• Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
REVIEW
Year : 2016  |  Volume : 2  |  Issue : 4  |  Page : 119-124

Metformin in ovarian cancer therapy: A discussion


1 Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China
3 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Date of Submission23-Dec-2015
Date of Acceptance10-Jun-2016
Date of Web Publication26-Aug-2016

Correspondence Address:
Jianfeng Guo
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.189306

Rights and Permissions
  Abstract 

Overweight and obesity are dramatically increasing worldwide. In addition to being the most important factor for the increase in diabetes prevalence, there is a growing evidence of obesity being also significantly associated with the risks and poor outcome in ovarian cancer (OVC). Metformin is the most widely used first-line type 2 diabetes drug, currently being studied for its association with the decreased risk of occurrence and better survival of OVC patients. In this review, we discussed the proposed mechanisms of metformin-exerted anticancer effects, as well as the preclinical and clinical data suggesting its beneficial effect against this devastating condition.

Keywords: Anticancer effect, metformin, ovarian cancer


How to cite this article:
Ouyang Y, Chen X, Zhang C, Bunyamanop V, Guo J. Metformin in ovarian cancer therapy: A discussion. Cancer Transl Med 2016;2:119-24

How to cite this URL:
Ouyang Y, Chen X, Zhang C, Bunyamanop V, Guo J. Metformin in ovarian cancer therapy: A discussion. Cancer Transl Med [serial online] 2016 [cited 2017 Nov 21];2:119-24. Available from: http://www.cancertm.com/text.asp?2016/2/4/119/189306


  Introduction Top


Owing to the change in food habits and lifestyle, overweight and obesity are on a dramatic rise worldwide; more than 60% of the adult obese population are distributed in developed countries, and obese population is increasing rapidly in developing countries.[1],[2],[3] Based on the National Health and Nutrition Examination Study (NHANES) in 2011–2012, the prevalence of obesity in the United States was 16.9% in youth and 34.9% in adults.[4] As Hippocrates wrote “Corpulence is not only a disease itself, but the harbinger of others,” apart from contributing to heart disease and diabetes, obesity is a major acknowledged risk factor for cancer such as carcinoma of breast (postmenopausal), ovaries (postmenopausal), endometrium (postmenopausal), kidney, and colon (in men).[5],[6],[7],[8],[9] Moreover, evidences point out the role of obesity in cancer recurrence and related mortality.[6] Obesity is also found to be associated with poor wound healing, postoperative infections, and lymphedema, as well as the development of comorbid illness (e.g., cardiovascular disease, cerebrovascular disease, and diabetes) and functional decline in cancer survivors.[10] In addition, obesity places individuals at a greater risk for developing second primary malignancies.[11],[12],[13]

Pertaining to the scope of this study, there is growing evidence that obesity is significantly associated with risks and poor outcome in ovarian cancer (OVC). Epidemiological study has reported that obesity is related to OVC incidence, with systematic reviews reporting that the risk of epithelial ovarian cancer (EOC) among obese women was up to 30% higher than that in women with a healthy body mass index (BMI; 95% confidence interval [CI], 1.1–1.5).[14] A recent meta-analysis including 25,157 women with OVC and 81,311 women without OVC reported that the relative risk for OVC occurrence, per 5 kg/m [2] increase in body mass index, was 1.10 (95% CI, 1.07–1.13; P < 0.001) in never-users of menopausal hormone replacement therapy (HRT) and 0.95 (95% CI, 0.92–0.99; P = 0.02) in ever-users of HRT, thus establishing a significant association between OVC and obesity.[15] According to the authors' postulation, the high concentrations of exogenous estrogen, associated with HRT, would prevail on the impact of endogenous estrogen originating from the adipose tissue. In addition, Poorolajal et al.[16] reported that an increase in BMI can increase the risk of OVC regardless of the menopausal status.[16] The effect of obesity on OVC survival has been evaluated by a large meta-analysis, reporting that obesity 5 years before OVC diagnosis and obesity at a young age were associated with a poor prognosis while the association between obesity at diagnosis and survival of OVC patients remains equivocal,[17] similar to the reported results of Yang et al.[18] which show a possible relationship between obesity in early adulthood and higher mortality.

Evidence from a study, based on the NHANES, supports that change in BMI over time was the most important factor for the increase in diabetes prevalence.[19] Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence of, and mortality associated with, many cancers. Multiple factors, including hyperinsulinemia, overexpressing insulin-like growth factor I, hyperglycemia, dyslipidemia, adipose tissue factors, and the changes in gut microbiome, potentially contribute to the progression of cancer in obesity and type 2 diabetes.[9],[20],[21] These metabolic changes may contribute directly or indirectly to cancer progression.

