Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: a role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation.
Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications.
School of Biotechnology, Banaras Hindu University, Varanasi 221005, India.
Ajay
A
Kumar
Shiva
S
Kant
Sukh Mahendra
SM
Singh
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D020287:In Situ Nick-End Labeling; D016399:Lymphoma, T-Cell / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D059016:Tumor Microenvironment / Q000187:drug effects*
D000970:Antineoplastic Agents; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D002945:Cisplatin
BMC; BMDM; Chemosensitization; DCA; DL; Dalton's lymphoma; Dichloroacetate; MDR; Myelopoiesis; PDH; PDK; ROS; TAM; Tumor microenvironment; Tumor-associated macrophages; bone marrow cells; bone marrow-derived macrophages; dichloroacetate; multidrug resistance; pyruvate dehydrogenase; pyruvate dehydrogenase kinase; reactive oxygen species; tumor associated macrophages