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Metformin as a novel component of metronomic chemotherapeutic use: a hypothesis

Contents lists available at Journal of Experimental and Clinical Medicine Metformin as a Novel Component of Metronomic Chemotherapeutic Use:A Hypothesis Jorge Eduardo Duque , Juliana Velez Ismael Samudio Enoch Lai 1 Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá DC, Colombia 2 Centro Oncológico de Antioquia, Medellín, Colombia3 Shuang Ho Medical Hospital, Taipei Medical University, Taipei, Taiwan The hypoglycemic agent metformin has been found to possess chemopreventive and direct antitumor properties. Several clinical studies worldwide are using it as a monotherapy or as an add-on therapy with Received: Jan 25, 2011 chemotherapeutic drugs to determine prospectively its efficacy and safety in treating human cancer. In Revised: Nov 5, 2011 terms of its mechanism of action, metformin moderately inhibits electron transport in mitochondria to Accepted: Nov 30, 2011 cause increased AMP:ATP ratios, which antagonize gluconeogenesis in hepatocytes, and to promotecatabolism in most tissues through activating AMP-activated kinase (AMPK). Inhibition of mammalian target of rapamycin signaling through activation of AMPK has been suggested to mediate the antitumor effects of metformin. However, AMPK-independent growth-inhibitory properties of metformin on tumor cells have also been described, suggesting that antagonizing electron transport per se may be cytostatic or cytotoxic to cancer cells. In addition, metformin was hypothesized to display antiviral and antimalarial effects in 1950s, and recently it has been found to promote the generation of CD8 T memory lympho- metronomic chemotherapy cytes, suggesting that its immune-activating effects may also contribute to its observed antitumor andchemopreventive properties. Chronic administration of metformin has an acceptable toxicity profile andis well tolerated by millions of patients with type 2 diabetes worldwide, suggesting that this agent couldpotentially be a therapeutic component with low intensity if given in continuous dosing/frequent usageschedules. These metronomic strategies show that metformin can inhibit tumor angiogenesis and acti-vate antitumor immunity, indicating a potential therapeutic interaction with immune potentiation,antitumor effects, and an acceptable toxicity profile. Here, we review current knowledge on metformin'ssignaling, metabolic, and immune effects, as well as data from clinical drug trials, to discuss how theinterplay may orchestrate the antitumor effects of this agent, particularly in combination with reduced-intensity or metronomic chemotherapeutic use.
Copyright Ó 2012, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
2. Major mechanisms related to antitumor effects ofmetformin Metformin, a biguanide, was approved by the United States Foodand Drug Administration in 1995 as an oral hypoglycemic agent.
The mechanisms underlying the action of metformin in exerting Given alone or in combination with a sulfonylurea, metformin antitumor effects can be summarized as follows.
improves glycemic control and lipid concentrations in patients whorespond poorly to dietary control or to a sulfonylurea alone.
2.1. Metabolic and signaling effects In this review, we discuss evidence for metformin's potential use as an antitumor drug. We will review the major mechanisms Anisimov et al, in their pioneer work to understand the antitumor related to its antitumor effects, clinical evidence of its antitumor mechanism of metformin, found that chronic administration of and chemopreventive effects, metronomic chemotherapydwhen metformin to female transgenic HER2/neu mice significantly reduced less is moredand the interaction of metronomic chemotherapy the number and size of mammary adenocarcinomas, partly through and metformin.
downregulation of the insulin/insulin-like growth factor axis (IGF).This mechanism has already been observed in patients with type 2diabetand women affected by polycystic ovary syndrome.
* Corresponding author. Ismael Samudio, 301 Edificio Jesús Emilio Ramírez, More recent experimental evidence indicates that this Pontificia Universidad Javeriana, Cra 7 Number 43e82, Bogotá, Colombia.