Metformin, a biguanide, approved to be used as an antidiabetic in 1970s in Europe and 1995 in the United States,[22] remains as the most widely used first-line drug in the treatment of type 2 diabetes.[23] Its common side effects are diarrhea, nausea, and irritation of abdomen, while its major side effects include toxicity due to lactic acidosis, rarely seen in patients prone to the condition (for example, advanced renal insufficiency and alcoholism).[23] Interest in the potential role of metformin in cancer was stimulated by a seminal 2005 study,[24] reporting reduced risk of cancer in diabetic patients treated with metformin, as compared to those treated with other therapies, which led to numerous epidemiologic and preclinical studies. Several preclinical studies have demonstrated that metformin is most likely to inhabit the respiratory chain complex I and then regulates cell physiological activities by activating or inhibiting downstream proteins such as LKB1, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and mTOR.[25],[26],[27],[28] Here, we discuss the proposed mechanisms of anticancer effect of metformin as well as the preclinical and clinical data in OVC.


  Epidemiology of Ovarian Cancer Top


Ovarian neoplasms are classified according to the tissue of origin, such as EOCs, sex cord-stromal tumors, and germ cell tumors. EOC accounts for over 90% of all ovarian malignancies and are managed similar to primary peritoneal cancer and  Fallopian tube More Details cancer.[29] In the United States, OVC is the second most frequent invasive malignancy of the female genital tract next to the uterine corpus carcinoma, which also ranks as the 5th deadliest cancers in women.[30] OVC is the most lethal gynecologic malignancy, largely due to the advanced stage at diagnosis in most patients (approximately 61%), with a very poor 5-year survival rate.[24] OVC is primarily a disease of postmenopausal women; approximately, 70% of the diagnosis and 85% of the deaths occur after the age of 55.[31] In the United States alone, 21,980 new OVC cases and 14,270 related deaths were estimated in 2014.[30]

Few risk factors identified to increase the risk of OVC are HRT,[32] talcum powder,[33] high body mass index,[15] and endometriosis,[34] which is associated with greater lifetime ovulation and/or greater lifetime estrogen exposure or inflammatory conditions. In addition, approximately, 17% of all OVCs are attributable to a mutation in an OVC susceptibility gene that confers a lifetime OVC risk of 5% or more. Mutations in BRCA1 and BRCA2 are responsible for 13% of all OVCs, while mutations in the four mismatch repair genes MSH2, MLH1, MSH6, and PMS2 that cause hereditary nonpolyposis colorectal cancer (Lynch syndrome) account for about 0.8% of OVCs, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2, also contribute to the condition.[35],[36] The known prognosis-determining factors include stage, age, histology, success of debulking surgery, and performance status, while the stage of disease at diagnosis remains the most significant predictor of survival time.


  Preclinical Studies of Metformin and Ovarian Cancer Top


Numerous experimental data show that metformin exerts anti-cancer effects through indirect effect, by circulating blood glucose and insulin, and through direct effect, by regulating cellular energy and signal pathway, in OVC.[37],[38] AMPK plays an important role in these effects.[39],[40] A large amount of evidences demonstrate that metformin activates AMPK with a likely underlying mechanism of suppressing respiratory chain complex I [25],[26] and increasing AMP/ATP ratio, resulting in LKB1-mediated [28],[41] activation of AMPK by phosphorylating its α subunit 172 site tyrosine residues.[42],[43] Being a crucial cellular energy regulator, AMPK, a heterotrimeric serine/threonine kinase, in its activated form can modulate the activity of downstream protein to regulate cellular metabolism and diverse signal pathway including suppressing lipogenesis, inhibiting ark-mTOR pathway, and causing cell cycle arrest.[39],[44]

Metformin's indirect effect on ovarian cancer

Several preclinical studies demonstrate the metformin's indirect effect on OVC, the mechanism of which includes the inhibition of hepatic gluconeogenesis and increasing peripheral glucose uptake,[45],[46],[47] subsequently resulting in lower glucose, insulin, and IGF-1 levels in circulation.[48],[49] Hyperglycemia attenuates metformin sensitivity in OVC while stimulating the OVC progression.[50],[51] Similarly, in hyperinsulinemia, IGF-1 levels also stimulate the risk of OVC by activating PI3K/Akt/mTOR pathway, through IGF-1R signaling.[37],[52],[53],[54] A careful observation of the above data also suggested that the metformin cannot play an indirect effect in nondiabetic patients.[55]

Metformin's direct effect on ovarian cancer

Both in vivo and in vitro studies have proved that metformin could significantly inhibit the proliferation of OVC cells and stem cells.[55],[56],[57] Further, recent studies indicate that metformin suppresses OVC cell proliferation through both AMPK-independent and AMPK-dependent pathway.[58],[59]

