Enhancement of cancer cell sensitivity to radiotherapy through increasing oxidative stress by inhibition of glutathione reductase (GR) or a combined inhibition of GR and glutathione biosynthesis.

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Overview

Glutathione reductase (GR, EC 1.8.1.7) catalyzes the reduction of glutathione disulfide (GSSG) back to glutathione (GSH) to maintain a reducing intracellular environment. GR plays a key role in the cellular defense against oxidative stress. High levels of GR activity are often associated with tumor growth and/or resistance mechanisms against chemo- and radiotherapy. Inhibitors of GR are found to be promising agents for the treatments of malaria and cancer. Two mechanisms are known by which the inhibition of GR could impair tumor growth: (a) the resulting build-up of the substrate GSSG could inhibit protein synthesis; (b) the tumor cells may become unable to cope with the cytotoxic reactive oxygen species (ROS) launched against them by activated macrophages. Therefore, inhibition of GR could increase oxidative stress.;This project was aimed to investigate whether oxidatively stressed cancer would be more sensitive to radiotherapy. Specifically, oxidative stress was created through inhibition of GR by an irreversible inhibitor 2-AAPA which was developed from this laboratory with Ki and kinact values of 56 muM and 0.1 min-1 respectively. The effect of GR inhibition on cancer sensitivity to radiotherapy was investigated in four human cancer cell lines. The impact of GR inhibition on intracellular redox and related systems were investigated in CV-1 cells-a monkey kidney cell line. In addition, the effect of a combined inhibition of GR by 2-AAPA and GSH biosynthesis by BSO was also studied.;Our data demonstrated that 2-AAPA inhibited 90-97% GR activities leading to a 5 to 7 fold increase in GSSG and ∼30% decrease in GSH in the normal cell line CV-1 cells. The other changes observed were an increase in the ratio of NADPH/NADP+ and NADH/NAD+, and a significant increase in protein glutathionylation. It produced no significant effect on ROS formation, gene and protein expression of enzymes involved in antioxidant defense systems and in GSH biosynthesis pathway. It did not affect intracellular energy ATP content. These data indicated that 2-AAPA established a thiol oxidative stress with limited effects on other redox systems.;The cancer sensitivity study revealed that 2-AAPA increased the sensitivity of all four studied cancer cell lines to X-ray radiation. X-ray dose response curves were shifted left- and downwards by 2-AAPA which indicated that 2-AAPA increased cancer cell sensitivity to X-ray. The IC50 values of X-ray alone for A431, MCF7, NCI-H226 and OVCAR-3 cells were 24.4Gy, 42.5Gy, 43.0Gy, 27.8Gy, which were reduced to 6.75Gy, 8.1Gy, 6.75Gy, and 12.1Gy respectively when the cells were first treated by 2-AAPA followed by X-ray. Under the condition which produced the best sensitizing effect in OVCAR-3 cell line, 80% of GR was inhibited, and a 3 to 4 fold increase in GSSG was observed by 2-AAPA while an additional increase in GSSG was noticed by 2-AAPA plus X-ray indicating that this drug combination produced additional oxidative stress in the cells. The combination of 2-AAPA and X-ray significantly increased the content of total disulfides by 25.8% which appears to be in agreement with the effect of the drug combination on GSSG. Together, these data demonstrated that a prior establishment of thiol oxidative stress by inhibition of GR can increase cancer sensitivity to radiation.;A combined inhibition of GR and GSH biosynthesis by 2-AAPA and BSO respectively further increased oxidative stress in cancer cells and, as a result, further enhanced cancer cell sensitivity to X-ray irradiation than 2-AAPA alone or BSO alone. The dose response curves of X-ray with four cell lines shifted further left- and downwards by 2-AAPA plus BSO than these two drugs used alone. The IC50 values of X-ray alone for A431, MCF7, NCI-H226 and OVCAR-3 cells were 24.4Gy, 42.5Gy, 43.0Gy, and 27.8Gy, which were reduced to less than 6.7Gy for all four cell lines by the combination of BSO and 2-AAPA. The ratio of GSSG/GSH increased in OVCAR-3 cells when BSO and/or 2-AAPA were used together with X-ray. 2-AAPA + BSO + X-ray produced the highest GSSG/GSH ratio, which indicated that the combination treatment of the three (2-AAPA, BSO and X-ray) produced additional oxidative stress in the cancer cells.;In conclusion, inhibition of GR by 2-AAPA itself increased cancer cell sensitivity to X-ray radiation. The combined inhibition of GR and GSH biosynthesis further increased oxidative stress in cancer cells and, as a result, produced a further enhancement in cancer cell sensitivity to X-ray radiation was observed. (Abstract shortened by UMI.)
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Product Details

  • ISBN-13: 9781244066311
  • Publisher: BiblioLabsII
  • Publication date: 9/11/2011
  • Pages: 170
  • Product dimensions: 8.00 (w) x 10.00 (h) x 0.44 (d)

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