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Home , Biguanide, Buformin

Pharmacotherapeutics

What every dentist should know about , , and cancer

Matthew R. Frykenberg n Abraham Schneider, DDS, PhD n Nasir Bashirelahi, PhD

Metformin has long been the drug of choice for treating patients with potential mechanisms of action underlying the anticancer properties of . Because of its effectiveness, safety profile, and affordabili- metformin and discusses the possible use of this antidiabetic in ty, it is used by millions of people worldwide. Emerging evidence indicates the chemoprevention and treatment of head and neck cancer. that metformin might also have antineoplastic effects in both diabetic Received: October 29, 2014 and nondiabetic individuals. This article reviews studies that examine the Accepted: March 11, 2015

etformin, commercially available France approved the metformin, that metformin was no more successful as Glucophage (Bristol-Myers , and for the treat- than placebo.17,18 However, a 2012 study MSquibb Company), Glumetza ment of type 2 diabetes.11 In the 1970s, observed that, compared with clomiphene (Salix Pharmaceuticals, Inc.), Carbophage buformin and phenformin were banned citrate, metformin can promote ovulation (Merck Serono), Riomet (Ranbaxy due to harmful side effects in patients induction and pregnancy rate in women Laboratories, Inc.), and Fortamet (Shionogi with renal, cardiovascular, and hepatic with polycystic ovary syndrome.19 The Inc.), is the first-line drug for treating type disorders, leaving metformin as the only effect of metformin combined with clomi- 2 diabetes. Because it is affordable and has hypoglycemic biguanide.11-14 Metformin phene citrate is better than that of either of few adverse side effects, metformin is cur- was cleared by the US Food and Drug the drugs used alone.19 rently used worldwide by approximately Administration in 1994, and a commercial It has also been suggested that met- 120 million people.1-3 As an oral antihy- formulation was patented by Bristol-Myers formin could control dementia and perglycemic agent and sensitizer, Squibb Company in 1995.11,15,16 Parkinson disease and trigger the growth metformin functions primarily by reducing of nerve cells.20 Preclinical studies in basal hepatic and sec- Adverse effects of biguanides rodents revealed that metformin extends ondarily by improving peripheral insulin Phenformin and buformin can cause lactic health span and life span in adult male sensitivity.4-6 Metformin decreases the rate acidosis, which is why they were removed mice and simulates some of the benefits of glucose absorption from the intestine, from the US market in the 1970s.11 of calorie restriction, such as improved but overall glucose absorption remains Metformin also carries the risk of lactic physical performance.5 Compelling unaffected.6 In addition to its beneficial acidosis but at a rate of about 1/10 to observations gathered in the past decade control of blood glucose levels, metformin 1/20 of that associated with phenformin.6 have also indicated that metformin may has been also associated with maintenance The risk of lactic acidosis in patients trigger antineoplastic actions in a variety of current weight or weight loss; decreased taking metformin is estimated to be 0.03 of tumor types.1,2,4,21-25 levels of cholesterol, triglycerides, and per 1000 patient-years.6 Lactic acidosis low-density lipoprotein; increased levels of associated with metformin results in death Anticancer properties of high-density lipoprotein; and reduced risk in 50% of cases.6 metformin of cardiovascular diseases.1,5,6 In fewer than 5% of patients, metformin Evidence in the literature Metformin is a biguanide originally causes gastrointestinal symptoms such as One of the many consequences associ- derived from , the pharmacologi- nausea, vomiting, anorexia, abdominal pain, ated with type 2 diabetes is the increased cally active component of the plant Galega and diarrhea.6 The incidence of these symp- risk of cancer. As interest in this link officinalis.7 , also known toms can be reduced by taking metformin increased, various lines of research as French honeysuckle, French lilac, goat’s with meals and initiating treatment with exposed additional ties between the 2 rue, Italian fitch, or galega, was brewed as metformin at low doses.6 Reportedly, 3% of afflictions. In experimental preclini- a tea in medieval times for the treatment patients develop a metallic taste sensation.6 cal studies, metformin has been shown of maladies such as snakebite, plague, fre- In 9% of patients, vitamin B12 is reduced, to reduce tumor burden, delay tumor quent urination, and worms.7 Biguanides though development of anemia is rare.6 onset, and increase life span in healthy, were derived from Galega officinalis in nondiabetic mice.5 In 2005, Evans et al 1922 by Werner & Bell, and were discov- New uses for metformin reported that type 2 diabetes patients ered to be an antihyperglycemic agent in Despite metformin’s long-time use for type who were taking metformin appeared 1929 by Slotta & Tschesche.8,9 2 diabetes, new uses are coming to light. to be less likely to develop cancer.26 Because of the attention the discovery It has had an off-label use in the treat- Likewise, University of Alberta investi- of insulin received, the biguanides escaped ment of polycystic ovary syndrome since gators reported in 2006 that mortality notice for several decades.10 In the 1950s, 2004, although 2 clinical studies found associated with cancer was less likely to

