3-Methyl pyruvate enhances radiosensitivity through increasing mitochondria-derived reactive oxygen species in tumor cell lines

Abstract

Considerable interest has recently been focused on the special characteristics of cancer metabolism, and several drugs designed to modulate cancer metabolism have been tested as potential anticancer agents. To date, however, very few studies have been conducted to investigate the combined effects of anticancer drugs and radiotherapy. In this study, to evaluate the role of mitochondria-derived reactive oxygen species (ROS) in the radiation-induced cell death of tumor cells, we have examined the effect of 3-methyl pyruvate (MP). MP is a membrane-permeable pyruvate derivative that is capable of activating mitochondrial energy metabolism in human lung carcinoma A549 cells and murine squamous carcinoma SCCVII cells. Pretreatment with MP significantly enhanced radiation-induced cell death in both cell lines, and also led to increases in the mitochondrial membrane potential, intracellular adenosine triphosphate content, and mitochondria-derived ROS production following the exposure of the cells to X-rays. In A549 cells, MP-induced radiosensitization was completely abolished by vitamin C. In contrast, it was partially abolished in SCCVII cells. These results therefore suggest that the treatment of the cells with MP induced radiosensitization via the production of excess mitochondria-derived ROS in tumor cells.

Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma

“…Intracellular oxidative stress was evaluated by DCFDA staining, as reported [ 10 ]. Cells were treated with 0–1,000 μM SAS for 24 h. After SAS treatment, cells were stained with 20 μM DCFDA for 30 min at 37°C.…”

Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

“…Compared to the cytotoxicity induced by cisplatin alone, enhanced cytotoxicity was observed when cisplatin was delivered to mitochondria of chemoresistant A2780/CP70 cells by nanoparticles (NP); the cisplatin-nanoparticle combination decreased mtDNA levels and mitochondrial function [8]. In contrast, 3-methyl pyruvate, an activating agent for mitochondrial ETC, enhances radiosensitivity by increasing mitochondria-derived ROS levels in human lung carcinoma A549 cells and murine squamous carcinoma SCCVII cells [9]. These reports strongly suggested mitochondria as novel targets for radiation and chemotherapy in tumor tissue.…”

Monitoring Mitochondrial Complex-I Activity Using Novel PET Probe 18F-BCPP-EF Allows Early Detection of Radiotherapy Effect in Murine Squamous Cell Carcinoma

“…Such specificity for MC-I caused its uptake to be uninfluenced by inflammation caused by IR in the current study and as observed by microglia in the brain after ischemic damage [ 9 ]. The patterns of delayed and protracted uptake of 18 F-BCPP-EF closely resembled those of mitochondrial ROS production after irradiation in a variety of cell lines [ 5 , 20 , 21 ]. Likewise, the current study disclosed a highly significant positive correlation between 18 F-BCPP-EF uptake and radiation dose and its efficacy early after IR.…”