Hypoxic state and glycolysis as a possible anticancer therapeutic target

In this review the role of hypoxia and glycolysis in tumor expansion is described. Experimental results demonstrate that glycolysis functions in tumor cells are not restrict only energy supply. Glycolysis stimulates the activity of transcription factor HIF-1α. Assemble of HIF1α and protein ARNT stimulates expression of numerous genes. Among others there are genes coding glycolysis proteins, telomerase, P-glycoproteins, antiapoptotic proteins belonging to Bcl-2 family, inhibitor of pyruvate dehydrogenase – pyruvate dehydrogenase kinase and others. The inhibition of mitochondia respiratory chain by inhibition of pyruvate dehydrogenase stimulates accumulation in cell pyruvate. Lactate dehydrogenase transforms pyruvate in lactate. Accumulation of lactate in tumour cells activates monocarboxylate transporter. Lactate and proton transport into intercellular region. Due to it is observed pH drop in tumour tissue. The low level of pH in tumour tissue stimulates metalloprotease activity. Metalloprotease activity disrupt the intercellular matrix. In tumour region with low pH level the enhancement of invasion is observed. The restoration of normal pH level in tumor tissue inhibits invasion and metastasis. It is possible to conclude that hypoxia is a physiological tumour state that support and promote tumor process. It is some informaton about antitumour effects of inhibitors of different stages of glycolysis. Inhibitors of hexokinase – 2‑deoxy-D-glucose and lonidamine inhibit adenosine triphosphate formation as well as
P-glycoprotein activity. For some tumour types these compounds are toxic. The inhibition of P-glycoprotein activity stimulates antineoplastic activity of cytostatics. Dichloroacetate inhibits pyruvate dehydrogenase kinase activity. Inclusion of respiratory chain in situation when oxygen level is low stimulates reactive oxygen species formation. Reactive oxygen species are able stimulate apoptosis. It is shown that dichloroacetate is very toxic for some forms of tumour. It is discussed the possibility to use the different inhibitors of the different glycolytic stages as anticancer compounds

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