Metformin against cancer stem cells through the modulation of energy metabolism: Special considerations on ovarian cancer

BioMed Research International

Volumn 2014, Issue , 2014, Pages

  Kim, Tae Hun ^a   Suh, Dong Hoon ^b   Kim, Mi Kyung ^c   Song, Yong Sang ^c,d  

^a Korea Institute of Radiation and Medical Science   (South Korea)

^b Seoul National University Bundang Hospital   (South Korea)

^c Seoul National University   (South Korea)

^d Seoul National University College of Medicine   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOPLATIN; CISPLATIN; HYPOXIA INDUCIBLE FACTOR 1; METFORMIN; PROTEIN P53; UVOMORULIN;

ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ASSOCIATION; CANCER GROWTH; CANCER STEM CELL; CARCINOGENESIS; CELL CYCLE ARREST; CELL POPULATION; CELL PROLIFERATION; DIABETIC PATIENT; DNA DAMAGE; ENERGY METABOLISM; ENERGY YIELD; HUMAN; IN VITRO STUDY; IN VIVO STUDY; METABOLIC STRESS; OVARY CANCER; PHENOTYPE; PHENOTYPIC PLASTICITY; PLURIPOTENT STEM CELL; REVIEW; TUMOR MICROENVIRONMENT; BIOLOGICAL MODEL; DRUG EFFECTS; DRUG RESISTANCE; FEMALE; METABOLISM; OVARIAN NEOPLASMS; PATHOLOGY;

DRUG RESISTANCE, NEOPLASM; ENERGY METABOLISM; FEMALE; HUMANS; METFORMIN; MODELS, BIOLOGICAL; NEOPLASTIC STEM CELLS; OVARIAN NEOPLASMS;

EID: 84904133341     PISSN: 23146133     EISSN: 23146141     Source Type: Journal    
DOI: 10.1155/2014/132702     Document Type: Review

References (99)

1. Siegel R., Naishadham D., Jemal A., Cancer statistics, 2013. CA Cancer Journal for Clinicians 2013 63 1 11 30 2-s2.0-84872967522 10.3322/caac.21166
2. Akhtar-Danesh N., Lytwyn A., Elit L., Five-year trends in mortality indices among gynecological cancer patients in Canada. Gynecologic Oncology 2012 127 3 620 624 2-s2.0-84868541938 10.1016/j.ygyno.2012.08.038
3. Ozols R. F., Bundy B. N., Greer B. E., Fowler J. M., Clarke-Pearson D., Burger R. A., Mannel R. S., DeGeest K., Hartenbach E. M., Baergen R., Mackey D., Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. Journal of Clinical Oncology 2003 21 17 3194 3200 2-s2.0-0141688377 10.1200/JCO.2003.02.153 (Pubitemid 46606249)
4. Wang V., Li C., Lin M., Welch W., Bell D., Wong Y.-F., Berkowitz R., Mok S. C., Bandera C. A., Ovarian cancer is a heterogeneous disease. Cancer Genetics and Cytogenetics 2005 161 2 170 173 2-s2.0-23644444497 10.1016/j.cancergencyto. 2004.12.014 (Pubitemid 41133485)
5. Alvero A. B., Chen R., Fu H.-H., Montagna M., Schwartz P. E., Rutherford T., Silasi D.-A., Steffensen K. D., Waldstrom M., Visintin I., Mor G., Molecular phenotyping of human ovarian cancer stem cells unravel the mechanisms for repair and chemo-resistance. Cell Cycle 2009 8 1 158 166 2-s2.0-60749103183
6. Alison M. R., Lin W.-R., Lim S. M. L., Nicholson L. J., Cancer stem cells: in the line of fire. Cancer Treatment Reviews 2012 38 6 589 598 2-s2.0-84861656466 10.1016/j.ctrv.2012.03.003
7. Dang C. V., Links between metabolism and cancer. Genes and Development 2012 26 9 877 890 2-s2.0-84860512005 10.1101/gad.189365.112
8. Menendez J. A., Joven J., Cufí S., Corominas-Faja B., Oliveras-Ferraros C., Cuyàs E., Martin-Castillo B., Lopez-Bonet E., Alarcón T., Vazquez-Martin A., The warburg effect version 2.0: metabolic reprogramming of cancer stem cells. Cell Cycle 2013 12 8 1166 1179 2-s2.0-84876231133 10.4161/cc.24479
9. Rattan R., Ali Fehmi R., Munkarah A., Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. Journal of Oncology 2012 2012 12 2-s2.0-84863686386 10.1155/2012/928127 928127
