Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo

Tingting Zhang, Long Zhang, Tao Zhang, Jinhai Fan, Kaijie Wu, Zhenfeng Guan, Xinyang Wang, Lei Li, Jer Tsong Hsieh, Dalin He, Peng Guo

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Although neo-adjuvant radiotherapy is generally successful in treatment of advanced prostate cancer, radioresistance is still a major therapeutic problem in many patients. In the current study, we investigated the effects of metformin (1,1-dimethylbiguanide hydrochloride), a widely used antidiabetic drug, on tumor cell radiosensitivity in prostate cancer. Through clonogenic survival assays, we found that metformin treatment enhanced radiosensitivity of prostate cancer cells with a dose enhancement factor. Moreover, irradiation of subcutaneous C4-2 tumors in mice treated with metformin resulted in an increase in radiation-induced tumor growth delay (17.3 days to 29.5 days, P < 0.01), which indicates that the tumor radiosensitivity increased by metformin in vivo. We also measured the sublethal damage repair and analyzed double-strand breaks (DSBs) in X-irradiated cells. γ-H2AX, as an indicator of DSBs, had significantly more foci per cell in the group treated with metformin and radiation compared to groups treated with metformin or irradiation, respectively. Moreover, mice with subcutaneous tumor implants lived longer after a combined treatment of metformin and radiation. In addition, the reduced phosphorylation of DNA-PKcs caused by EGFR/PI3K/Akt down-regulation is essential for metformin to induce radiosensitivity in prostate cancer cells. Our results indicate that metformin enhances prostate cancer cell radiosensitivity in vitro and in vivo. Exposure to metformin before radiation therapy could be a beneficial option for the treatment of prostate cancer.

Original languageEnglish (US)
Pages (from-to)641-649
Number of pages9
JournalRadiation Research
Volume181
Issue number6
DOIs
StatePublished - 2014

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lysyl-arginyl-alanyl-lysyl-alanyl-lysyl-threonyl-threonyl-lysyl-lysyl-arginine
Metformin
radiation tolerance
Prostatic Neoplasms
deoxyribonucleic acid
cancer
Radiation
tumors
Radiation Tolerance
DNA
radiation
strands
mice
radiation therapy
Neoplasms
phosphorylation
irradiation
hydrochlorides
In Vitro Techniques
drugs

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Zhang, T., Zhang, L., Zhang, T., Fan, J., Wu, K., Guan, Z., ... Guo, P. (2014). Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo. Radiation Research, 181(6), 641-649. https://doi.org/10.1667/RR13561.1

Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo. / Zhang, Tingting; Zhang, Long; Zhang, Tao; Fan, Jinhai; Wu, Kaijie; Guan, Zhenfeng; Wang, Xinyang; Li, Lei; Hsieh, Jer Tsong; He, Dalin; Guo, Peng.

In: Radiation Research, Vol. 181, No. 6, 2014, p. 641-649.

Research output: Contribution to journalArticle

Zhang, T, Zhang, L, Zhang, T, Fan, J, Wu, K, Guan, Z, Wang, X, Li, L, Hsieh, JT, He, D & Guo, P 2014, 'Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo', Radiation Research, vol. 181, no. 6, pp. 641-649. https://doi.org/10.1667/RR13561.1
Zhang, Tingting ; Zhang, Long ; Zhang, Tao ; Fan, Jinhai ; Wu, Kaijie ; Guan, Zhenfeng ; Wang, Xinyang ; Li, Lei ; Hsieh, Jer Tsong ; He, Dalin ; Guo, Peng. / Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo. In: Radiation Research. 2014 ; Vol. 181, No. 6. pp. 641-649.
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