In the AMPK-independent pathway, metformin can induce mTOR inhibition and cell-cycle arrest through REDD1[60] and through a rag GTPase-dependent manner,[59],[61] whereas in AMPK-dependent pathway, metformin-induced pAMPK can induce the cell cycle's arrest through several mechanisms as follows: (1) The activated AMPK will not only reduce the cyclinD1 levels, but also increase p21 levels which then suppress the cell cycle at G1-phase. However, metformin cannot affect p27.[58],[62] (2) pAMPK can negatively regulate mTOR through direct suppression or through tuberous sclerosis complex 2 (TSC2) phosphorylation, and through Rheb.[40],[63],[64],[65] PIK3/Ark/mTOR pathway is a typical pro-survival signaling pathway that always shows hyperactivity in OVC.[66],[67] Activation of this pathway can promote proliferation of cancer cells by stimulating protein synthesis,[68],[69] and it is pointed out that this pathway also have a strong potential association with the invasive and migratory capacities of human OVC cell lines.[70] More importantly, the activated PI3K/AKT/mTOR pathway will activate the apoptotic inhibitor, survivin, and abolish p53 response to pro-apoptotic factors, thus supporting the chemoresistance of OVC.[62],[71],[72],[73] In other words, the combination therapy using metformin and chemotherapeutic drug, such as metformin and cisplatin or metformin and LY294002, can be more useful.[56],[62],[74],[75],[76] (3) Metformin-induced AMPK can change the cellular metabolism by suppressing lipogenesis in the AMPK-independent pathway.[77] While metformin-induced AMPK will alter the activity of acetyl-CoA carboxylase to promote fatty acid oxidation, it will also regulate transcription factors such as sterol regulatory element-binding protein-1 to inhibit adipogenesis.[77],[78],[79]

Recent studies also suggest that metformin exhibits slight cytotoxicity to OVC cells.[48],[57],[58] However, if the cells lose the compensatory mechanism, like the function of AMPK, LKB1, or p53, metformin can exert a higher cytotoxicity.[80] A recent study indicates that under hyperglycemic condition, metformin can increase c-myc gene expression which will stimulate ATP production, as a response to ATP depletion, through increasing the anaerobic glycolysis flux.[50] In line with this, some studies demonstrate an attenuation in anti-tumor effects of metformin under simulated hyperglycemic conditions (25 mM glucose), in vitro.[50],[55] Furthermore, although several in vitro studies have demonstrated that metformin could induce apoptosis in cancer cells, as evidenced through decreased anti-apoptotic Bcl-2, Survivin and Bcl-xL, and increasing Bax and Cytochrome c,[81],[82],[83] few studies link this effect to the concentration of metformin used in such studies which is significantly higher than what is achieved under in vivo conditions.[38],[84] However, some investigators suggest that, to compensate for the short duration of in vitro studies, high doses of metformin should be used to mimic its effect under longer periods of treatment in vivo.[74]

In addition, a recent study reported that metformin could not only induce autophagy by detecting increased LC3B conversion, improved ATG12-ATG5 expression, and decreased p62 levels, but also could induce unfold protein response (UPR) through protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2 alpha kinase pathway in OVC.[85] However, further research indicates that metformin-induced autophagy and UPR will inhibit metformin-induced cell apoptosis.[86] Currently, few studies also suggest that metformin will suppress cytokines such as monocyte chemotactic protein-1, interleukin-6, and the angiogenic factor vascular endothelial growth factor to reduce inflammation and angiogenesis.[77],[79],[87]


  Epidemiology of Metformin and Ovarian Cancer Top


There are few epidemiological studies assessing the association between metformin and the risk of OVC. Home et al.[88] extracted data for malignancies in two randomized controlled clinical trials in diabetes patients: a diabetes outcome progression trial (ADOPT) and Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes (RECORD) studies, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone. In ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide group developed malignancies, and this was reported as a serious adverse event (excluding nonmelanoma skin cancers), which corresponds to 1.03, 1.12, and 1.31 per 100 person-years, respectively, giving hazard ratios (HRs) for metformin of 0.92 (95% CI, 0.63–1.35) vs. rosiglitazone and 0.78 (95% CI, 0.53–1.14) vs. glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, as compared to 56 (5.1%) in the rosiglitazone group (HR: 1.22 [0.85–1.74]).[67] In this study, no significant differences were found in OVC incidence between metformin users and nonmetformin users, in addition to the number of OVCs being small in both trials.