10. Bednar F., Simeone D. M., Metformin and cancer stem cells: old drug, new targets. Cancer Prevention Research 2012 5 3 351 354 2-s2.0-84859461497 10.1158/1940-6207.CAPR-12-0026
11. 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 Research 2009 69 7507 7511
12. Hirsch H. A., Iliopoulos D., Struhl K., Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proceedings of the National Academy of Sciences of the United States of America 2013 110 3 972 977 2-s2.0-84872529696 10.1073/pnas.1221055110
13. Shank J. J., Yang K., Ghannam J., Cabrera L., Johnston C. J., Reynolds R. K., Buckanovich R. J., Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecologic Oncology 2012 127 2 390 397 2-s2.0-84867405520 10.1016/j.ygyno.2012.07.115
14. Pignata S., Scambia G., Ferrandina G., Savarese A., Sorio R., Breda E., Gebbia V., Musso P., Frigerio L., Del Medico P., Lombardi A. V., Febbraro A., Scollo P., Ferro A., Tamberi S., Brandes A., Ravaioli A., Valerio M. R., Aitini E., Natale D., Scaltriti L., Greggi S., Pisano C., Lorusso D., Salutari V., Legge F., Di Maio M., Morabito A., Gallo C., Perrone F., Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. Journal of Clinical Oncology 2011 29 27 3628 3635 2-s2.0-80053074385 10.1200/JCO.2010.33.8566
15. Kwon M. J., Shin Y. K., Regulation of ovarian cancer stem cells or tumor-initiating cells. International Journal of Molecular Sciences 2013 14 4 6624 6648 2-s2.0-84875480132 10.3390/ijms14046624
16. Zhou B.-B. S., Zhang H., Damelin M., Geles K. G., Grindley J. C., Dirks P. B., Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nature Reviews Drug Discovery 2009 8 10 806 823 2-s2.0-70349638289 10.1038/nrd2137
17. Rizzo S., Hersey J. M., Mellor P., Dai W., Santos-Silva A., Liber D., Luk L., Titley I., Carden C. P., Box G., Hudson D. L., Kaye S. B., Brown R., Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Molecular Cancer Therapeutics 2011 10 2 325 335 2-s2.0-79951825513 10.1158/1535-7163.MCT-10-0788
18. Latifi A., Luwor R. B., Bilandzic M., Nazaretian S., Stenvers K., Pyman J., Zhu H., Thompson E. W., Quinn M. A., Findlay J. K., Ahmed N., Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PLoS ONE 2012 7 10 2-s2.0-84867320871 10.1371/journal.pone.0046858 e46858
19. Abubaker K., Latifi A., Luwor R., Nazaretian S., Zhu H., Quinn M. A., Thompson E. W., Findlay J. K., Ahmed N., Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden. Molecular Cancer 2013 12 1, article 24 2-s2.0-84875320058 10.1186/1476-4598-12-24
20. Steg A. D., Bevis K. S., Katre A. A., Ziebarth A., Dobbin Z. C., Alvarez R. D., Zhang K., Conner M., Landen C. N., Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clinical Cancer Research 2012 18 3 869 881 2-s2.0-84856534355 10.1158/1078-0432.CCR-11-2188
21. Kurrey N. K., Jalgaonkar S. P., Joglekar A. V., Ghanate A. D., Chaskar P. D., Doiphode R. Y., Bapat S. A., Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 2009 27 9 2059 2068 2-s2.0-70349859809 10.1002/stem.154
22. Ahmed N., Abubaker K., Findlay J., Quinn M., Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Current Cancer Drug Targets 2010 10 3 268 278 2-s2.0-77952855239 10.2174/156800910791190175
23. Latifi A., Abubaker K., Castrechini N., Ward A. C., Liongue C., Dobill F., Kumar J., Thompson E. W., Quinn M. A., Findlay J. K., Ahmed N., Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile. Journal of Cellular Biochemistry 2011 112 10 2850 2864 2-s2.0-80053211466 10.1002/jcb.23199
