2-Deoxy-D-Glucose Enhances Dichloroacetate Antitumor Action Against Lewis Lung Carcinoma

Abstract

Aerobic glycolysis that supports high proliferation rate and survival of tumor cells in unfavorable conditions is among fundamental features of tumor metabolism. The search for active modulators of energetic metabolism capable of suppressing tumor growth and metastasis could result in higher effectiveness of anticancer therapy. Aim: To study antitumor and antimetastatic activity of the modulators of energetic metabolism dichloroacetate (DCA) and 2-deoxy-D-glucose (2DG) used in combination treatment of Lewis lung carcinoma (LLC). Materials and Methods: As experimental tumor model, LLC/R9 variant was used. DCA and 2DG were administered per os to С57Bl/6 mice 5 times per week for 3 weeks at a total dose of 1.5 and 0.98 g/kg, respectively, as single agents or in combination starting from the following day after tumor cell transplantation. Growth of primary tumor and number and volume of lung metastases were registered. Lactate and pyruvate content was determined by enzymatic methods using lactate dehydrogenase. Electron paramagnetic resonance was used for analyzing the functional state of the components of mitochondrial respiratory chain. Engulfing activity and reactive oxygen species (ROS) production in tumor-associated CD14+ cells was analyzed by flow cytometer with the use of FITC-labeled staphylococcus, and by spectrofluorometry with the use of 2.7-dichlorofluorescein diacetate, respectively. Results: DCA administered as a single agent did not affect primary tumor growth but decreased the number and volume of lung metastases by 60% (p < 0.05) and 90% (p < 0.05), respectively. In mice treated with 2DG only, primary tumor volume as well as the number and volume of lung metastases were not affected. Combination treatment with DCA and 2DG resulted in the decrease of primary tumor volume, the number and volumes of lung metastases by 70; 46, and 90%, respectively (р < 0.05). High antitumor activity of DCA + 2DG was associated with 31% decrease (p < 0.05) of lactate content in tumor tissue and 120% increase (p < 0.01) of ROS production in СD14+ cells recruited to the region of tumor growth. Conclusion: 2DG that possesses neither antitumor nor antimetastatic activity against LLC/R9 significantly enhanced antitumor activity of DCA with accompanying inhibition of glycolysis and increase of cytotoxic activity of CD14+ cells infiltrating tumor tissue. Taking into account significant antimetastatic activity of DCA this substance could be considered as a promising antimetastatic agent.

Antitumor Activity of Alloy and Core-Shell-Type Bimetallic AgAu Nanoparticles

“…An in vivo antitumor activity of the administered NPs was estimated based on the rate of primary tumor growth inhibition (TGI), lung metastasis growth inhibition (MGI), and metastasis inhibition (MI) indexes [ 15 ]. An inhibitory effect of NPs towards LLC primary tumor growth was observed for mice treated with NPs either with different Ag:Au molar ratio (AgAu(1:3), AgAu(1:1), AgAu(3:1)) or with different topology (Au core Ag shell , Ag core Au shell ) (Table 1 ).…”

“…Antitumor and antimetastatic activities of the NPs were evaluated on day 18 after tumor transplantation based on morphological parameters of primary tumor volume and number and size of lung metastases [ 15 ]. Primary tumor diameter was measured three times per week starting from day 5 after tumor inoculation.…”

“…Primary tumor diameter was measured three times per week starting from day 5 after tumor inoculation. Tumor volume ( V ) was calculated by the formula V = 0.52 d 3 , where d is the tumor diameter [ 15 ]. Anticancer activity was evaluated as tumor growth inhibition (TGI) rate calculated by the formula where V 0 and V 1 are average tumor volumes in animals of a control and experimental group respectively.…”

Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core–Shell-Radiosensitizer for Breast Cancer Therapy

“…The exploration of drug therapy combinations is a promising strategy, as synergistic effects from multiple drugs potentially lead to better therapeutic outcomes and a reduced probability of drug resistance in cancer cells [ 7 ]. 2-Deoxy glucose (2-DG) and dichloroacetate (DCA) are drug combinations currently used in cancer clinical trials [ 8 ]. Both 2-DG and DCA are established as BC chemotherapeutic treatments and have been combined with radiotherapy (RT) in clinical trials.…”

Streptomyces nigra sp. nov. Is a Novel Actinobacterium Isolated From Mangrove Soil and Exerts a Potent Antitumor Activity in Vitro

“…Finally, 2-deoxy- D -glucose is a glycolysis inhibitor that differentially enhances the radiation and chemotherapeutic drug-induced cell death in cancer cells in vitro . Its potential as an immunomodulator, in addition to a direct effect on the tumor, is specifically employed in a combination treatment of Lewis lung carcinoma ( Farooque et al, 2014 ; Pyaskovskaya et al, 2016 ). The antitumor activity and low toxicity of the above compounds have been documented in numerous studies, supporting the notion that they at least partially, account for the cytotoxic activity of the strain 452 T extract.…”