Frontiers in Pharmacology (Jul 2019)
Diverse Stakeholders of Tumor Metabolism: An Appraisal of the Emerging Approach of Multifaceted Metabolic Targeting by 3-Bromopyruvate
Abstract
Malignant cells possess a unique metabolic machinery to endure unobstructed cell survival. It comprises several levels of metabolic networking consisting of 1) upregulated expression of membrane-associated transporter proteins, facilitating unhindered uptake of substrates; 2) upregulated metabolic pathways for efficient substrate utilization; 3) pH and redox homeostasis, conducive for driving metabolism; 4) tumor metabolism-dependent reconstitution of tumor growth promoting the external environment; 5) upregulated expression of receptors and signaling mediators; and 6) distinctive genetic and regulatory makeup to generate and sustain rearranged metabolism. This feat is achieved by a “battery of molecular patrons,” which acts in a highly cohesive and mutually coordinated manner to bestow immortality to neoplastic cells. Consequently, it is necessary to develop a multitargeted therapeutic approach to achieve a formidable inhibition of the diverse arrays of tumor metabolism. Among the emerging agents capable of such multifaceted targeting of tumor metabolism, an alkylating agent designated as 3-bromopyruvate (3-BP) has gained immense research focus because of its broad spectrum and specific antineoplastic action. Inhibitory effects of 3-BP are imparted on a variety of metabolic target molecules, including transporters, metabolic enzymes, and several other crucial stakeholders of tumor metabolism. Moreover, 3-BP ushers a reconstitution of the tumor microenvironment, a reversal of tumor acidosis, and recuperative action on vital organs and systems of the tumor-bearing host. Studies have been conducted to identify targets of 3-BP and its derivatives and characterization of target binding for further optimization. This review presents a brief and comprehensive discussion about the current state of knowledge concerning various aspects of tumor metabolism and explores the prospects of 3-BP as a safe and effective antineoplastic agent.
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