Abstract P6-12-04: Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy

Abstract

Abstract Radiation therapy plays an important role in controlling the growth and progression of breast cancer. However, its efficacy is limited by the radiation-associated toxicity to normal tissue, and the intrinsic or acquired radioresistance developed in cancer cells. It was well documented that radiation onto cancer tissues cause complex changes in gene expression patterns. Thus, it may be possible to manipulate the expression of specific genes in cancer cells to increase radiosensitivity and reduce radioresistance. Accumulating studies strongly demonstrated that signal transducers and activators of transcription 3 (STAT3) is involved in cell survival, proliferation, inflammation, invasion, metastasis, angiogenesis and immune responses. Particularly, STAT3 is activated by ionizing radiation. We hypothesized that blocking STAT3 will increase sensitivity to irradiation in cancer cells. To this end, we synthesized a series of novel STAT3 inhibitors to address the challenge of radioresistance in breast cancer cells including metastatic and triple-negative lines. Among them, the compound HJC0152 and HJC0123 displayed significant inhibition of proliferation of MDA-MB-231, MCF-7 and MCF-7/Adr in dose and time dependent manners. HJC0152 and HJC0123 also induced apoptosis and necrosis in comparison to the control cells. We also found that these STAT3 inhibitors induce apoptosis of MDA-MB-231, MCF-7 and MCF-7/Adr cells by inhibiting anti-apoptotic protein Bcl-2 expression, increasing the expression of apoptotic effector protein caspase-3 and Bax. In addition, we found that HJC0152 and HJC0123 in combination with X-ray irradiation induce G2/M cell cycle arrest in MDA-MB-231, MCF-7 andMCF-7/Adr cells. The new STAT3 inhibitors increased the radiosensitivity of MDA-MB-231, MCF-7 and MCF-7/Adr cell lines, inhibited radiation-induced DNA damage repair, and promoted cells to enter mitosis, a phase more sensitive to irradiation. These changes were accompanied with decreased activation of STAT3 and decreased expression of the STAT3 downstream gene, Bcl-2. Our findings suggest that STAT3 blockade may represent an effective strategy to overcome radiation resistance, using STAT3 inhibitors as radiation sensitizers to restore the sensitivity of cancer cells to radiation therapy. Citation Format: Lili Wang, Zhengduo Yang, Qing Xia, Haijun Chen, Guoshuai Cai, Christopher Wild, Jia Zhou, Qiang Shen. Targeting STAT3 with novel small molecule inhibitors to sensitize breast cancer cells to radiation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-04.