|Year : 2016 | Volume
| Issue : 4 | Page : 119-124
Metformin in ovarian cancer therapy: A discussion
Yeling Ouyang1, Xi Chen2, Chunyun Zhang1, Vichitra Bunyamanop1, Jianfeng Guo3
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 Submission||23-Dec-2015|
|Date of Acceptance||10-Jun-2016|
|Date of Web Publication||26-Aug-2016|
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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.,, 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. 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).,,,, Moreover, evidences point out the role of obesity in cancer recurrence and related mortality. 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. In addition, obesity places individuals at a greater risk for developing second primary malignancies.,,
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). 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  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. 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. reported that an increase in BMI can increase the risk of OVC regardless of the menopausal status. 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, similar to the reported results of Yang et al. 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. 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.,, 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, remains as the most widely used first-line drug in the treatment of type 2 diabetes. 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). Interest in the potential role of metformin in cancer was stimulated by a seminal 2005 study, 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.,,, 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|| |
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. 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. 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. OVC is primarily a disease of postmenopausal women; approximately, 70% of the diagnosis and 85% of the deaths occur after the age of 55. In the United States alone, 21,980 new OVC cases and 14,270 related deaths were estimated in 2014.
Few risk factors identified to increase the risk of OVC are HRT, talcum powder, high body mass index, and endometriosis, 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., 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|| |
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., AMPK plays an important role in these effects., A large amount of evidences demonstrate that metformin activates AMPK with a likely underlying mechanism of suppressing respiratory chain complex I , and increasing AMP/ATP ratio, resulting in LKB1-mediated , activation of AMPK by phosphorylating its α subunit 172 site tyrosine residues., 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.,
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,,, subsequently resulting in lower glucose, insulin, and IGF-1 levels in circulation., Hyperglycemia attenuates metformin sensitivity in OVC while stimulating the OVC progression., Similarly, in hyperinsulinemia, IGF-1 levels also stimulate the risk of OVC by activating PI3K/Akt/mTOR pathway, through IGF-1R signaling.,,, A careful observation of the above data also suggested that the metformin cannot play an indirect effect in nondiabetic patients.
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.,, Further, recent studies indicate that metformin suppresses OVC cell proliferation through both AMPK-independent and AMPK-dependent pathway.,
In the AMPK-independent pathway, metformin can induce mTOR inhibition and cell-cycle arrest through REDD1 and through a rag GTPase-dependent manner,, 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., (2) pAMPK can negatively regulate mTOR through direct suppression or through tuberous sclerosis complex 2 (TSC2) phosphorylation, and through Rheb.,,, PIK3/Ark/mTOR pathway is a typical pro-survival signaling pathway that always shows hyperactivity in OVC., Activation of this pathway can promote proliferation of cancer cells by stimulating protein synthesis,, 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. 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.,,, In other words, the combination therapy using metformin and chemotherapeutic drug, such as metformin and cisplatin or metformin and LY294002, can be more useful.,,,, (3) Metformin-induced AMPK can change the cellular metabolism by suppressing lipogenesis in the AMPK-independent pathway. 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.,,
Recent studies also suggest that metformin exhibits slight cytotoxicity to OVC cells.,, However, if the cells lose the compensatory mechanism, like the function of AMPK, LKB1, or p53, metformin can exert a higher cytotoxicity. 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. In line with this, some studies demonstrate an attenuation in anti-tumor effects of metformin under simulated hyperglycemic conditions (25 mM glucose), in vitro., 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,,, 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., 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.
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. However, further research indicates that metformin-induced autophagy and UPR will inhibit metformin-induced cell apoptosis. 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.,,
| Epidemiology of Metformin and Ovarian Cancer|| |
There are few epidemiological studies assessing the association between metformin and the risk of OVC. Home et al. 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]). 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. 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  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, while the benefits of metformin therapy on the reduced risk for nondiabetic OVC patients are still unknown.
Romero et al. 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., 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|| |
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.
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