70 September/October 2015 General Dentistry www.agd.org occur in patients with type 2 diabetes It should also be noted that cancer tumor cell proliferation by disrupting if they were taking metformin.27 In a cells thrive in a milieu of high glucose mTOR signaling–driven translational con- retrospective clinical study of 2592 breast and high insulin. Studies indicate that trol of a specific subset of messenger RNAs cancer patients, including 157 with type metformin might be indirectly inhibiting encoding cell cycle regulators.4,30 2 diabetes, Jiralerspong et al found that cancerous growth by lowering both glu- The effect of metformin occurs primar- patients undergoing only chemotherapy cose and insulin.21,22 ily in the basal layer of oral premalignant had a recovery rate of 8%.28 In contrast, lesions, where proliferation occurs.2 In a in patients who were taking metformin Head and neck cancer study of oral cancer induced by an oral- in addition to chemotherapy, the recovery Head and neck cancers, which largely com- specific carcinogen in mice, Vitale-Cross rate increased to 24%.28 This promising prise malignant lesions in the oral cavity et al reported, “metformin prevented the evidence triggered the design and imple- and pharynx, are often fatal and are of great development of HNSCC by significantly mentation of a number of randomized importance to oral healthcare providers. reducing the size and number of carcino- control trials in patients with a variety of Annually, health professionals diagnose an gen-induced oral tumoral lesions, and by cancer types.29 estimated 600,000 cases of head and neck preventing their spontaneous conversion Metformin can potentially be used to cancer worldwide, 47,560 of which occur to squamous cell carcinomas.”2 The strong treat a variety of cancers, including but not in the United States.4 Because it is often growth inhibition of HNSCC by metfor- limited to skin, uterine, liver, pancreatic, detected late, head and neck cancer has a min is not associated with any prominent colon, lung, ovarian, breast, and head and 5-year survival rate of approximately 50%.4 cell death.4 These results support the neck cancers.2,4,25 In fact, metformin may Almost 75% of head and neck cancer potential clinical use of metformin as a help to prevent carcinogenesis in those cases are associated with the risk factors targeted chemopreventive agent in the patients with high risk of developing malig- of tobacco and alcohol use.4 Infection control of HNSCC. nancies.2 Anticancer drugs must go through with human papillomavirus has recently years of trials and are expensive when made emerged as another risk factor for head Conclusion available to patients. Because metformin and neck cancer.4 More than 85% of head The literature supports the need for clini- is relatively inexpensive, it can be afforded and neck cancers are accounted for by cal trials on, and possibly the eventual by many patients and by governments that head and neck squamous cell carcinoma implementation of, the use of metformin would be unable to finance other drugs for (HNSCC).4 HNSCC affects the oral in the oncologic setting. Because of its their citizens. However, more studies are cavity, salivary glands, paranasal sinuses, anticancer action, metformin has the still needed before metformin can be