E-mail: I. Samudio > biguanide can activate AMP-dependent kinase (AMPK), either by 1878-3317/$ e see front matter Copyright Ó 2012, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Metformin as a novel component of metronomic chemotherapy schemes 2.3. Immune and hypothalamic effects promoting an increase in AMP:ATP ratiosActivated AMPK canin turn phosphorylate and activate TSC2, a negative regulator of It is important to consider immune-modulating effects of metfor- mammalian target of rapamycin Inhibiting mTOR min as a mechanism underlying antitumor activity. This concept kinase activity can reduce signaling transduction through the was originally proposed in the 1950s by the Philippine physician kinase Akt, and decrease the efficiency of protein synthesis via Garcia,who first recognized the important component of the decreased phosphorylation of the mTOR targets 4EBP-1 and S6K, antitumor effects of metformin. A recent thought-provoking report which are essential components of the cap-dependent trans- has shown that metformin can increase the number memory CD8 T lation machineryThe inhibition of cap-dependent translation cells in wildtype mice, and in consequence significantly improve in response to metformincan result in decreased expression of the efficacy of an experimental anticancer vThis report the oncogene Her2and the cell cycle protein cyclin D1, suggested the mechanism that increased fatty acid oxidation in illustrating a potential avenue via which metformin can modu- response to metformin can mediate the generation of CD8 T cells.
late signaling and cell cycle effects.
However, this notion does not agree with the observation that Because AMPK is the energy sensor of the cell, metformin metformin inhibits electron transport in hepatocytes and hepato- also increases oxidative metabolism and reduces anabolism, cyte mitochondria, and it is thus intriguing to hypothesize that resulting in decreased lipid synthesis, protein synthesis, and so metformin modulates tissue-specific responses in mitochondrial on,in part through direct phosphorylation effects on key metabolism by inhibiting electron transport in hepatocytes instead metabolic targets such as acetyl CoA carboxylase (a committed of promoting fatty acid oxidation in lymphocytes. Irrespective of step in fatty acid synthesis) and phosphofructokinase-2 (the this, the mechanism for the generation of memory CD8 T cells could master regulator of glycolysis).How metformin activates LKB1 be a critical component of the antitumor action of metformin.
remains unclear, but it has been shown that metformin can Lastly, Ropelle et al have shown that hypothalamic AMPK acti- increase the AMP:ATP ratio, the canonical signal to activate vation in response to metformin reverses cancer anorexia in tumor- AMPK, as a result of moderate inhibition of the electron trans- bearing rats through inhibiting the production of proinflammatory port chain at the entry point of NADH, the mitochondrial molecules and controlling neuropeptide expression in the hypo- thalamus,suggesting another potential benefit of the use of This latter evidence is also intriguing in light of Anisimov et al's metformin as an adjuvant in cancer treatment, which warrants original findings that metformin can also prolong the life span of further clinical exploration.
Her2 mice, because it highlights the possibility that the reduction inmitochondrial bioenergetics induced by metformin may be the 2.4. Metformin might have multiple mechanisms in exerting its cellular mimic of caloric restriction, a well-documented longevity and chemopreventive strategy.
Taken together, the observations described above indicate that the 2.2. Direct mitochondrial effects beneficial effects of metformin as an adjuvant in cancer treatmentmay be orchestrated via many (AMPK-dependent and -indepen- Both the AMPK-independent antitumor effects of metformin dent) mechanisms that might antagonize tumor initiation and/or action, such as the Rag GTPase-dependent inhibition of mTOR, progression, decrease cancer anorexia, and improve antitumor and metformin-induced growth inhibition of AMPK-silenced ovarian cancer cells are important.Nearly 10 years ago, Owenet al described how metformin can inhibit the mitochondrial 3. Clinical evidence for the antitumor and chemopreventive oxidation of complex I-dependent substrates in hepatocytes, an effects of metformin effect that can also be observed in isolated mitochondria.Asdiscussed above, this inhibition of complex I may contribute to the Recently, the Zwolle Outpatient Diabetes Project Integrating activation of AMPK due to the decrease in capacity for oxidative Available Care (ZODIAC) study in The Netherlands reported that phosphorylation and the subsequent increase in AMP:ATP ratio.
