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Natural Medicine Journal

February 9, 2014

Metformin Improves Ovarian Cancer Survival

Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity

Katherine Neubauer

ND, FABNO
A study comparing survival times among 341 epithelial ovarian cancer patients of whom 297 were non-diabetic, 28 were type II diabetics who did not use metformin, and 16 were type II diabetics who used metformin to find out if metformin use is associated with significantly longer progression free survival and overall survival in ovarian cancer patients.

Reference

Romero IL, McCormick A, McEwen KA, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61-67.
 

Design

Single institution retrospective cohort chart review
 

Participants

The study compared survival times among 341 epithelial ovarian cancer patients, of whom 297 were non-diabetic, 28 were type II diabetics who did not use metformin, and 16 were type II diabetics who used metformin. 
 

Intervention

Type II diabetes diagnosis and metformin usage were compared with progression-free survival (PFS), overall survival (OS), and chemotherapy resistance rate. Subgroups had similar grade and stage and received similar surgical and chemotherapy treatment.
 

Outcome Measures

Kaplan-Meier curves and hazard ratios were calculated for the relationship between PFS, OS, and metformin usage.
 

Key Findings

The 5-year PFS was 51% for diabetics using metformin, 23% for non-diabetics, and 8% for diabetics not using metformin (P=0.03). The 5-year OS was 63% for the diabetics taking metformin, 37% for non-diabetics, and 23% for diabetics not taking metformin (P=0.03).
 

Practice Implications

In this study Romero et al report that metformin use was associated with significantly longer progression-free survival and overall survival in ovarian cancer patients receiving standard treatments. In fact, over an 18-year period, the survival rate among the metformin group was so elevated that it was not possible to estimate the upper confidence interval for PFS and OS. In contrast, the typical median survival time after completion of first-line chemotherapy is just 15 months.1
 
The possibility that a common, inexpensive, and relatively safe drug might have a profound impact on cancer survival has taken root in recent months. ClinicalTrials.gov currently lists 20 studies on 'metformin and cancer.' The association of metformin usage with improved cancer survival may be surprising at first, given that diabetics have additional comorbidities and a higher overall risk of cancer mortality. However, the results are not unexpected when metformin’s multiple antineoplastic mechanisms of action are considered.
 
Metformin users in the Romero study also trended toward greater chemosensitivity to platinum, a first-line chemotherapy in ovarian cancer. Preclinical data indicate that metformin may chemosensitize ovarian cancer cells to platinum therapy. Metformin generates a mild and transient inhibition of the mTOR pathway, suggesting that ongoing therapy would be needed for best effects.2 Dosage ranges in the cancer clinical trials are 500 to 1,500 mg daily.
 
Several cohort studies have found an association between metformin use and decreased cancer incidence in general. Romero’s findings are consistent with those of the Dutch ZODIAC trial that found a 57% decrease in cancer mortality for diabetics taking metformin. ZODIAC also found a dose-dependent relationship, with a 42% decrease in cancer mortality for each 1-gram/day increase in dose.3 A large case-control study found that long-term metformin use was associated with a decreased risk of ovarian cancer, while long-term insulin use increased risk. Sulfonylurea use did not affect cancer risk.4 It is unclear what proportion of the results are due to direct drug effects or to overall glycemic control, as insulin-dependence is a marker of disease progression in type II diabetics. A 2011 Dutch study of 11,140 diabetics that prescribed intensive pharmaceutical glycemic control with insulin, sulfonylurea, and metformin did not find that this approach lowered cancer incidence.5 In March 2012, a Taiwanese study, looking at 1 million participants, reported that the use of hypoglycemic medications was associated with a 40% decreased risk of lung cancer. The study did not distinguish between types of hypoglycemic agents.6
 
Japanese researchers are assessing the use of metformin for colorectal cancer prevention, investigating whether use will prevent progression of dysplastic aberrant crypt foci (ACF). In a randomized pilot study of 26 nondiabetic patients with biopsy-proven ACF, metformin 250 mg daily for 1 month significantly decreased the number of ACF and the cellular proliferation index.7 This study provides biopsy evidence of chemopreventive activity. Earlier animal studies by the same researchers had found that metformin decreases ACF.8
 
While both hyperinsulinemia and hyperglycemia promote tumor growth and are predictive of decreased ovarian cancer survival, there are also other mechanisms at work.9,10  Metformin acts on several antiproliferative pathways. While clinical trials obviously show that metformin increases insulin sensitivity, biopsies taken during cancer trials reveal that metformin decreases cancer cell proliferation (measured via Ki67 and cellular proliferation index), induces apoptosis (measured via p53), and decreases expression of BRCA-1.11–13
 
