Radiosensitization effect of zidovudine on human malignant glioma cells

doi:10.1016/j.bbrc.2006.12.180

Biochemical and Biophysical Research Communications

Volume 354, Issue 2, 9 March 2007, Pages 351-356

https://doi.org/10.1016/j.bbrc.2006.12.180 Get rights and content

Abstract

Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of γ-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

Section snippets

Materials and methods

Experimental groupings. Human malignant glioma cells U251 (CCTCC) were cultured in RPMI 1640 media supplement with 10% calf serum (Gibco). Cells were incubated at 37 °C in humidified atmosphere containing 5% CO₂. Exponentially growing cells in 50 cm² culture flasks were divided into four groups: (1) Control: without AZT or irradiation treatment; (2) Irradiation: treated with irradiation (⁶⁰Co therapeutic machine, GWXJ80 type, Chengdu, China. Radiation dose: 2Gy at the rate of 61.22 cGy/min, SSD = 80

Increase of TA by irradiation and decrease of TA by AZT

A significant increase in TA was observed between irradiation group and control group (1.902 ± 0.224 vs. 1.567 ± 0.037, p < 0.05). We can see gradual up-regulation of TA in irradiation group after 2Gy-radiation exposure, and nearly maximum at 6 h (increased by about 40%). Obviously, TA decreased in drug group compared to control group (1.019 ± 0.116 vs. 1.567 ± 0.037, p < 0.05). It indicated that AZT could suppress the TA of the U251 cells. Compared to the irradiation group, the TA in the drug and

Discussion

In this report, we have observed that, after in vitro exposure to 2Gy γ-radiation, telomerase activation has been increased in U251 cells and reached a maximum at 6 h postirradiation, confirming that low dose irradiation can induce an up-regulation of TA in tumor cell lines [4], [5]. We favor the hypothesis that telomerase may participate in the process of DNA repair and the up-regulation of TA may be a reaction to DNA damage induced by irradiation, which may be one of the mechanisms involved in

Acknowledgments

We are grateful to Dr Wen Jie Zhang for critical review of the manuscript. This work was supported by the Natural Science Foundation of China (30171063).

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¹: These authors contributed equally to this work.

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