By using the UK-based General Practice Research Database, a retrospective case–control study by Bodmer et al.[89] compared metformin with other hypoglycemic agents, and assessed the relation between exposure to metformin and the risk of OVC. They noted that the long-term use (s30 prescriptions) of metformin, without sulfonylureas, was associated with a tendency toward reduced risk of OVC (OR: 0.61, 95% CI: 0.30–1.25), whereas the long-term use (s40 prescriptions) of insulin was associated with a slightly increased risk of OVC (OR: 2.29, 95% CI: 1.13–4.65). Further, in a nested case–control analysis, restricted to women with diabetes mellitus, the protective effect of metformin was found to be slightly stronger as reflected by a statistically significant association of ≥ 10 prescriptions of metformin with a decreased risk of OVC (OR: 0.38, 95% CI: 0.18–0.81).

Tseng [90] pooled the currently available data from a system of NHI, implemented in Taiwan, to examine the association between metformin therapy and OVC among Asian patients with T2DM. Data of a total of 479,475 Taiwanese female patients, newly diagnosed of type 2 diabetes mellitus between 1998 and 2002, were retrieved for follow-up until the end of 2009, tracking for an incidence of OVC. The results of the trial showed a significant lower risk of OVC occurrence associated with the use of metformin, with the overall fully adjusted HR for ever-users vs. never-users found to be 0.658 (95% CI: 0.593–0.730). Further, a significantly reduced risk was observed with increasing cumulative duration and cumulative dose of metformin. However, the first tertile of the dose–response parameters showed a significantly higher risk associated with metformin use, while the second and the third tertiles showed opposite trends. Furthermore, sulfonylurea, but not the other antidiabetic drugs, was also observed to be associated with a reduced risk of OVC.

A few clinical studies suggest that metformin is associated with a decreased incidence of OVC in diabetic population,[90] while the benefits of metformin therapy on the reduced risk for nondiabetic OVC patients are still unknown.

Romero et al.[91] conducted a retrospective cohort study assessing the association between diabetes, metformin use, and OVC, among 341 OVC patients. The progression-free survival rate, at 5 years, of women without diabetes not using metformin, women with diabetes not using metformin, and diabetic women using metformin was 23%, 8%, and 51% (the adjusted HR was 0.38 [95% CI, 0.16–0.90]), respectively. While, the adjusted HR for overall survival of diabetic patients using metformin, nondiabetic patients using metformin, and diabetic patients not using metformin was 0.43 (95% CI, 0.16–1.19), showing no significant association.

In a retrospective cohort study by Kumar et al.,[92] the OVC patients were divided into an OVC cohort (72 cases with metformin therapy and 143 controls without metformin therapy) and an EOC cohort (61 cases with metformin therapy and 178 controls without metformin therapy). In the OVC cohort, the 5-year disease-specific survival for cases vs. controls was 73% vs. 44% (P = 0.002), respectively. In addition, the adjusted HR (95% CI) was 0.37 (0.19–0.71), indicating a significant association between metformin and better survival in OVC patients. The result in the EOC cohort was similar to that of the OVC cohort, but the adjusted HR in diabetes patients was not reported. Overall, they noted an association of metformin intake with better survival in patients with OVC, despite the small sample size.

There are several clinical trials (www.clinical trials.gov) underway assessing OVC patients with metformin in combination with chemotherapy. The University of Michigan is conducting a phase II, open-label evaluation of metformin in combination with chemotherapy before and after surgery for the treatment of advanced ovarian/fallopian tube and primary peritoneal cancer (NCT01579812). The University of Chicago is conducting a phase II, randomized trial of metformin in combination with standard chemotherapy for the treatment of advanced ovarian/fallopian tube and primary peritoneal cancer (NCT02122185). The University Medical Center Groningen is conducting a phase I, open-label evaluation for the safety of metformin in combination with chemotherapy for the treatment of advanced OVC (NCT02312661). The Gynecologic Oncology Associates has recently initiated a phase II, open-label, nonrandomized, pilot study of metformin in combination with chemotherapy for the treatment of advanced ovarian/fallopian tube and primary peritoneal cancer (NCT02437812). The results of these trials are hoped to be of value in establishing/strengthening the association of metformin in the prognosis of OVC patients.