24. Huang R. Y.-J., Chung V. Y., Thiery J. P., Targeting pathways contributing to epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer. Current Drug Targets 2012 13 13 1649 1653 2-s2.0-84870176548 10.2174/138945012803530044
25. Ahmed N., Abubaker K., Findlay J., Quinn M., Cancerous ovarian stem cells: obscure targets for therapy but relevant to chemoresistance. Journal of Cellular Biochemistry 2013 114 1 21 34 2-s2.0-84869445970 10.1002/jcb.24317
26. Foster R., Buckanovich R. J., Rueda B. R., Ovarian cancer stem cells: working towards the root of stemness. Cancer Letters 2013 338 1 147 157 2-s2.0-84882843353 10.1016/j.canlet.2012.10.023
27. Bapat S. A., Mali A. M., Koppikar C. B., Kurrey N. K., Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Research 2005 65 8 3025 3029 2-s2.0-17144403478 (Pubitemid 40524578)
28. Ferrandina G., Martinelli E., Petrillo M., Prisco M. G., Zannoni G., Sioletic S., Scambia G., CD133 antigen expression in ovarian cancer. BMC Cancer 2009 9, article 221 2-s2.0-68049123605 10.1186/1471-2407-9-221
29. Ferrandina G., Bonanno G., Pierelli L., Perillo A., Procoli A., Mariotti A., Corallo M., Martinelli E., Rutella S., Paglia A., Zannoni G., Mancuso S., Scambia G., Expression of CD133-1 and CD133-2 in ovarian cancer. International Journal of Gynecological Cancer 2008 18 3 506 514 2-s2.0-43449110421 10.1111/j.1525-1438.2007.01056.x (Pubitemid 351668323)
30. Gao M.-Q., Choi Y.-P., Kang S., Youn J. H., Cho N.-H., CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene 2010 29 18 2672 2680 2-s2.0-77952240931 10.1038/onc.2010.35
31. Zhang S., Balch C., Chan M. W., Lai H.-C., Matei D., Schilder J. M., Yan P. S., Huang T. H.-M., Nephew K. P., Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Research 2008 68 11 4311 4320 2-s2.0-49249091523 10.1158/0008-5472.CAN-08-0364
32. Landen C. N. Jr., Goodman B., Katre A. A., Steg A. D., Nick A. M., Stone R. L., Miller L. D., Mejia P. V., Jennings N. B., Gershenson D. M., Bast R. C. Jr., Coleman R. L., Lopez-Berestein G., Sood A. K., Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Molecular Cancer Therapeutics 2010 9 12 3186 3199 2-s2.0-78650455641 10.1158/1535-7163.MCT-10-0563
33. Goodell M. A., McKinney-Freeman S., Camargo F. D., Isolation and characterization of side population cells. Methods in Molecular Biology 2005 290 343 352 2-s2.0-16644394284
34. Silva I. A., Bai S., McLean K., Yang K., Griffith K., Thomas D., Ginestier C., Johnston C., Kueck A., Reynolds R. K., Wicha M. S., Buckanovich R. J., Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Research 2011 71 11 3991 4001 2-s2.0-79957917044 10.1158/0008-5472.CAN-10-3175
35. Burgos-Ojeda D., Rueda B. R., Buckanovich R. J., Ovarian cancer stem cell markers: prognostic and therapeutic implications. Cancer Letters 2012 322 1 1 7 2-s2.0-84861460366 10.1016/j.canlet.2012.02.002
36. Zhan Q., Wang C., Ngai S., Ovarian cancer stem cells: a new target for cancer therapy. BioMed Research International 2013 2013 10 2-s2.0-84874644333 10.1155/2013/916819 916819
37. Warburg O., On the origin of cancer cells. Science 1956 123 3191 309 314 2-s2.0-12444279265
38. Suh D. H., Kim M. A., Kim H., Kim M.-K., Kim H. S., Chung H. H., Kim Y.-B., Song Y. S., Association of overexpression of hexokinase II with chemoresistance in epithelial ovarian cancer. Clinical and Experimental Medicine 2013 2-s2.0-84881347194 10.1007/s10238-013-0250-9
39. Chung S., Dzeja P. P., Faustino R. S., Perez-Terzic C., Behfar A., Terzic A., Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nature Clinical Practice Cardiovascular Medicine 2007 4 1 S60 S67 2-s2.0-33846501510 10.1038/ncpcardio0766 (Pubitemid 46151906)
