Metabolism targeting therapy of dichloroacetate-loaded electrospun mats on colorectal cancer

Abstract

Differences in energy metabolism between tumor cells and normal cells offer an attractive avenue of research into drug targets for tumor therapy. The use of a metabolic modulator (sodium dichloroacetate, DCA), administered in situ, to reverse the ''Warburg effect'' of tumor cells has been demonstrated as an effective tumor therapy. Herein, DCA and diisopropylamine dichloroacetate (DADA) were incorporated separately into polylactide (PLA) electrospun mats and applied to C26 tumor-bearing mice via in situ administration. After 12 d of treatment, the tumor suppression rates of 75% and 84% were achieved in the DC group (treated with a DCA-loaded mat) and the DA group (treated with a DADA-loaded mat), respectively. With tolerable physiologic toxicity under high local concentration, the DA group showed a 95% tumor suppression rate without any recurrence after 15 d of therapy. The desirable therapeutic effects of these metabolic modulators should ascribe to the energy-central metabolismtargeting effects of DCA and DADA, which were demonstrated both in vitro and in vivo. Therefore, DCA-and DADA-loaded mats are the effective anti-cancer drugs dosages to discriminate between tumor cells and normal cells for minimizing systemic toxicity. KeywordsColorectal cancer, diisopropylamine dichloroacetate (DADA), electrospun mats, metabolism targeting, sodium dichloroacetate (DCA) History

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

“…It has been demonstrated with moderate antitumor activity (31)(32)(33) and to induce apoptosis in tumors of patients with glioblastoma by restoring the mitochondrial activity (34). Several studies have also used it as a radiosensitizer in lung (11), colorectal (13), and prostate cancer cells (12) in vitro.…”

Superior anti-tumor efficacy of diisopropylamine dichloroacetate compared with dichloroacetate in a subcutaneous transplantation breast tumor model

“…The tricarboxylic acid (TCA) cycle is a major link among carbohydrate, lipid, and amino acid metabolism [ 25 ]. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which can preferentially divert glucose metabolism from glycolysis towards oxidative phosphorylation through the activation of pyruvate dehydrogenase [ 26 , 27 ]. DCA has been shown to have anti-tumor properties in various carcinoma models, and its clinical application is currently being investigated in trials [ 26 , 27 ].…”

Crystal structure of diisopropylaminium dichloroacetate

“…For the background to the biological activity of the title compound, see: Gelernt & Herbert (2009); Yamane et al (2014); Liu et al (2015). For a related structure, see: Yu & Qian (2009 Table 1 Hydrogen-bond geometry (Å , ).…”

“…Moreover the desirable therapeutic effects of colorectal cancer in mat is shown (Liu et al, 2015). No data about the crystal structure of diisopropylaminium dichlorocacetate has been reported so far.…”