Metabolic Enzymes: New Targets for the Design of Antitumor Drugs
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Pharmaceutical Chemistry Journal, Vol. 54, No. 6, September, 2020 (Russian Original Vol. 54, No. 6, June, 2020)
MOLECULAR-BIOLOGICAL PROBLEMS OF DRUG DESIGN AND MECHANISM OF DRUG ACTION METABOLIC ENZYMES: NEW TARGETS FOR THE DESIGN OF ANTITUMOR DRUGS L. A. Braun,1,* E. E. Varpetyan,1,* G. A. Zav’yalov,1,* F. V. Kulikov,1,* V. E. Marievskii,1,* D. A. Tyul’ganova,1,* A. O. Shishnenko,1,* D. S. Stepanova,1,** and N. L. Shimanovskii1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 6, pp. 3 – 10, June, 2020.
Original article submitted April 30, 2020. The awareness of malignant metabolism transformations has recently emerged. Since Otto Warburg found that tumor cells prefer glycolysis to oxidative phosphorylation even in the presence of oxygen, studies have shown that cancer cells also depend on upregulated fatty-acid synthesis and glutaminolysis. The present review covers the key metabolic enzymes known as metabolic oncogenes and suggests ways of modulating their activity. It is concluded that metabolic transformations during carcinogenesis present opportunities for targeted action on neoplasms and provide a new field for antitumor drug development. Keywords: malignant metabolism transformation, metabolic triad, glycolysis, fatty acid synthetase, glutaminase.
Mammalian cells obtain energy through several interrelated pathways. The preferred pathway in most tissues in the presence of oxygen is the citric-acid cycle (Krebs cycle) with subsequent transfer through the mitochondrial electron-transport chain. Glycolysis is preferred under hypoxic conditions and in certain tissues, e.g., muscle. The Krebs cycle is supported by b-oxidation of fatty acids when deficiencies of carbohydrates develop. Finally, cells can produce energy via glutaminolysis of proteins during prolonged shortages of nutrients (Fig. 1). However, malignant transformations can drastically alter the regulation of cellular metabolic pathways. The metabolic restructuring that occurs in cancer cells was first reported long ago. Already in the 1920s, the famous German biochemist Otto Warburg hypothesized that carcinogenesis involving a transition from oxygen respiration to glycolytic en-
ergy production was the main cause of cancerous cell transformations [1]. Warburg noted that cancer cells preferred glycolysis to oxidative phosphorylation even in the presence of oxygen. As a result, this phenomenon was called the Warburg effect. Next, such behavior of cancer cells was found to be an effect and not the cause so that interest in studying cancer metabolism began to wane with time. However, interest in tumor metabolism again waxed after a certain pause in studies of carcinogenetic processes. Today, the ability to grow rapidly, proliferate constantly, and circumvent apoptosis are known to be characteristic features of tumor cells. The demand for energy is elevated in cancer cells because of the high proliferation rate. However, normal energy-exchange pathways turn out to be unfavorable in tumors because of the accumulation of mutations and a g
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