40. Folmes C. D. L., Nelson T. J., Martinez-Fernandez A., Arrell D. K., Lindor J. Z., Dzeja P. P., Ikeda Y., Perez-Terzic C., Terzic A., Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metabolism 2011 14 2 264 271 2-s2.0-79960945131 10.1016/j.cmet.2011.06.011
41. Panopoulos A. D., Yanes O., Ruiz S., Kida Y. S., Diep D., Tautenhahn R., Herrerías A., Batchelder E. M., Plongthongkum N., Lutz M., Berggren W. T., Zhang K., Evans R. M., Siuzdak G., Belmonte J. C. I., The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Research 2012 22 1 168 177 2-s2.0-84855490988 10.1038/cr.2011.177
42. Zhang J., Khvorostov I., Hong J. S., Oktay Y., Vergnes L., Nuebel E., Wahjudi P. N., Setoguchi K., Wang G., Do A., Jung H.-J., McCaffery J. M., Kurland I. J., Reue K., Lee W.-N. P., Koehler C. M., Teitell M. A., UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO Journal 2011 30 24 4860 4873 2-s2.0-83455235489 10.1038/emboj.2011.401
43. Zhang J., Nuebel E., Daley G. Q., Koehler C. M., Teitell M. A., Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 2012 11 5 589 595 2-s2.0-84868351585 10.1016/j.stem.2012.10.005
44. Folmes C. D., Nelson T. J., Terzic A., Energy metabolism in nuclear reprogramming. Biomarkers in Medicine 2011 5 6 715 729 2-s2.0-82755195582 10.2217/bmm.11.87
45. Liao J., Qian F., Tchabo N., Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS ONE 2014 9 e84941
46. Martinez-Outschoorn U. E., Prisco M., Ertel A., Tsirigos A., Lin Z., Pavlides S., Wang C., Flomenberg N., Knudsen E. S., Howell A., Pestell R. G., Sotgia F., Lisanti M. P., Ketones and lactate increase cancer cell "stemness" driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via metabolo-genomics. Cell Cycle 2011 10 8 1271 1286 2-s2.0-79954537559 10.4161/cc.10.8.15330
47. Heddleston J. M., Li Z., Lathia J. D., Bao S., Hjelmeland A. B., Rich J. N., Hypoxia inducible factors in cancer stem cells. British Journal of Cancer 2010 102 5 789 795 2-s2.0-77649273107 10.1038/sj.bjc.6605551
48. Strauss R., Li Z.-Y., Liu Y., Beyer I., Persson J., Sova P., Möller T., Pesonen S., Hemminki A., Hamerlik P., Drescher C., Urban N., Bartek J., Lieber A., Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS ONE 2011 6 1 2-s2.0-79251540883 10.1371/journal.pone.0016186 e16186
49. Abelson S., Shamai Y., Berger L., Shouval R., Skorecki K., Tzukerman M., Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer. Stem Cells 2012 30 3 415 424 2-s2.0-84857485231 10.1002/stem.1029
50. Mor G., Yin G., Chefetz I., Yang Y., Alvero A., Ovarian cancer stem cells and inflammation. Cancer Biology and Therapy 2011 11 8 708 713 2-s2.0-79954622491 10.4161/cbt.11.8.14967
51. McLean K., Gong Y., Choi Y., Deng N., Yang K., Bai S., Cabrera L., Keller E., McCauley L., Cho K. R., Buckanovich R. J., Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. Journal of Clinical Investigation 2011 121 8 3206 3219 2-s2.0-79961006281 10.1172/JCI45273
52. Medema J. P., Cancer stem cells: the challenges ahead. Nature Cell Biology 2013 15 4 338 344 2-s2.0-84876489727 10.1038/ncb2717
53. Kelly M. G., Alvero A. B., Chen R., Silasi D.-A., Abrahams V. M., Chan S., Visintin I., Rutherford T., Mor G., TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Research 2006 66 7 3859 3868 2-s2.0-33645727988 10.1158/0008-5472.CAN-05-3948
