Abstract 115: Combined treatment of letrozole or olaparib with aspirin inhibits cell proliferation and induces apoptosis through upregulation of wild p53 and modulation of aurora kinases in human breast cancer cell lines

Abstract

Abstract Although, there are several breakthroughs in the treatment of breast cancer on the past few decades, high incidence of relapse and progression after conventional therapies is deeply concerning, indicating a great need for developing new therapeutics for breast cancer. In the present study, the anti-cancer effects of combinational therapy of Letrozole (Aromatase inhibitor) or Olaparib (PARP inhibitor) with Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), were examined on well differentiated ER-positive and poorly differentiated triple negative breast cancer cell lines, T-47D and MDA-MB-231, respectively. In addition, the effect of combined treatment was also examined by detecting cell survival, cell cycle analysis, and alterations in signaling pathway that play a role in breast cancer progression such as β -catenin, STAT3, cyclin D1, Bax, c-PARP, wild and Mutant p53. In addition the effect of combined treatments were examined on gene expression levels of Cytochromes; CYP1A1, CYP1B1, Aurora kinases; Aurora-A and Aurora-B were determined by RT-PCR.Our data showed that combined treatments of 50 nmol Letrozole or 250 nmol Olaparib with 5 mmol, 2.5mmol Aspirin for 24 and 48 h, respectively, promoted apoptosis induction through enhanced histone release and caspase-3 activation compared to control and cells treated with each drug alone. Furthermore, apoptotic induction was associated with upregulation of Bax and downregulation of Bcl-2, cyclin D1, β-catenin, and STAT3 signaling pathways in both tested cell lines compared to control, suggesting that Aspirin may enhance the sensitivity of tested cells to Letrozole or Olaparib in both (ER) positive and triple negative breast cancer cell lines. In addition, cell cycle analysis showed a cell arrest at G0/G1 phase in both cell lines. Interestingly, in T-47D cells, combined treatment of Letrozole with Aspirin significantly upregulated wild p53 at protein level and downregulated CYP1A1, CYP1B1, Aurora-A, and Aurora-B expression at gene level compared to control, suggesting that combined treatment may inhibit breast cancer cell proliferation via down-regulation of Aurora-A and Aurora-B. In MDA-MB-231 cells, combined treatment of Olaparib with Aspirin showed a significant downregulation of Mutant p53 at protein level and CYP1A1, CYP1B1, Aurora-B and upregulation of Aurora-A at gene level compared to control, suggesting that there is a crosstalk between Olaparib/Aspirin and P53 In conclusion, combined treatment of Letrozole or Olaparib with Aspirin might be a promising approach to inhibit both ER (+) and triple negative breast cancer cell lines survival and proliferation. Citation Format: Marwa Elsayed ElKamel, Salah Sheweita, Ahmed Sultan. Combined treatment of letrozole or olaparib with aspirin inhibits cell proliferation and induces apoptosis through upregulation of wild p53 and modulation of aurora kinases in human breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 115.