repur- nasal cavity, pharynx, larynx, and the potential to save lives, reduce costs, and posed for the oncologic setting. surrounding lymph nodes.4 Even a slight prevent morbidity associated with the pro- elevation in the risk of cancer becomes a gression of neoplasms. This is relevant for Potential underlying mechanisms considerable social burden. It is therefore dental treatment because there are prom- It has been proposed that the potential imperative to find novel approaches for ising indications that metformin could antineoplastic effects of metformin lie in cancer prevention. be effective in the treatment of HNSCC. a pathway activated by its antihypergly- Treatment plans for head and neck can- Clinical trials studying this link should be cemic function.21,22 Metformin partially cers usually involve either surgery or radio- initiated, and dentists should be aware of inhibits the mitochondrial respiratory therapy. Surgery results in the removal the possible future use of metformin for chain complex I, resulting in decreased of noncancerous tissue in proximity to treatments other than type 2 diabetes. hepatic gluconeogenesis.3 The subsequent the tumor. Thus surgery is undesirable, metabolic stress causes an increase in the because it can easily result in dysphagia, Author information adenosine monophosphate–adenosine dysarthria, clotting disorders, and damage Mr. Frykenberg is a dental student, triphosphate ratio, which in turn activates to sinuses, glands, and lymph nodes.4 University of Maryland School of the upstream tumor suppressor LKB1 Radiotherapy is preferable because it Dentistry, Baltimore, where Dr. Schneider protein kinase.4 This results in activation is more accurate and provides a greater is an associate professor and Dr. Bashirelahi of the adenosine 5’monophosphate–acti- probability of organ preservation. is a professor of biochemistry. vated protein kinase (AMPK) pathway, However, as Sikka et al wrote, “… resis- which signals cells to conserve energy in tance to radiation and recurrence after References order to restore intracellular adenosine therapy are major drawbacks for patients 1. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in 4 diabetic patients treated with metformin: a systemat- triphosphate levels. Activation of the with head and neck cancer and remains a ic review and meta-analysis. PLoS One. 2012;7(3): AMPK pathway leads to inhibition of point of emphasis for newer strategies of e33411. the mammalian target of rapamycin treatments in the future.”4 2. Vitale-Cross L, Molinolo A, Martin D, et al. Metformin (mTOR) pathway, an important regulator Metformin is thought to be an effective prevents the development of oral squamous cell carci- of metabolism and cell growth.4 Because drug for arresting the development and nomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila). 2012;5(4):562-573. metabolism and cell growth are vital to growth of HNSCC because of the unregu- 3. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, cancer progression, metformin may be lated activity of the mTOR pathway. In Andreelli F. Cellular and molecular mechanisms of useful in the prevention and management a study of human-derived HNSCC cell metformin: an overview. Clin Sci (Lond). 2012;122(6): of neoplasms.4 lines, metformin selectively inhibited 253-270.