54. Chen R., Alvero A. B., Silasi D. A., Kelly M. G., Fest S., Visintin I., Leiser A., Schwartz P. E., Rutherford T., Mor G., Regulation of IKK β by miR-199a affects NF- B activity in ovarian cancer cells. Oncogene 2008 27 34 4712 4723 2-s2.0-49149091917 10.1038/onc.2008.112
55. Cao L., Shao M., Schilder J., Guise T., Mohammad K. S., Matei D., Tissue transglutaminase links TGF- Β epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene 2012 31 20 2521 2534 2-s2.0-84861344069 10.1038/onc.2011.429
56. Pasquier J., Rafii A., Role of the microenvironment in ovarian cancer stem cell maintenance. BioMed Research International 2013 2013 10 2-s2.0-84874599849 10.1155/2013/630782 630782
57. Liang D., Ma Y., Liu J., Trope C. G., Holm R., Nesland J. M., Suo Z., The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells. BMC Cancer 2012 12, article 201 2-s2.0-84861466196 10.1186/1471-2407-12-201
58. Chau W. K., Ip C. K., Mak A. S. C., Lai H.-C., Wong A. S. T., C-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/ β -catenin-ATP-binding cassette G2 signaling. Oncogene 2013 32 22 2767 2781 2-s2.0-84879410940 10.1038/onc.2012.290
59. Yin G., Alvero A. B., Craveiro V., Holmberg J. C., Fu H.-H., Montagna M. K., Yang Y., Chefetz-Menaker I., Nuti S., Rossi M., Silasi D.-A., Rutherford T., Mor G., Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential. Oncogene 2013 32 1 39 49 2-s2.0-84871952125 10.1038/onc.2012.33
60. Chen R., Nishimura M. C., Bumbaca S. M., Kharbanda S., Forrest W. F., Kasman I. M., Greve J. M., Soriano R. H., Gilmour L. L., Rivers C. S., Modrusan Z., Nacu S., Guerrero S., Edgar K. A., Wallin J. J., Lamszus K., Westphal M., Heim S., James C. D., VandenBerg S. R., Costello J. F., Moorefield S., Cowdrey C. J., Prados M., Phillips H. S., A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 2010 17 4 362 375 2-s2.0-77950502115 10.1016/j.ccr.2009.12.049
61. Gupta P. B., Fillmore C. M., Jiang G., Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011 146 633 644 10.1016/j.cell.2011.07.026
62. Chan D. K., Miskimins W. K., Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures. Journal of Ovarian Research 2012 5 1, article 19 2-s2.0-84863583356 10.1186/1757-2215-5-19
63. Erices R., Bravo M. L., Gonzalez P., Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. Reproductive Sciences 2013 20 1433 1446 10.1177/1933719113488441
64. Rattan R., Graham R. P., Maguire J. L., Giri S., Shridhar V., Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in Vivo. Neoplasia 2011 13 5 483 491 2-s2.0-79955834631 10.1593/neo.11148
65. Yasmeen A., Beauchamp M.-C., Piura E., Segal E., Pollak M., Gotlieb W. H., Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecologic Oncology 2011 121 3 492 498 2-s2.0-79957438835 10.1016/j.ygyno.2011.02.021
66. Rattan R., Giri S., Hartmann L. C., Shridhar V., Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. Journal of Cellular and Molecular Medicine 2011 15 1 166 178 2-s2.0-78751692291 10.1111/j.1582-4934.2009.00954.x
67. Gotlieb W. H., Saumet J., Beauchamp M.-C., Gu J., Lau S., Pollak M. N., Bruchim I., In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecologic Oncology 2008 110 2 246 250 2-s2.0-47249088612 10.1016/j.ygyno.2008.04.008
68. Iliopoulos D., Hirsch H. A., Struhl K., Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Research 2011 71 9 3196 3201 2-s2.0-79955490053 10.1158/0008-5472.CAN-10-3471
69. Prigione A., Lichtner B., Kuhl H., Struys E. A., Wamelink M., Lehrach H., Ralser M., Timmermann B., Adjaye J., Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming. Stem Cells 2011 29 9 1338 1348 2-s2.0-80052015415 10.1002/stem.683
