TY - JOUR
T1 - Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo
AU - Zhang, Tingting
AU - Zhang, Long
AU - Zhang, Tao
AU - Fan, Jinhai
AU - Wu, Kaijie
AU - Guan, Zhenfeng
AU - Wang, Xinyang
AU - Li, Lei
AU - Hsieh, Jer Tsong
AU - He, Dalin
AU - Guo, Peng
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84902437461&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902437461&partnerID=8YFLogxK
U2 - 10.1667/RR13561.1
DO - 10.1667/RR13561.1
M3 - Article
C2 - 24844651
AN - SCOPUS:84902437461
SN - 0033-7587
VL - 181
SP - 641
EP - 649
JO - Radiation research
JF - Radiation research
IS - 6
ER -