  Conclusion Top


The epidemiologic and preclinical data evaluated in this review are supportive of the use of metformin for the prevention and treatment of OVC. Preclinical evidence suggests that metformin possesses anticancer effects on OVC. Results of clinical studies, although a few, suggest that using metformin, pertaining to its cumulative dose and duration of therapy, is associated with a decreased incidence of OVC in diabetic population. In addition, it is also found to be associated with a better survival of OVC patients with diabetes. There are many unanswered questions though, including: (1) Whether metformin has anti-cancer activity in nondiabetics? (2) Whether we can use tumor genetic profiling to identify patients who are most likely to benefit from metformin treatment? (3) Considering the supra-clinical doses of metformin used in preclinical in vitro models to obtain an antineoplastic effect, should the optimal dose of metformin for OVC be revised and/or should it need a new route of drug delivery? (4) Do the serious side effects of supra-clinical doses or long-term therapy of metformin exist? If so, how to avoid these side effects? Future studies are hoped to warrant such questions, the results of which should be of value in determining metformin as a standard line of treatment for OVC patients.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (81202058).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006; 84 (2): 289–98.  Back to cited text no. 1
    
2.
Popkin BM, Slining MM. New dynamics in global obesity facing low- and middle-income countries. Obes Rev2013; 14 Suppl 2: 11–20.  Back to cited text no. 2
    
3.
Wang GR, Li L, Pan YH, Tian GD, Lin WL, Li Z, Chen ZY, Gong YL, Kikano GE, Stange KC, Ni KL, Berger NA. Prevalence of metabolic syndrome among urban community residents in China. BMC Public Health 2013; 13: 599.  Back to cited text no. 3
    
4.
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311 (8): 806–14.  Back to cited text no. 4
    
5.
Keum N, Greenwood DC, Lee DH, Kim R, Aune D, Ju W, Hu FB, Giovannucci EL. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. J Natl Cancer Inst 2015; 107 (2): pii: djv088.  Back to cited text no. 5
    
6.
Larsson SC, Wolk A. Obesity and colon and rectal cancer risk: A meta-analysis of prospective studies. Am J Clin Nutr 2007; 86 (3): 556–65.  Back to cited text no. 6
    
7.
Cheraghi Z, Poorolajal J, Hashem T, Esmailnasab N, Doosti Irani A. Effect of body mass index on breast cancer during premenopausal and postmenopausal periods: a meta-analysis. PLoS One 2012; 7 (12): e51446.  Back to cited text no. 7
    
8.
Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19 (12): 3119–30.  Back to cited text no. 8
    
9.
Gallagher EJ, LeRoith D. Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol Rev 2015; 95 (3): 727–48.  Back to cited text no. 9
    
10.
Ligibel JA, Alfano CM, Courneya KS, Demark-Wahnefried W, Burger RA, Chlebowski RT, Fabian CJ, Gucalp A, Hershman DL, Hudson MM, Jones LW, Kakarala M, Ness KK, Merrill JK, Wollins DS, Hudis CA. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol 2014; 32 (31): 3568–74.  Back to cited text no. 10
    
11.
Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, Abbruzzese JL. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009; 301 (24): 2553–62.  Back to cited text no. 11
    
12.
Park JS, Choi GS, Jang YS, Jun SH, Kang H. Influence of obesity on the serum carcinoembryonic antigen value in patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev 2010; 19 (10): 2461–8.  Back to cited text no. 12
    
13.
Li CI, Daling JR, Porter PL, Tang MT, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer. J Clin Oncol 2009; 27 (32): 5312–8.  Back to cited text no. 13
    
14.
Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer 2007; 43 (4): 690–709.  Back to cited text no. 14
    
15.
Beral V, Hermon C, Peto R, Reeves G, Brinton L, Marchbanks P, Negri E, Ness R, Peeters P, Vessey M, Gapstur S, Patel A, Dal Maso L, Talamini R, Chetrit A, Hirsh G, Lubin F, Sadetzki S, Allen N, Beral V, Bull D, Callaghan K, Crossley B, Gaitskell, Goodill, Green J, Hermon C, Key T, Moser K, Reeves G, Collins R, Doll R, Peto R, Gonzalez C, Lee N, Marchbanks P, Ory H, Peterson H, Wingo P, Martin N, Pardthaisong T, Silpisornkosol S, Theetranont C, Boosiri B, Jimakorn P, Virutamasen P, Wongsrichanalai C, Tjonneland A, Titus-Ernstoff L, Byers T, Rohan T, Mosgaard B, Vessey M, Yeates D, Freudenheim J, Chang-Claude J, Kaaks R, Anderson K, Folsom A, Robien K, Rossing M, Thomas D, Weiss N, Riboli E, Clavel-Chapelon F, Cramer D, Hankinson S, Tworoger SS, Franceschi S, Negri E, Magnusson C, Riman T, Weiderpass E, Wolk A, Schouten L, van den Brandt P, Chantarakul N, Koetsawang S, Rachawat D, Palli D, Black A, Berrington de Gonzalez A, Brinton L, Freedman D, Hartge P, Hsing A, Lacey J Jr., Hoover R, Schairer C, Graff-Iversen S, Selmer R, Bain C, Green A, Purdie D, Siskind V, Webb P, McCann S, Hannaford P, Kay C, Binns C, Lee A, Zhang M, Ness R, Nasca P, Coogan P, Palmer J, Rosenberg L, Kelsey J, Paffenbarger R, Whittemore A, Katsouyanni K, Trichopoulou A, Trichopoulos D, Tzonou A, Dabancens A, Martinez L, Molina R, Salas O, Goodman M, Lurie G, Carney M, Wilkens L, Hartman L, Manjer J, Olsson H, Grisso J, Morgan M, Wheeler J, Peeters P, Casagrande J, Pike M, Ross R, Wu A, Miller A, Kumle M, Lund E, McGowan L, Shu X, Zheng W, Farley T, Holck S, Meirik O, Risch H. Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med 2012; 9 (4): e1001200.  Back to cited text no. 15
    
