Abstract 4107: The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis

Abstract

Abstract Aim: The emergence of breast cancer resistance to chemotherapy represents a major obstacle in cancer therapy. Multiple cellular signalling pathways augment such resistance including the nuclear factor (NF)-κB. In the presented work, we investigated the impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptotic cell death via Annexin V/PI flow cytometry and other molecular biology-based assays. Methods: Doxorubicin (DOX)-resistant MCF-7 and MDA-MB-231 breast cancer cell lines were developed and utilized for the current study. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of different NF-κB pharmacological inhibitors. Chemotherapy-induced apoptosis in parental and resistant breast cancer cells was assessed in the presence or absence of different NF-κB pharmacologic inhibitors such as pentoxifylline (PTX) and bortezomib (BTZ). Results: Treatment of MDA-MB-231 cell line with a sub-cytotoxic concentration of PTX significantly enhanced DOX-induced apoptosis by 6-fold (p<0.001) in wild type cells, and by 8-fold (p<0.01) in the resistant subclones. Similarly, BTZ significantly boosted the percentage of apoptotic cells by 6-fold (p<0.001) in parental cells co-treated with DOX. However, the same treatment boosted the percentage of apoptotic cells by 11-fold (p<0.01) in DOX-resistant MDA-MB-231 cells. It is noteworthy that the increased sensitivity to DOX-induced apoptosis that was mediated via NF-κB inhibition was more prominent in the resistant clones. Conclusion: The data generated from this study support the potential merit of NF-κB inhibitors as adjuvants to improve breast cancer sensitivity to chemotherapy. Further mechanistic investigations are currently in progress in our laboratories to characterize the relationship between NF-κB inhibition and key signaling pathways for breast cancer chemoresistance. Funding: This work was supported by grant # 1801110326-P from the Research Funding Department, University of Sharjah, UAE, and grant #AJF2018050 from Al Jalila Foundation, UAE. Citation Format: Shifaa M. Abdin, Mai F. Tolba, Dana M. Zaher, Hany A. Omar. The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4107.