Tumor Decelerating and Chemo-Potentiating Action of Methyl Jasmonate on a T Cell Lymphoma In Vivo: Role of Altered Regulation of Metabolism, Cell Survival, Drug Resistance, and Intratumoral Blood Flow.

Methyl jasmonate (MJ), a natural oxylipin, possesses a broad spectrum of antineoplastic potential in vitro. However, its tumor growth impeding and chemo-potentiating action has not been adequately investigated in vivo. Using a murine thymus-derived tumor named Dalton's Lymphoma (DL), in the present study, we examined if intra-tumoral administration of MJ can cause tumor growth impedance. We also explored the associated molecular mechanisms governing cell survival, carbohydrate & lipid metabolism, chemo-potentiation, and angiogenesis. MJ administration to tumor-transplanted mice caused deceleration of tumor growth accompanying prolonged survival of the tumor-bearing mice. MJ-dependent tumor growth retardation was associated with the declined blood supply in tumor milieu, cell cycle arrest, augmented induction of apoptosis and necrosis, deregulated glucose and lipid metabolism, enhanced membrane fragility of tumor cells, and altered cytokine repertoire in the tumor microenvironment. MJ administration modulated molecular network implicating Hsp70, Bcl-2, TERT, p53, Cyt c, BAX, GLUT-1, HK 2, LDH A, PDK-1, HIF-1α, ROS, MCT-1, FASN, ACSS2, SREBP1c, VEGF, cytokine repertoire, and MDR1, involved in the regulation of cell survival, carbohydrate and fatty acid metabolism, pH homeostasis, and drug resistance. Thus, the present study unveils novel molecular mechanisms of the tumor growth decelerating action of MJ. Besides, this preclinical study also establishes the adjunct therapeutic potential of MJ. Hence, the present investigation will help to design novel anti-cancer therapeutic regimens for the treatment of hematological malignancies.

Protective and recuperative effects of 3-bromopyruvate on immunological, hepatic and renal homeostasis in a murine host bearing ascitic lymphoma: Implication of niche dependent differential roles of macrophages.

3-bromopyruvate (3-BP) possesses promising antineoplastic potential, however, its effects on immunological homeostasis vis a vis hepatic and renal functions in a tumor bearing host remain unclear. Therefore, the effect of 3-BP administration to a murine host bearing a progressively growing tumor of thymoma origin, designated as Dalton's lymphoma (DL), on immunological, renal and hepatic homeostasis was investigated. Administration of 3-BP (4 mg/kg) to the tumor bearing host reversed tumor growth associated thymic atrophy and splenomegaly, accompanied by altered cell survival and repertoire of splenic, bone marrow and tumor associated macrophages (TAM). TAM displayed augmented phagocytic, tumoricidal activities and production of IL-1 and TNF-α. 3-BP-induced activation of TAM was of indirect nature, mediated by IFN-γ. Blood count of T lymphocytes (CD4+ & CD8+) and NK cells showed a rise in 3-BP administered tumor bearing mice. Moreover, 3-BP administration triggered modulation of immunomodulatory cytokines in serum along with refurbished hepatic and renal functions. The study indicates the role of altered cytokines balance, site specific differential macrophage functions and myelopoiesis in restoration of lymphoid organ homeostasis in 3-BP administered tumor bearing host. These observations will have long lasting impact in understanding of alternate mechanisms underlying the antitumor action of 3-BP accompanying appraisal of safety issues for optimizing its antineoplastic actions.

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.

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.