Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects.
Understanding the complexity of cancer and of the underlying regulatory networks provides a new paradigm that tackles cancer development and treatment through a system biology approach, contemporarily acting on various intersecting pathways. Cancer cell metabolism is an old pathogenetic issue that has recently gained new interest as target for therapeutic approaches. More than 70 years ago, Warburg discovered that malignant cells generally have altered metabolism with high rates of glucose uptake and increased glycolysis, even under aerobic condition. Observational studies have provided evidence that impaired metabolism, obesity, hyperglycemia and hyperinsulinemia may have a role in cancer development, progression and prognosis, and actually diabetic and obese patients have increased cancer risk. On the other hand, caloric restriction has been shown to prolong life span and reduce cancer incidence in several animal models, having an impact on different metabolic pathways. Metformin, an antidiabetic drug widely used for over 40 years, mimics caloric restriction acting on cell metabolism at multiple levels, reducing all energy-consuming processes in the cells, including cell proliferation. By overviewing molecular mechanisms of action, epidemiological evidences, experimental data in tumor models and early clinical study results, this review provides information supporting the promising use of metformin in cancer prevention and treatment.
Scientific Directorate, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. marco.pierotti@istitutotumori.mi.it
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Gariboldi
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Melani
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Mogavero
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Pasanisi
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D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C469991:DDIT4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D008687:Metformin; D017526:Receptor, IGF Type 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases