Dr. Weeks’ Comment: And why do they still ignore the role of diet or at least the avoidance of sugar? We all know that cancer cells eat only sugar! Why feed them? Why not encourage patients to improve their diets? Why give CANDY out in the waiting rooms!!!
Eur J Cancer. 2010 Sep;46(13):2369-80. Epub 2010 Jul 23.
Metformin: taking away the candy for cancer?
Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, de Vries EG.
Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands. email@example.com
Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin’s anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.
REMEMBER OTTO?? (the Nobel laureate…)
Med Hypotheses. 2009 Jul;73(1):48-51. Epub 2009 Mar 4.
Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate.
Department of Intensive Care, Surgical Intensive Care Unit, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. firstname.lastname@example.org
The avid consumption of glucose with concomitant lactate production by malignant cells, even under aerobic conditions, is called the Warburg effect, or aerobic glycolysis. This metabolic state is a final common pathway that apparently serves various invasive purposes. As most invasive tumours display the Warburg effect, this has proven of great clinical importance in detecting malignancies with 18-fluorine 2-deoxyglucose positron emission tomography (FDG-PET) scans. However, using the Warburg effect to target malignancies has proven more difficult. Since hypoglycaemia has been shown to be tumouricidal for cancers that display the Warburg effect, various schemes to block glucose utilization have been investigated. But in vivo it is difficult to selectively target glucose utilization in malignant cells without harming normal cells. Cancer cells produce large amounts of lactate under the Warburg effect, without fully oxidizing it to CO(2). In contrast normal cells can completely oxidize lactate under aerobic conditions. Recent studies have demonstrated that vital organs such as the brain, heart, liver, kidneys and muscle are capable of oxidizing lactate as a fuel alternative to glucose. It has also been shown that during hypoglycaemia intravenous lactate can serve as a salvage fuel in man. Other clinical studies showed that patients can effectively metabolize large amounts of exogenous lactate. All this appears to reflect the recently recognized major physiological role of lactate as a glucose alternative. Consequently, lactate is the most logical candidate to serve as a salvage fuel when local or systemic hypoglycemia is induced. Thus, we hypothesize that the combination of hypoglycaemia induced by insulin and concomitant lactate administration will selectively suppress cancers manifesting the Warburg effect, since such cancers will have great difficulty in metabolizing lactate. This metabolic therapy could be modulated in many ways both in amplitude, in duration and in timing with respect to other therapies. The validated isolated limb perfusion (ILP) model for sarcoma appears an attractive model to evaluate local therapy with insulin and lactate and test its (adjuvant) tumouricidal effects in animals and man. Such effects could be evaluated with modern metabolic detection techniques such as FDG-PET and magnetic resonance imaging in local models both in animals and humans. Subsequently the systemic effects of hypoglycaemia combined with sodium lactate administration could be evaluated.
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