metformin exerts chemoprotective activity against all types of This phenomenon may also account for the occasionally observed cancer in patients with type 2 diabetes.Retrospective studies by lactic acidosis in response to high doses of because a group from the University of Washington at Seattle, USA,and pyruvate is converted to lactate rather than to acetyl CoA in the another group from M. D. Anderson Cancer Center in Houston, confirmed that patients with type 2 diabetes treated with The inhibition of hepatic gluconeogenesis in response to metformin had a reduced risk of prostate and pancreatic cancer, metformin is an AMPK-independent consequence of decreased intracellular ATP levels.This notion suggests that the pleio- Based on the available clinical and experimental data, Goodwin, tropic effects of metformin could be the result of a targeted in an editorial in the 2009 Journal of Clinical Oncology, proposed the effect on electron transport in the mitochondria.In light of use of metformin in the adjuvant treatment of breast cancer recent observations, this intriguing effect shows that inhibiting mainly citing the drug's ability to reduce h electron transport in cancer cells is a lethal insult,not which she had reported to be a negative prognostic factor for because of an ensuing energetic catastrophe - cancer cells derive recurrence.Of note, reduction in insulin level and the associated most of their ATP from glycolysis - but because the accumula- decrease in IGF-1 signaling transduction were also suggested to be tion of NADH in the mitochondrial matrix can inhibit the Krebs a mechanism of action in the studies of Anisimov et al.
cycle and the associated amphibolic reactions that support the The first evidence of the efficacy and safety of metformin as an generation of biomass.
adjuvant in the treatment of breast cancer was reported by the Electron transport, uncoupled from oxidative phosphorylation, breast medical oncology group at M. D. Anderson Cancer Center in antagonizes the onset of apoptosis in tumor This a retrospective study of 68 diabetic patients taking metformin, 87 supports the hypothesis that the antitumor and chemosensitizing diabetic patients not taking metformin, and 2,374 nondiabetic effects of metformin could also be mediated through inhibiting patients.Their results showed that diabetic patients with breast electron transport in complex I.
cancer who received metformin and neoadjuvant therapy had

J.E. Duque et al.
a higher pathological response rate than diabetic patients not consecutive days, followed by 3e4-week periods of rest to allow receiving this agent. Importantly, the use of metformin was not recovery of normal progenitor However, the fact that most associated with adverse effects in cancer patients receiving cancer patients still suffer relapses suggests that high-dose chemotherapy is largely ineffective in killing 100% of tumor cells, Subsequently, Stanosz reported that treatment with metformin and perhaps that the genomic instability caused by high-dose in combination with hormonal agents in young women with well- defined stage 1 endometrial carcinoma led to complete remission damage DNA or the machinery necessary for its maintenance/ of the disease after a 6-month treatment and 2-year follow replicationdis the fire that the cellular heterogeneity of tumors These findings suggest that the potential therapeutic benefits of fuels in choosing drug-resistant subclones that will no longer metformin are not limited to breast cancers. Most recently, a group respond to the MTD approach. Moreover, the inhibitory effects of at Yokohama City University reported that a 1-month treatment high-dose chemotherapy on the function of the immune system with metformin reduced the formation of aberrant crypt foci in may provide a window of time for these drug-resistant cells to nine patients without diabetes, suggesting a potential use of met- escape detection and/or to formin in preventing colon tumorigen Interestingly, recent evidence shows that targeted anti- Taken together, the above-mentioned results and observations angiogenic agents provide a moderate therapeutic benefit in many suggest that chronic use of metformin antagonizes the initiation cancer supporting a concept put forward nearly 40 years and progression of cancer, as well as improving the outcome of ago by Folkman, who proposed targeting the tumor vasculature traditional chemotherapeutic strategies.