70. Vazquez-Martin A., Vellon L., Quirós P. M., Cufí S., De Galarreta E. R., Ferraros C. O., Martin A. G., Martin-Castillo B., Lopez-Otin C., Menendez J. A., Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells. Cell Cycle 2012 11 5 974 989 2-s2.0-84857927867 10.4161/cc.11.5.19450
71. Buckendahl A.-C., Budczies J., Fiehn O., Darb-Esfahani S., Kind T., Noske A., Weichert W., Sehouli J., Braicu E., Dietel M., Denkert C., Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: correlation of protein expression and GC/TOF-MS-based metabolomics. Oncology Reports 2011 25 4 1005 1012 2-s2.0-79952215103 10.3892/or.2011.1162
72. Lee J.-Y., Jeon I., Kim J. W., Song Y.-S., Yoon J.-M., Park S. M., Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies. International Journal of Gynecological Cancer 2013 23 3 402 412 2-s2.0-84876229777 10.1097/IGC.0b013e31828189b2
73. Bakhru A., Buckanovich R. J., Griggs J. J., The impact of diabetes on survival in women with ovarian cancer. Gynecologic Oncology 2011 121 1 106 111 2-s2.0-79952817723 10.1016/j.ygyno.2010.12.329
74. Jalving M., Gietema J. A., Lefrandt J. D., Jong S. D., Reyners A. K. L., Gans R. O. B., Vries E. G. E. D., Metformin: taking away the candy for cancer? European Journal of Cancer 2010 46 13 2369 2380 2-s2.0-77955923866 10.1016/j.ejca.2010.06.012
75. Evans J. M. M., Donnelly L. A., Emslie-Smith A. M., Alessi D. R., Morris A. D., Metformin and reduced risk of cancer in diabetic patients. The British Medical Journal 2005 330 7503 1304 1305 2-s2.0-20444461067 10.1136/bmj.38415. 708634.F7 (Pubitemid 40813563)
76. Kumar S., Meuter A., Thapa P., Langstraat C., Giri S., Chien J., Rattan R., Cliby W., Shridhar V., Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer 2013 119 3 555 562 2-s2.0-84872978681 10.1002/cncr.27706
77. Dilokthornsakul P., Chaiyakunapruk N., Termrungruanglert W., Pratoomsoot C., Saokeaw S., Sruamsiri R., The effects of metformin on ovarian cancer: a systematic review. International Journal of Gynecological Cancer 2013 23 1544 1551 10.1097/IGC.0b013e3182a80a21
78. Pollak M., Insulin and insulin-like growth factor signalling in neoplasia. Nature Reviews Cancer 2008 8 12 915 928 2-s2.0-56749184290 10.1038/nrc2536
79. Goodwin P., Pritchard K., Ennis M., Clemons M., Graham M., Fantus I. G., Insulin-lowering effects of metformin in women with early breast cancer. Clinical Breast Cancer 2008 8 6 501 505 2-s2.0-60549102941 10.3816/CBC.2008.n. 060
80. Owen M. R., Doran E., Halestrap A. P., Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal 2000 348 3 607 614 2-s2.0-0034659785 10.1042/0264-6021:3480607 (Pubitemid 30410251)
81. Pollak M. N., Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discovery 2012 2 9 778 790 2-s2.0-84866322945 10.1158/2159-8290.CD-12-0263
82. No J. H., Jeon Y.-T., Park I.-A., Kim Y.-B., Kim J. W., Park N.-H., Kang S.-B., Han J. Y., Lim J. M., Song Y.-S., Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer. Gynecologic Oncology 2011 121 1 8 12 2-s2.0-79952818313 10.1016/j.ygyno.2010.12. 364
83. Viollet B., Guigas B., Sanz Garcia N., Leclerc J., Foretz M., Andreelli F., Cellular and molecular mechanisms of metformin: an overview. Clinical Science 2012 122 6 253 270 2-s2.0-84855603512 10.1042/CS20110386
84. 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. Molecular Cell 2005 18 3 283 293 2-s2.0-20844449238 10.1016/j.molcel.2005.03.027 (Pubitemid 41350534)