In vitro and animal research indicates that metformin potentiates cisplatin, induces apoptosis (via decreased BCL-2 and BCL-XL, increased BAX and BAD, and activated caspases 3 and 7), decreases inflammation (via Il-6), decreases cell proliferation (via Ki67 and cyclin D1), decreases tumor cell adhesion, and decreases angiogenesis (via VEGF, mTOR, and microvessel density).14–21
 
The mTOR and AMP-activated protein kinase  (AMPK) pathways are particularly relevant to metformin and cancer. Angiogenesis and cellular energy are regulated by mTOR and AMPK. Metformin decreases hepatic gluconeogenesis in diabetics via the AMPK pathway, which also regulates cell energy.22 When metformin increases AMPK and decreases mTOR, it also slows tumor metabolism.  Protein translation and cell proliferation are also regulated by mTOR.23
 
A phase 1 trial of the mTOR inhibitor temsirolimus paired with metformin produced a response in 6 out of 11 patients with treatment refractory solid tumors.
 
 
A phase 1 trial of the mTOR inhibitor temsirolimus paired with metformin produced a response in 6 out of 11 patients with treatment refractory solid tumors.24
 
Metformin’s mTOR inhibition sensitizes ovarian tumor cells and targets stem cells to radiation in vitro.25 Furthermore, metformin-induced AMPK blocks the tendency for elevated luteinizing hormone, a risk factor for ovarian cancer to promote angiogenesis.26
 
It should be mentioned that berberine both in vitro and in vivo activates many of the same antiproliferative pathways that metformin does, though this is not yet confirmed in clinical trials.27–31
 
This current study by Romero et al suggests that metformin provides diabetic women with ovarian cancer a benefit so compelling that we should be hard pressed to find a reason for them not to take metformin. Related studies in breast cancer and colorectal dysplasia suggest that metformin may also have antineoplastic benefits in non-diabetics. While prospective trials are certainly needed to clarify therapeutic effectiveness, given metformin’s relative safety, off-label usage of this medication in ovarian cancer patients is gaining in popularity.
 
For more research involving integrative oncology, click here.

Categorized Under

Katherine Neubauer

ND, FABNO

Katherine Neubauer, ND, FABNO, practices in Tulsa, Okla.,with a focus on women's health. She completed residency in naturopathic oncology at Cancer Treatment Centers of America and then practiced on staff at Southwestern Regional Medical Center. Neubauer trained at Southwest College of Naturopathic Medicine and at the University of California at Berkeley. Her work has been published through Naturopathic Doctor News and Review, the American Public Health Association, and the Centers for Disease Control and Prevention.

References

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  2.  Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270.
  3.  Landman GW, Kleefstra N, van Hateren KJ, et al. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33(2):322-326.
  4.  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):200-204.
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  6.  Lai SW, Liao KF, Chen PC, Tsai PY, Hsieh DP, Chen CC. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin Lung Cancer. 2012;13(2):143-148.
  7.  Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3(9):1077-1083.
  8.  Hosono K, Endo H, Takahashi H, et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog. 2010;49(7):662-671.
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  11.  Hadad S, Iwamoto T, Jordan L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat. 2011;128(3):783-794.
  12.  Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3(9):1077-1083.
  13.  Hadad S, Iwamoto T, Jordan L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat. 2011;128(3):783-794.
  14.  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. Oncol Rep. 2012;27(6):1873-1878.
  15.  Luque-Ramírez M, Escobar-Morreale HF. Treatment of polycystic ovary syndrome(PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations. Horm Metab Res. 2010;42(11):815-820.
  16.  Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270.
  17.  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):166-178.
  18.  Gotlieb WH, Saumet J, Beauchamp MC, et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 2008;110(2):246-250.
  19.  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):483-491.
  20.  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 1;121(3):492-498.
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  22.  Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270.
  23.  Hosono K, Endo H, Takahashi H, et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog. 2010;49(7):662-671.
  24.  MacKenzie MJ, Ernst S, Johnson C, Winquist E. A phase I study of temsirolimus and metformin in advanced solid tumours. Invest New Drugs. 2012;30(2):647-652.
  25.  Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362.
  26.  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. Oncol Rep. 2012;27(6):1873-1878.
  27.  Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99-105.
  28.  Wang Y, Liu Q, Liu Z, et al. Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells. Mutat Res. 2012;734(1-2):20-29.
  29.  Chidambara Murthy KN, Jayaprakasha GK, Patil BS. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur J Pharmacol. 2012;688(1-3):14-21.
  30.  Park KS, Kim JB, Lee SJ, Bae J. Berberine-induced growth inhibition of epithelial ovarian carcinoma cell lines. J Obstet Gynaecol Res. 2012;38(3):535-540.
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