Authors:
Saveg Yadav, Shrish Kumar Pandey, Yugal Goel, Mithlesh Kumar Temre, Sukh Mahendra Singh
The Use Of 3-Bromopyruvate For Inhibiting Tumor Metabolism
The importance of unique metabolic characteristics of cancer cells was aptly recognized by Nobel laureate Sir Otto Heinrich Warburg, who described that neoplastic cells predominantly acquire energy through the fermentation of glucose to lactate irrespective of the presence or absence of oxygen and functional mitochondrial machinery. This phenomenon of “aerobic glycolysis” is also denoted as the “Warburg effect” or substrate level fermentation.
The alternative fuels of neoplastic cells include a variety of biomolecules such as lactate, acetate, glutamine, cysteine, alanine, and several proteins, which can be channeled into fermentation pathways.
Given the diverse stakeholders of tumor metabolism, it is essential to evolve a multifaceted targeting strategy for effective control of neoplastic cells’ survival, invasion, and metastasis. A drug fulfilling the objective of targeting multiple aspects of tumor metabolism is a brominated derivative of pyruvate, designated as 3-BP.
3-BP is capable of inhibiting several aspects of tumor metabolism related to nutrient uptake, rewired metabolic pathways, pH homeostasis, and metabolism-dependent cellular interactions in the Tumor Microenvironment. Being an alkylating agent, 3-BP targets a plethora of biomolecules of neoplastic cells, and moreover, 3-BP shows a high degree of specificity for its anticancer activity. The tumor cell-specific selectivity of 3-BP mainly depends on the similarity of this molecule with lactate and pyruvate, and hence it utilizes common transporters to gain cellular entry.
In addition to its ability to inhibit metabolic enzymes, 3-BP also causes overexpression of the reactive oxygen species, along with depletion of ROS scavenger glutathione , in neoplastic cells, which in turn can induce cell death by induction of apoptosis and necrosis.
It has been demonstrated that the antitumor action of 3-BP is accompanied by protective and recuperative effects on immunological, hepatic, and renal homeostasis, with normalization of liver and kidney functions, reduction of tumor growth-associated splenomegaly, restored thymic homeostasis, normalization of blood lymphocytes, and upregulated myelopoiesis.