Soy Isoflavones Augment Radiation Effect by Inhibiting APE1/Ref-1 DNA Repair Activity in Non-small Cell Lung Cancer

作者：Singh Gupta Vinita; Joiner Michael C; Runyan Lindsay; Yunker Christopher K; Sarkar Fazlul H; Miller Steven; Gadgeel Shirish M; Konski Andre A; Hillman Gilda G^*

来源：Journal of Thoracic Oncology, 2011, 6(4): 688-698.

DOI：10.1097/JTO.0b013e31821034ae

• Lung cancer
• Soy isoflavones
• Radiation
• gamma-H2AX
• APE1/Ref-1

Introduction: Soy isoflavones sensitize cancer cells to radiation both in vitro and in vivo. To improve the effect of radiotherapy for non-small cell lung cancer, we assessed the potential of using a complementary approach with soy isoflavones.
Methods: Human A549 non-small cell lung cancer cells were treated with soy isoflavones, radiation, or both and tested for cell growth. DNA double-strand breaks (DSBs) were detected by immunostaining for gamma-H2AX foci. Expressions of gamma-H2AX, HIF-1 alpha, and APE1/Ref-1 were assessed by Western blots. DNA-binding activities of HIF-1 alpha and NF-kappa B transcription factors were analyzed by electrophoretic mobility shift assay.
Results: Soy isoflavones increased A549 cell killing induced by radiation. Multiple gamma-H2AX foci were detectable at 1 hour after radiation but decreased at 24 hours after radiation. Soy isoflavones also caused DNA DSBs, but gamma-H2AX foci increased over time. Soy isoflavones and radiation caused an increase in gamma-H2AX foci, which persisted at 24 hours, indicating both increased DNA damage and inhibition of repair. Soy isoflavones inhibited the radiation-induced activity of the DNA repair/redox enzyme APE1/Ref-1 and the transcription factors NF-kappa B and HIF-1 alpha. E3330, which inhibits the redox activity of APE1/Ref-1, did not alter the repair of radiation-induced DSBs. Methoxyamine, which inhibits APE1/Ref-1 DNA repair activity, partly blocked the decrease in radiation-induced DSBs at 24 hours, suggesting partial mitigation of radiation-induced DNA repair akin to the effect of soy combined with radiation, in agreement with cytotoxic assays.
Conclusions: Inhibition of APE1/Ref-1 DNA repair activity by soy could be involved in the mechanism by which soy alters DNA repair and leads to cell killing.

• 出版日期2011-4