EFFETTO WARBURG PDF

Questo rimedio non solo aiuterebbe e preverrebbe la malattia, ma limiterebbe gli effetti collaterali della chemioterapia. Otto Warburg Il primo chiarimento riguarda il Sig. Warburg, anzi Prof. Warburg linked mitochondrial respiratory defects in cancer cells to aerobic glycolysis; this theory of his gradually lost its importance with the lack of conclusive evidence confirming the presence of mitochondrial defects in cancer cells. Scientists began to believe that this altered mechanism of energy production in cancer cells was more of an effect than the cause.

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Correspondence: Karl J. Morten ku. This article has been cited by other articles in PMC. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria.

It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types.

However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

Keywords: cancer, glycolysis, mitochondrial respiration, Warburg effect The Warburg effect Despite decades of research and countless financial investments, cancer continues to elude our complete understanding and more importantly our therapies. Pivotal research in the s by Warburg and Cori demonstrated that cancer avidly consumes glucose and excretes lactate [ 1 , 2 ]. When oxygen is present, normal cells use mitochondria to oxidise glucose, but in the absence of oxygen, glucose is converted into lactate.

Otto Warburg first described in the s that cancer cells utilised higher levels of glucose in the presence of oxygen with an associated increase in lactate production. The phenomenon of aerobic glycolysis, termed the Warburg effect, has been observed in a variety of other tumour types, including colorectal cancer [ 3 ], breast [ 4 ], lung [ 5 ] and glioblastoma [ 6 , 7 ]. From his observations, Warburg concluded that the mitochondria were dysfunctional [ 8 , 9 ].

The Warburg effect has been confirmed in previous studies including those of DeBerardinis et al. In addition, Fantin et al. These data were interpreted as tumourigenicity being dependent on high levels of energy derived from glycolysis. Another study by Schulz et al. The authors suggest that rather than an increase in glycolysis being the main cause of malignant tumour growth, it is the efficiency of mitochondrial energy conversion that is the key metabolic factor.

In the last decade, research has shown that different tumour types and indeed subpopulations within a tumour have different bioenergetic alterations. This was shown as early as , when Weinhouse reported that slow-growing rat hepatoma cells were oxidative, whereas the more proliferative hepatomas were glycolytic [ 15 ]. The Warburg effect is not consistent across all tumours, and the phenomenon of aerobic glycolysis has now been challenged by several groups with many cell lines reported as having mitochondrial function [ 16 — 18 ].

In a tumour, it is likely that a dynamic interplay exists between oxidative metabolism and glycolysis. Metabolic flexibility has now been observed in a range of cancers, including cervical, breast and pancreatic cancer see ref.

In fact, the ATP generated through glycolysis was highly dependent on the cell type and could be as low as 0. In addition to metabolic flexibility linked to environmental conditions, there is also the influence of various cancer-associated mutations, many of which have an impact on metabolism.

Mutations in the mitochondrial tricarboxylic acid cycle and respiratory chain component succinate dehydrogenase, for example, can cause phenochromocytoma and paraganglioma, where neuroendocrine tumours arise in the adrenal medulla and paraganglia in the autonomic nervous system [ 21 , 22 ]. Mutations in isocitrate dehydrogenase 1 are associated with adult cases of glioblastoma and appear to have a major role in the development of the tumour by a gain-of-function effect [ 23 , 24 ].

Cancer hallmarks and metabolic reprogramming Cancer cells show complex, dynamic behaviour allowing survival even in the most unfavourable conditions of substrate and oxygen stress. Advances in technology have helped in furthering our knowledge of the underlying molecular processes underpinning cancer, but there are still many unanswered questions. In , Hanahan and Weinberg published a highly cited review article identifying six cancer hallmarks [ 25 ].

These included uncontrolled proliferative signalling, resistance to apoptosis, initiating angiogenesis, acquiring replicative immortality, activating invasion and metastasis and evading growth suppressors. Uncontrolled proliferation is one of the essential characteristics of cancer. It has been proposed that reprogramming energy metabolism is essential to fuel and maintain such behaviour [ 26 ].

The exact reasons behind the metabolic switch are not known, but likely reasons include: i sustaining high proliferative rates in hypoxia [ 27 ] and ii evading apoptosis as a result of reduced mitochondrial function [ 28 ]. Increases in glycolysis have been linked to invasiveness, with changes in glycolysis identified in several studies [ 29 , 30 ]. However, in all studies listed above, cancer cells were grown on cell culture media containing high levels of glucose between 10 and 25 mM.

This is considerably higher than plasma glucose, which lies between 4 and 6 mM. Levels in a rapidly dividing tumour with poor vasculature are considerably lower. The same is true of studies investigating the role of hypoxia in down-regulating mitochondrial respiration and increasing glycolysis, where 25 mM glucose is used in the culture media of key publications [ 31 — 34 ].

The impact of high levels of glucose on the above findings is a key consideration for future studies, where it is crucial to test new drugs targeting cancer cell metabolism under physiologically relevant conditions.

Metformin, for example, a drug currently being investigated as an anticancer agent in a wide range of cancers [ 35 ], has recently been shown to be more effective in enhancing chemotherapy sensitivity of oesophageal squamous cancer cells under reduced glucose conditions [ 36 ].

Although its mode of action on cancer cells in vivo is not entirely clear, mitochondrial studies suggest that metformin can directly impair complex I of the respiratory chain [ 37 , 38 ].

The effect observed by Yu et al. Previous studies have shown that high levels of glucose in the culture media can significantly reduce levels of mitochondrial respiration, with reduced glucose conditions showing much higher rates of mitochondrial respiration, as cells use other substrates for cellular ATP production [ 39 , 40 ].

Similar results are shown in Figure 1 , where the oxygen consumption rates OCRs; mitochondrial respiration and extracellular acidification rates ECAR; glycolysis of a range of cancer cell lines are compared under high 25 mM and low 1 mM glucose conditions.

A finding highly relevant to the situation in vivo is that when cultured under low glucose 1 mM conditions, all cancer lines tested show high—moderate OCR with very little ECAR glycolysis.

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Warburg effect

Tuttavia, la maggior parte delle cellule tumorali prevalentemente producono la loro energia attraverso un alto tasso di glicolisi seguita da fermentazione lattica anche in presenza di ossigeno abbondante. Nel cancro del rene , questo effetto potrebbe essere dovuto alla presenza di mutazioni nel tumore soppressore von Hippel-Lindau gene upregulating enzimi glicolitici, compresa la giunzione isoforma M2 della piruvato chinasi. TP53 mutazione colpisce il metabolismo energetico e aumenta la glicolisi nel cancro al seno. Nel marzo , Lewis C. Acido dicloroacetico DCA , un inibitore della piccola molecola di mitocondriale chinasi piruvato deidrogenasi , "downregulates" glicolisi in vitro e in vivo. I ricercatori della University of Alberta teorizzato nel che DCA potrebbe avere benefici terapeutici contro molti tipi di cancro. DCA agisce un analogo strutturale del piruvato e attiva il complesso della piruvato deidrogenasi PDC per inibire chinasi piruvato deidrogenasi, per mantenere il complesso nella sua forma non-fosforilata.

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Effetto Warburg Inverso: Un Nuovo Modello di Tumore.

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