16.
Poorolajal J, Jenabi E, Masoumi SZ. Body mass index effects on risk of ovarian cancer: a meta-analysis. Asian Pac J Cancer Prev 2014; 15 (18): 7665–71.  Back to cited text no. 16
    
17.
Bae HS, Kim HJ, Hong JH, Lee JK, Lee NW, Song JY. Obesity and epithelial ovarian cancer survival: a systematic review and meta-analysis. J Ovarian Res 2014; 7: 41.  Back to cited text no. 17
    
18.
Yang HS, Yoon C, Myung SK, Park SM. Effect of obesity on survival of women with epithelial ovarian cancer: a systematic review and meta-analysis of observational studies. Int J Gynecol Cancer2011; 21 (9): 1525–32.  Back to cited text no. 18
    
19.
Menke A, Rust KF, Fradkin J, Cheng YJ, Cowie CC. Associations between trends in race/ethnicity, aging, and body mass index with diabetes prevalence in the United States: a series of cross-sectional studies. Ann Intern Med 2014; 161 (5): 328–35.  Back to cited text no. 19
    
20.
Hursting SD, Berger NA. Energy balance, host-related factors, and cancer progression. J Clin Oncol 2010; 28 (26): 4058–65.  Back to cited text no. 20
    
21.
Berger NA. Obesity and cancer pathogenesis. Ann N Y Acad Sci 2014; 1311: 57–76.  Back to cited text no. 21
    
22.
Quinn BJ, Kitagawa H, Memmott RM, Gills JJ, Dennis PA. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab 2013; 24 (9): 469–80.  Back to cited text no. 22
    
23.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55 (6): 1577–96.  Back to cited text no. 23
    
24.
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330 (7503): 1304–5.  Back to cited text no. 24
    
25.
El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275 (1): 223–8.  Back to cited text no. 25
    
26.
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(Pt 3): 607–14.  Back to cited text no. 26
    
27.
Li C, Liu VW, Chiu PM, Yao KM, Ngan HY, Chan DW. Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer. Mol Cancer 2014;13:49.  Back to cited text no. 27
    
28.
Jiang ZZ, Hu MW, Ma XS, Schatten H, Fan HY, Wang ZB, Sun QY. LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. Oncotarget 2016; 7 (5): 5738–53.  Back to cited text no. 28
    
29.
Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin 2011; 61 (3): 183–203.  Back to cited text no. 29
    
30.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64 (1): 9–29.  Back to cited text no. 30
    
31.
Sopik V, Iqbal J, Rosen B, Narod SA. Why have ovarian cancer mortality rates declined? Part I. Incidence. Gynecol Oncol 2015; 138 (3): 741–9.  Back to cited text no. 31
    
32.
Zhou B, Sun Q, Cong R, Gu H, Tang N, Yang L, Wang B. Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol 2008; 108 (3): 641–51.  Back to cited text no. 32
    
33.
Terry KL, Karageorgi S, Shvetsov YB, Merritt MA, Lurie G, Thompson PJ, Carney ME, Weber RP, Akushevich L, Lo-Ciganic WH, Cushing-Haugen K, Sieh W, Moysich K, Doherty JA, Nagle CM, Berchuck A, Pearce CL, Pike M, Ness RB, Webb PM; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group, Rossing MA, Schildkraut J, Risch H, Goodman MT; Ovarian Cancer Association Consortium. Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prev Res (Phila) 2013; 6 (8): 811–21.  Back to cited text no. 33
    
34.
Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. Gynecol Oncol 2012; 124 (1): 164–9.  Back to cited text no. 34
    
35.
Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, Schilder RJ, Cortesi L. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int 2015; 2015: 341723.  Back to cited text no. 35
    
36.
Sopik V, Rosen B, Giannakeas V, Narod SA. Why have ovarian cancer mortality rates declined? Part III. Prospects for the future. Gynecol Oncol 2015; 138 (3): 757–61.  Back to cited text no. 36
    
