There has been great interest in finding structural targets in cancer for the widely prescribed type 2 diabetes drug metformin. Metformin is a synthetic product derived from galegine, a guanide natural product found in French lilac. Documented use of galegine for human disease dates back to 1620, when John Parkinson first described the use of lilac plants for medicinal purposes in his treatise Theatrum Botanicum. Despite this long history, defining all relevant structural targets for metformin remains a challenge.
Repurposing of metformin for cancer is currently being explored in multiple clinical trials of prevention and treatment. Cancer prevention studies with metformin remain of interest despite the fact that the first randomized placebo controlled trial for metformin in advanced disease – in pancreatic cancer – showed no benefit of the drug (Kordes et al.). One example of an ongoing trial is the MA.32 trial of metformin to prevent recurrence of breast cancer after primary treatment (Goodwin et al.).
At the center of this interest in metformin is the idea that this drug may prevent cancer cells from effectively using nutrients to build tumor size. Tumors that fail to grow are less likely to cause morbidity. While there are a number of theories of how metformin or similar molecules inhibit cancer, such as reducing insulin levels, these haven’t yet led to insights on how to make metformin more potent or specific for cancer therapeutics.
To improve our understanding of metformin activity against cancer, Guo et al. discovered that metformin unexpectedly co-crystalizes in the active site of the liver enzyme cytochrome P450 3A4 (CYP3A4), which metabolizes about half of prescription drugs. Breast cancer cells were discovered to unexpectedly co-opt CYP3A4 for their own growth, by moving this enzyme to their mitochondria, energy powerhouses of the cell, where CYP3A4 was unexpectedly found to regulate mitochondrial energy production.
In a team science approach, led by the Department of Medicine, Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota with collaborator institutions including U.C. Irvine, U. Illinois Urbana/Champaign, University of Michigan, George Mason University and University of Pennsylvania, Guo et al. discovered that metformin binds to the active site of CYP3A4 and prevents the synthesis of physiological fatty acid oxidation products called epoxyeicosatrienoic acids (EETs), which were previously known to regulate blood pressure. Using the crystal structure of metformin bound to the active site of the CYP3A4 enzyme, Guo et al. used in silico docking to discover more potent chemical variants of metformin, including hexyl-benzyl-biguanide (HBB).
This molecule had already been the subject of a patent (Kim et al.) licensed to ImmunoMet Therapeutics. Most importantly, HBB inhibited breast tumor growth in an animal model at ~100-fold lower dosing than metformin and with acceptable toxicity. This mechanism provides a novel avenue for cancer drug development. To identify a patient population which may potentially benefit and bring HBB to clinical trials, CYP3A4 expression was found to correlate with the estrogen receptor, a known breast cancer classifier and therapeutic target, expressed in about 70% of breast cancers. As expected, there was selective activity of HBB against estrogen receptor positive breast cancer in animal models.
Furthermore, tumor response to HBB was found to correlate with a reduction of another breast cancer target protein, mTOR, which regulates the processing of nutrients to promote tumor growth. HBB and drug candidates like it may thus provide an advantage over metformin for cancer treatment and provide a novel approach to treat estrogen receptor positive breast cancer. Metformin has thus been linked to a novel area of cancer biology. Understanding this new mechanism of cancer bioenergetics may allow the development of new, more potent, metformin-like drugs that leap beyond prevention and go into the arena of cancer treatment.
References
Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, Rastogi P, Mayer IA, Hobday TJ, Lemieux J, Thompson AM, Pritchard KI, Whelan TJ, Mukherjee SD, Chalchal HI, Oja CD, Tonkin KS, Bernstein V, Chen BE, Stambolic V. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015;107(3).
Guo Z, Sevrioukova IF, Denisov IG, Zhang X, Chiu T-L, Thomas DG, Hanse EA, Cuellar RAD, Grinkova YV, Langenfeld VW, Swedien DS, Stamschror JD, Alvarez J, Luna F, Galván A, Bae YK, Wulfkuhle JD, Gallagher RI, Petricoin EF, 3rd, Norris B, Flory CM, Schumacher RJ, O’Sullivan MG, Cao Q, Chu H, Lipscomb JD, Atkins WM, Gupta K, Kelekar A, Blair IA, Capdevila JH, Falck JR, Sligar SG, Poulos TL, Georg GI, Ambrose E, Potter DA. Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chemical Biology. 2017; Sept. 14. pii: S2451-9456(17)30283-0. doi: 10.1016/j.chembiol.2017.08.009. [Epub ahead of print]
Kim SW, Jun SS, Min CH, Kim YW, Kang M, S., Oh BK, Park SH, Kim YE, Kim D, Lee JS, Ho JH. Biguanide Derivative, A Preparation Method Thereof and a Pharmaceutical Composition Containing the Biguanide Derivative as an Active Ingredient. In: Office USPaT 9,416,098. Korea: Hanall Biopharma Co., Ltd.; 2015:1-15.
Kordes S, Pollak MN, Zwinderman AH, MathĂ´t RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015 Jul;16(7):839-47
This study, Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria, was recently published in the journal Cell Chemical Biology by David Potter, MD, PhD at the Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota.