Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death

• Published in: Toxicology and applied pharmacology 2018-01, Vol.339, p.52-64
• Main Authors: Yadav, Saveg, Kujur, Praveen Kumar, Pandey, Shrish Kumar, Goel, Yugal, Maurya, Babu Nandan, Verma, Ashish, Kumar, Ajay, Singh, Rana Pratap, Singh, Sukh Mahendra
• Format: Article
• Language: English
• Subjects: 3-Bromopyruvate; Tumor metabolism; Tumor milieu; Tumor progression
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2017.12.004

Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. [Display omitted] •3-BP retards tumor progression.•3-BP induces tumor cell death in vivo by apoptosis and necrosis.•Cell death induction implicates mitochondrial alteration and cell cycle arrest.•3-BP administration alters cellular, biophysical and soluble components of TME.•Tumor milieu derived signals are implicated in induction of cell death.