Influence of Metformin, Sodium Dichloroacetate and Their Combination on the Hematological and Biochemical Blood Parameters of Rats With Gliomas C6

Abstract

Background: The efficacy of antimetabolic therapy of malignant neoplasms could not be explained solely by the direct mechanisms of action of such energy metabolism inhibitors as sodium dichloroacetate (DCA) and metformin (MTF). The indirect effects of DCA and MTF on the organs and tissues, which could play significant role in the antitumor activity of these agents, have not been thoroughly explored. Aim: To investigate the effect of MTF, DCA and their combination on the survival of rats with C6 glioma and major haematological and biochemical blood parameters. Materials and Methods: DCA and MTF were administered orally to inbred female rats for 11 days starting from the second day after tumor cell transplantation at a total dose of 1.1 and 2.6 g/kg, respectively. When combined treatment was used, MTF was administered 3 hours after the administration of DCA. The content of lactate and pyruvate in blood plasma was determined on the ChemWell® 2910 (Combi) automatic analyzer. Blood parameters were determined using the Particle Counter PCE­210 automatic hematology analyzer. Results: The administration of DCA did not significantly affect the life span of rats with C6 glioma. Duration of life of rats, which were administered with MTF only, was significantly higher (by 19.1%, p < 0.01). Combined administration of DCA + MTF prolonged life span of animals with glioma by 50% (p < 0.001). The positive result of antitumor activity of MTF alone and in combination with DCA correlated with a decrease in the mean platelet volume/platelet count (MPV/PLT) ratio by 75.0% (p < 0.05) compared with tumor control. In addition, the expressed antitumor effect of combination therapy with DCA and MTF was associated with a decrease (p < 0.05) in glucose and lactate levels in blood plasma of rats with C6 glioma by 10% and 41.4%, respectively, compared to tumor control. Analysis of blood parameters showed that the growth of C6 glioma was accompanied by the development of leukopenia, anemia and thrombocytopenia. The introduction of DCA caused the correction of manifestations of anemia and leukopenia, but did not affect the level of platelets in the blood of animals with glioma. MTF alone and in combination with DCA positively influenced the number of white blood cells and caused complete thrombocytopenia correction, increasing platelet count by more than 200% (p < 0.001). Conclusion: The ability of MTF either used alone or in combination with DCA to influence the development of C6 glioma which is manifested in an increase in the lifespan of rats has been revealed. The most pronounced antitumor effect was recorded against the background of the combined use of these agents, which may be due to their ability to lower the levels of lactate and glucose in the blood of tumor­bearing rats. It is proved that MTF both in monotherapy and in combination with DCA provides correction of anemia and thrombocytopenia, which arise at the background of glioma C6 growth.

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

“…Similar results were obtained in melanoma cells in which the administration of retinoic acid receptor β (RAR β ) inhibitors confer sensitization to DCA [41]. A positive effect of DCA coadministration with metformin, a hypoglycaemic drug widely used to treat diabetes was demonstrated in a preclinical model of glioma [42] as well as in a low metastatic variant of Lewis lung carcinoma (LLC) [43]. Jiang and colleagues investigated the effects of phenformin, a metformin analog, and DCA in glioblastoma, demonstrating that contemporary inhibition of complex I and PDK by phenformin and DCA, respectively, decreased self-renewal and viability of glioma stem cells (GSCs), thus suggesting their possible employment to affect cancer stem cell fraction [44].…”

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

“…In animals, DCA has been shown to have side effects such as lowering the blood glucose level [99,125,126,127] and the lactate level in blood serum and tumor tissue [126,128,129,130]. It has numerous toxic adverse effects on the testicular tissue [131] and induced birth defects [54,97], while hepatomegaly was consistently observed across species [97,132,133,134].…”

Cancer cachexia has many symptoms but only one cause: anoxia

“…• DCA targets mainly cells that cannot use the oxidative metabolism 248 . This concept is further confirmed by the synergy between DCA and metformin [267][268][269][270][271][272][273][274] . The fundamentals of this association stem from the fact that metformin inhibits mitochondrial Complex I and reduces oxidative metabolism while DCA inhibits glycolysis.…”