www.agd.org General Dentistry September/October 2015 71 Published with permission of the Academy of General Dentistry. © Copyright 2015 by the Academy of General Dentistry. All rights reserved. For printed and electronic reprints of this article for distribution, please contact [email protected].

4. Sikka A, Kaur M, Agarwal C, Deep G, Agarwal R. Met- 15. Cruzan SM. FDA Approves New Diabetes Drug. US 25. Lehraiki L, Abbe P, Cerezo M, et al. Inhibition of mela- formin suppresses growth of human head and neck Food and Drug Administration. December 30, 1994. nogenesis by the antidiabetic metformin. J Invest Der- squamous cell carcinoma via global inhibition of pro- Available at: http://web.archive.org/web/ matol. 2014;134(10):2589-2597. tein translation. Cell Cycle. 2012;11(7):1374-1382. 20070929152824/http://www.fda.gov/bbs/topics/ 26. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, 5. Martin-Montalvo A, Mercken E, Mitchell S, et al. Met- ANSWERS/ANS00627.html. Archived September 29, Morris AD. Metformin and reduced risk of cancer in formin improves healthspan and lifespan in mice. Nat 2007. Accessed May 20, 2015. diabetic patients. BMJ. 2005;330(7503):1304-1305. Commun. 2013;4:2192. 16. Glucophage Label and Approval History. US Food and 27. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. In- 6. Miller JW, Kraemer FB. Diabetes mellitus. In: Car- Drug Administration. Available at: http://www.fda.gov/ creased cancer-related mortality for patients with type ruthers S, Hofman B, Melmon K, Nierenberg D, eds. Drugs/InformationOnDrugs/ucm079750.htm. Accessed 2 diabetes who use or insulin. Diabetes Melmon and Morrelli’s Clincal Pharmacology. 4th ed. May 20, 2015. Care. 2006;29(2):254-258. New York: McGraw-Hill; 2000:529-550. 17. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, 28. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin 7. Witters L. The blooming of the French lilac. J Clin In- metformin, or both for infertility in the polycystic ovary and pathologic complete responses to neoadjuvant vest. 2001;108(8):1105-1107. syndrome. N Engl J Med. 2007;356(6):551-566. chemotherapy in diabetic patients with breast cancer. 8. Werner EA, Bell J. The preparation of methylguanidine, 18. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der J Clin Oncol. 2009;27(20):3297-3302. and of ββ-dimethylguanidine by the interaction of di- Veen F. Effect of clomifene citrate plus metformin and 29. Goodwin PJ, Ligibel JA, Stambolic V. Metformin in cyanodiamide, and methylammonium and dimethyl- clomifene citrate plus placebo on induction of ovula- breast cancer: time for action. J Clin Oncol. 2009; ammonium chlorides respectively. J Chem Soc Trans. tion in women with newly diagnosed polycystic ovary 27(20):3271-3273. 1922;121:1790-1795. syndrome; randomised double blind . BMJ. 30. Larsson O, Morita M, Topisirovic I, et al. Distinct per- 9. Slotta KH, Tschesche R. Uber Biguanide, II: Die Blut- 2006;332(7556):1485. turbation of the translatome by the antidiabetic drug zuckersenkendeWirkung der Biguanides. Ber Dtsch 19. Xiao J, Chen S, Zhang C, Chang S. The effectiveness of metformin. Proc Natl Acad Sci U S A. 2012;109(23): Chem Ges B Abh. 1929;62(6):1398-1405. metformin ovulation induction treatment in patients 8977-8982. 10. Campbell IW. Metformin—life begins at 50: a sympo- with PCOS: a systematic review and meta-analysis. sium held on the occasion of the 43rd annual meeting Gynecol Endocrinol. 2012;28(12):956-960. Manufacturers of the European Association for the Study of Diabetes, 20. Potts M, Lim DA. An old drug for new ideas: metfor- Bristol-Myers Squibb Company, New York, NY Amsterdam, The Netherlands, September 2007. Br J min promotes adult neurogenesis and spatial memory 800.332.2056, www.bms.com Diab Vasc Dis. 2007;7(5):247-252. formation. Cell Stem Cell. 2012;11(1):5-6. Merck Serono, Mumbai, India 11. Bailey CJ, Day C. Metformin: its botanical background. 21. Pollak M. Potential applications for biguanides in on- 91.22.6660.9000, www.emdserono.com Pract Diab Int. 2004;21(3):115-117. cology. J Clin Invest. 2013;123(9):3693-3700. Ranbaxy Laboratories, Inc., Princeton, NJ 12. Lucis O. The status of metformin in Canada. Can Med 22. Pollak MN. Investigating metformin for cancer preven- Assoc J. 1983;128(1):24-26. tion and treatment: the end of the beginning. Cancer 609.720.9200, www.riomet.com 13. Korhonen T, Idanpaan-Heikkila J, Aro A. Biguanide- Discov. 2012;2(9):778-790. Salix Pharmaceuticals, Inc., Raleigh, NC induced lactic acidosis in Finland. Eur J Clin Pharma- 23. Handelsman Y, LeRoith D, Bloomgarden ZT, et al. 919.862.1000, www.salix.com col. 1979;15(6):407-410. Diabetes and cancer—an AACE/ACE consensus Shionogi Inc., Florham Park, NJ 14. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in statement. Endocrine Pract. 2013;19(4):675-693. 973.966.6900, www.shionogi.com biguanide-treated diabetics: a review of 330 cases. 24. Wheaton WW, Weinberg SE, Hamanaka RB, et al. Met- Diabetologia. 1978;14(2):75-87. formin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. 2014;3:e02242.

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