37.
Stine JE, Bae-Jump V. Metformin and gynecologic cancers. Obstet Gynecol Surv 2014; 69 (8): 477–89.  Back to cited text no. 37
    
38.
Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2012; 2 (9): 778–90.  Back to cited text no. 38
    
39.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13 (4): 251–62.  Back to cited text no. 39
    
40.
Yung MM, Ngan HY, Chan DW. Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges. Acta Biochim Biophys Sin (Shanghai) 2016; 48 (4): 301–17.  Back to cited text no. 40
    
41.
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310 (5754): 1642–6.  Back to cited text no. 41
    
42.
Meng S, Cao J, He Q, Xiong L, Chang E, Radovick S, Wondisford FE, He L. Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. J Biol Chem 2015; 290 (6): 3793–802.  Back to cited text no. 42
    
43.
Vallianou NG, Evangelopoulos A, Kazazis C. Metformin and cancer. Rev Diabet Stud 2013; 10 (4): 228–35.  Back to cited text no. 43
    
44.
Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011; 25 (18): 1895–908.  Back to cited text no. 44
    
45.
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494 (7436): 256–60.  Back to cited text no. 45
    
46.
Turban S, Stretton C, Drouin O, Green CJ, Watson ML, Gray A, Ross F, Lantier L, Viollet B, Hardie DG, Marette A, Hundal HS. Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem 2012; 287 (24): 20088–99.  Back to cited text no. 46
    
47.
Sivalingam VN, Myers J, Nicholas S, Balen AH, Crosbie EJ. Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Hum Reprod Update 2014; 20 (6): 853–68.  Back to cited text no. 47
    
48.
Sarfstein R, Friedman Y, Attias-Geva Z, Fishman A, Bruchim I, Werner H. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. PLoS One 2013; 8 (4): e61537.  Back to cited text no. 48
    
49.
Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, Xu XJ, Han J, Yan Y, Yang Q, Li Q, Zang M. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes 2016; 65 (8): 2295–310.  Back to cited text no. 49
    
50.
Litchfield LM, Mukherjee A, Eckert MA, Johnson A, Mills KA, Panr S, Shridhar V, Lengyel E, Romero IL. Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. Oncotarget 2015; 6 (27): 23548–60.  Back to cited text no. 50
    
51.
Salani B, Del Rio A, Marini C, Sambuceti G, Cordera R, Maggi D. Metformin, cancer and glucose metabolism. Endocr Relat Cancer 2014; 21 (6): R461–71.  Back to cited text no. 51
    
52.
Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, Einstein MH, Kaplan RC, Burk RD, Wylie-Rosett J, Pollak MN, Anderson G, Howard BV, Strickler HD. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008; 17 (4): 921–9.  Back to cited text no. 52
    
53.
Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de la Longrais IA, Mayne S, Risch H, Yu H. IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors 2007; 25 (5): 346–54.  Back to cited text no. 53
    
54.
Lau MT, Leung PC. The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells. Cancer Lett 2012; 326 (2): 191–8.  Back to cited text no. 54
    
55.
Zhuang Y, Chan DK, Haugrud AB, Miskimins WK. Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo. PLoS One 2014; 9 (9): e108444.  Back to cited text no. 55
    
56.
Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia 2011; 13 (5): 483–91.  Back to cited text no. 56
    
57.
Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK, Buckanovich RJ. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol 2012; 127 (2): 390–7.  Back to cited text no. 57
    
58.
Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med 2011; 15 (1): 166–78.  Back to cited text no. 58
    
59.
Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, Pasanisi P, Pilotti S. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 2013; 32 (12): 1475–87.  Back to cited text no. 59
    
60.
Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 2011; 71 (13): 4366–72.  Back to cited text no. 60
    
61.
Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11 (5): 390–401.  Back to cited text no. 61
    
62.
Li C, Liu VW, Chan DW, Yao KM, Ngan HY. LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. Int J Gynecol Cancer 2012; 22 (1): 15–22.  Back to cited text no. 62
    
63.
Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005; 8 (3): 179–83.  Back to cited text no. 63
    
64.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149 (2): 274–93.  Back to cited text no. 64
    
65.
Cheaib B, Auguste A, Leary A. The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer 2015; 34 (1): 4–16.  Back to cited text no. 65
    
66.
Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK, Testa JR. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 2004; 23 (34): 5853–7.  Back to cited text no. 66
    
67.
Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol 2015; 137 (1): 173–9.  Back to cited text no. 67
    
68.
Dobbin ZC, Landen CN. The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 2013; 14 (4): 8213–27.  Back to cited text no. 68
    