instead of the tumor cell per se in order to inhibit the growth ofprimary tumors and the spread of malignant cells to distant 4. Metronomic chemotherapy: When less is more sites.In this context, a preponderance of evidence suggests thatlow-dose, continuous infusion or frequent administration of Traditional anticancer drugs are used at or near the maximum agentsdbut not high-dose MTD tolerated dose (MTD), with the goal of killing as many cancer cells approachesdcan inhibit the proliferation and differentiation of as possible, but with unintended consequences that impair quality tumor vasculaturIn terms of its mechanism of action, the of life and cause serious, dose-accumulative toxic To slowly proliferating phenotype of tumor vasculature, and the balance the efficacy and safety of this "MTD approach" with increased sensitivity of endothelial cells to cellular damage in particular emphasis on reducing myelosuppressive effects, high response to cytotoxic agents likely makes the tumor endothelium doses of chemotherapy are normally given once or on a few more sensitive to continuous, low-dose exposure to chemotherapy Figure 1 Diagrammatic representation of the mechanism of action of metformin, which may interact with metronomic chemotherapy at various levels. (1) Metformin can promotethe generation of CD8 memory T lymphocytes, which would complement the reduction in T regulatory lymphocytes and enhance the maturation of dendritic cells induced bymetronomic chemotherapy. (2) Inhibition of mTOR signaling coupled to the decrease in mitochondrial bioenergetics induced by metformin would generate more slowly prolif-erating, chemosensitive tumor cells that would be more appropriately targeted by reduced-intensity chemotherapeutic drugs. (3) Metformin inhibits the EMT transcriptionalprogram, which effectively reduces the formation of tumor stroma and could potentiate the antiangiogenic effects of metronomic chemotherapy. (4) Metformin antagonizes theexpression of P-glycoprotein (P-gp), which could maximize the cytotoxic effects of low doses of chemotherapy in cancer cells.(5) Metformin activates hypothalamic AMPK andmay antagonize cancer cachexia, a benefit most likely maximized in patients receiving metronomic regimens that are not anorexigenic or gastrotoAMP ¼ adenosinemonophosphate; AMPK ¼ AMP-activated kinase; ATP ¼ adenosine triphosphate; EMT ¼ epithelial-mesenchymal transition; mTOR, mammalian target of rapamycin.
Metformin as a novel component of metronomic chemotherapy schemes than to episodic near-MTD therapy. In 2000, Hanahan et al referred that they do to the immune system, yet they continue to be to this low-dose, continuous dosing strategy as "metronomic," and a mainstay of cancer therapy. Moreover, the devastating effects of suggested that its reduced systemic toxicity and its ability to target traditional treatment approaches, and the cost of dealing with the endothelial cells and slowly proliferating tumor cells could offer associated complications, reveal the urgency of developing potential clinical benefits.
chemotherapeutic strategies that lessen suffering, optimize costs, More recent clinical studies have shown that metronomic and allow the immune system to detect and destroy malignant chemotherapy is a potential clinical alternative to either primary systemic therapy or maintenance therapy, and preclinical studies Metformin is an effective and safe hypoglycemic drug with have suggested that, in addition to its well-established anti- a potential new indication for managing and preventing cancer. The angiogenic effects, metronomic chemotherapy can activate anti- evidence presented here suggests that metformin displays single- tumor immunity. The mechanisms underlying the activation of agent therapeutic efficacy, at least in the setting of chemo- antitumor immunity by metronomic chemotherapy have only prevention, and that it combines favorably with chemotherapy to recently been uncovered as most animal models are immunodefi- provide cancer patients with a therapeutic benefit. The above cient, but a number of published studies suggest that the effects are therapeutic considerations, and in addition the low economic cost orchestrated by a reduction in T regulatory lymphocytes, and the of metformin and metronomic chemotherapeutic regimens, maturation and activation of antigen-presenting dendritic cells.
warrant the initiation and support of additional clinical studies toevaluate the efficacy of metformin in patient populations that are 5. How can metronomic chemotherapy interact with not eligible for standard anticancer regimens. This may represent a novel paradigm for the treatment of human malignancies thatreduces the costs of initial treatment and management of As shown by Anisimov et phenformin potentiates the effects of treatment-related complications, which place such a heavy burden cyclophosphamide on various transplantable tumors, and recent on health systems around the globe.
evidence suggests that antagonizing mitochondrial bioenergeticspotentiates the therapeutic effects of cytarabine in mice trans- planted with human Those findings support the notionthat metformin could potentiate the effects of traditional chemo- This work was supported in part by funds from the Research therapeutic agents. Indeed, Jiralerspong and colleagues showed Rectorate and the Department of Nutrition and Biochemistry of the retrospectively that metformin potentiates the pathological Pontificia Universidad Javeriana. The authors thank Ludis Morales response to neoadjuvant chemotherapy in diabetic breast cancer and Ingrid Schuler for scientific and administrative support, and patients without any evidence of increased toxicity.
Angelica Pinzón for technical support.
Could metformin potentiate the effects of metronomic chemo- therapy? The evidence discussed so far suggests that metformincan interact at various levels with metronomic chemotherapy.
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