.1981.tb01206.x
  28. Segal ED, Yasmeen A, Beauchamp MC, Rosenblatt J, Pollak M, Gotlieb WH. Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem Biophys Res Commun 2011;414: 694-9. https://doi.org/10.1016/j.bbrc.2011.09.134
  29. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol 2012;48:R31-43. https://doi.org/10.1530/JME-12-0007
  30. Chae YK, Arya A, Malecek MK, Shin DS, Carneiro B, Chandra S, et al. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 2016 Mar 19 [Epub]. http://dx.doi.org/ 10.18632/oncotarget.8194.
  31. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol 2012; 30:2593-600. https://doi.org/10.1200/JCO.2011.39.3769
  32. Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, et al. The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer 2013;109:2792-7. https://doi.org/10.1038/bjc.2013.657
  33. Schuler KM, Rambally BS, DiFurio MJ, Sampey BP, Gehrig PA, Makowski L, et al. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med 2015;4:161-73. https://doi.org/10.1002/cam4.353

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