69.
Larsson O, Morita M, Topisirovic I, Alain T, Blouin MJ, Pollak M, Sonenberg N. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci U S A 2012; 109 (23): 8977–82.  Back to cited text no. 69
    
70.
Bai H, Li H, Li W, Gui T, Yang J, Cao D, Shen K. The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget 2015; 6 (28): 25520–32.  Back to cited text no. 70
    
71.
Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet 2014; 290 (6): 1067–78.  Back to cited text no. 71
    
72.
Foster H, Coley HM, Goumenou A, Pados G, Harvey A, Karteris E. Differential expression of mTOR signalling components in drug resistance in ovarian cancer. Anticancer Res 2010; 30 (9): 3529–34.  Back to cited text no. 72
    
73.
Husseinzadeh N, Husseinzadeh HD. mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: a critical review. Gynecol Oncol 2014; 133 (2): 375–81.  Back to cited text no. 73
    
74.
Chan DK, Miskimins WK. Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures. J Ovarian Res 2012; 5 (1): 19.  Back to cited text no. 74
    
75.
Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, Huang P, Yu D. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin J Cancer Res 2014; 26 (5): 564–72.  Back to cited text no. 75
    
76.
Mazzoletti M, Bortolin F, Brunelli L, Pastorelli R, Di Giandomenico S, Erba E, Ubezio P, Broggini M. Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res 2011; 71 (13): 4573–84.  Back to cited text no. 76
    
77.
Tebbe C, Chhina J, Dar SA, Sarigiannis K, Giri S, Munkarah AR, Rattan R. Metformin limits the adipocyte tumor-promoting effect on ovarian cancer. Oncotarget 2014; 5 (13): 4746–64.  Back to cited text no. 77
    
78.
Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA. Colorectal and prostate cancer risk in diabetes: metformin, an actor behind the scene. J Cancer 2014; 5 (9): 736–44.  Back to cited text no. 78
    
79.
Al-Wahab Z, Mert I, Tebbe C, Chhina J, Hijaz M, Morris RT, Ali-Fehmi R, Giri S, Munkarah AR, Rattan R. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction. Oncotarget 2015; 6 (13): 10908–23.  Back to cited text no. 79
    
80.
Kim TH, Suh DH, Kim MK, Song YS. Metformin against cancer stem cells through the modulation of energy metabolism: special considerations on ovarian cancer. Biomed Res Int 2014; 2014: 132702.  Back to cited text no. 80
    
81.
Patel S, Kumar L, Singh N. Metformin and epithelial ovarian cancer therapeutics. Cell Oncol (Dordr) 2015; 38 (5): 365–75.  Back to cited text no. 81
    
82.
Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M, Gotlieb WH. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol 2011; 121 (3): 492–8.  Back to cited text no. 82
    
83.
Takahashi A, Kimura F, Yamanaka A, Takebayashi A, Kita N, Takahashi K, Murakami T. Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int 2014; 14: 53.  Back to cited text no. 83
    
84.
Zhang R, Zhang P, Wang H, Hou D, Li W, Xiao G, Li C. Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+) CD117(+) ovarian cancer stem cells. Stem Cell Res Ther 2015; 6: 262.  Back to cited text no. 84
    
85.
Moon HS, Kim B, Gwak H, Suh DH, Song YS. Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis. Mol Carcinog 2016; 55 (4): 346–56.  Back to cited text no. 85
    
86.
Tomic T, Botton T, Cerezo M, Robert G, Luciano F, Puissant A, Gounon P, Allegra M, Bertolotto C, Bereder JM, Tartare-Deckert S, Bahadoran P, Auberger P, Ballotti R, Rocchi S. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis 2011; 2: e199.  Back to cited text no. 86
    
87.
Gao S, Jiang J, Li P, Song H, Wang W, Li C, Kong D. Attenuating tumour angiogenesis: a preventive role of metformin against breast cancer. Biomed Res Int 2015; 2015: 592523.  Back to cited text no. 87
    
88.
Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G; ADOPT Study Group; RECORD Steering Committee. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia 2010; 53 (9): 1838–45.  Back to cited text no. 88
    
89.
Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol 2011; 123 (2): 200–4.  Back to cited text no. 89
    
90.
Tseng CH. Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus. Diabetes Metab Res Rev 2015; 31 (6): 619–26.  Back to cited text no. 90
    
91.
Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, Pannain S, Lengyel E. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol 2012; 119 (1): 61–7.  Back to cited text no. 91
    
92.
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): 555–62.  Back to cited text no. 92
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Epidemiology of ...
Preclinical Stud...
Epidemiology of ...
Conclusion
References

 Article Access Statistics
    Viewed1517    
    Printed16    
    Emailed0    
    PDF Downloaded224    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]