85. Buzzai M., Jones R. G., Amaravadi R. K., Lum J. J., DeBerardinis R. J., Zhao F., Viollet B., Thompson C. B., Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Research 2007 67 14 6745 6752 2-s2.0-34547114031 10.1158/0008-5472.CAN-06-4447 (Pubitemid 47105521)
86. Algire C., Amrein L., Bazile M., David S., Zakikhani M., Pollak M., Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 2011 30 10 1174 1182 2-s2.0-79952538201 10.1038/onc.2010.483
87. Sahra I. B., Laurent K., Giuliano S., Larbret F., Ponzio G., Gounon P., Le Marchand-Brustel Y., Giorgetti-Peraldi S., Cormont M., Bertolotto C., Deckert M., Auberger P., Tanti J.-F., Bost F., Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Research 2010 70 6 2465 2475 2-s2.0-77950191479 10.1158/0008-5472.CAN-09-2782
88. Cheong J.-H., Park E. S., Liang J., Dennison J. B., Tsavachidou D., Nguyen-Charles C., Cheng K. W., Hall H., Zhang D., Lu Y., Ravoori M., Kundra V., Ajani J., Lee J.-S., Hong W. K., Mills G. B., Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Molecular Cancer Therapeutics 2011 10 12 2350 2362 2-s2.0-83355163333 10.1158/1535-7163.MCT-11-0497
89. Priebe A., Tan L., Wahl H., Kueck A., He G., Kwok R., Opipari A., Liu J. R., Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells. Gynecologic Oncology 2011 122 2 389 395 2-s2.0-79960455638 10.1016/j.ygyno.2011.04.024
90. Tanwar P. S., Mohapatra G., Chiang S., Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. Carcinogenesis 2013 35 3 546 553
91. Macciò A., Madeddu C., Inflammation and ovarian cancer. Cytokine 2012 58 2 133 147 2-s2.0-84859219044 10.1016/j.cyto.2012.01.015
92. Ersoy C., Kiyici S., Budak F., Oral B., Guclu M., Duran C., Selimoglu H., Erturk E., Tuncel E., Imamoglu S., The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Research and Clinical Practice 2008 81 1 56 60 2-s2.0-44649103918 10.1016/j.diabres.2008.02. 006
93. Lund S. S., Tarnow L., Stehouwer C. D. A., Schalkwijk C. G., Teerlink T., Gram J., Winther K., Frandsen M., Smidt U. M., Pedersen O., Parving H.-H., Vaag A. A., Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. European Journal of Endocrinology 2008 158 5 631 641 2-s2.0-43149110575 10.1530/EJE-07-0815 (Pubitemid 351639600)
94. Huang N.-L., Chiang S.-H., Hsueh C.-H., Liang Y.-J., Chen Y.-J., Lai L.-P., Metformin inhibits TNF- α -induced I B kinase phosphorylation, I B- α degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. International Journal of Cardiology 2009 134 2 169 175 2-s2.0-64849117472 10.1016/j.ijcard.2008.04.010
95. Salminen A., Hyttinen J. M. T., Kaarniranta K., AMP-activated protein kinase inhibits NF- B signaling and inflammation: impact on healthspan and lifespan. Journal of Molecular Medicine 2011 89 7 667 676 2-s2.0-79959956336 10.1007/s00109-011-0748-0
96. Wu B., Li S., Sheng L., Zhu J., Gu L., Shen H., La D., Hambly B. D., Bao S., Di W., Metformin inhibits the development and metastasis of ovarian cancer. Oncology Reports 2012 28 3 903 908 2-s2.0-84865317251 10.3892/or.2012.1890
97. Liao H., Zhou Q., Gu Y., Duan T., Feng Y., Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through the mTOR signaling pathway. Oncology Reports 2012 27 6 1873 1878 2-s2.0-84860784421 10.3892/or.2012.1745
98. Stambolic V., Woodgett J. R., Fantus I. G., Pritchard K. I., Goodwin P. J., Utility of metformin in breast cancer treatment, is neoangiogenesis a risk factor? Breast Cancer Research and Treatment 2009 114 2 387 389 2-s2.0-59449091120 10.1007/s10549-008-0015-4
99. Lonardo E., Cioffi M., Sancho P., Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS ONE 2013 8 e76518