Abstract 1863: Ursolic acid sensitizes rhTRAIL-resistant triple negative breast carcinoma to rhTRAIL-induced apoptosis

Abstract

Abstract Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) possesses the ability to induce apoptosis in cancer cells independent of their p53 status while exhibiting minimal toxicity to normal, non-transformed cells, and thus, it is a promising anti-cancer therapeutic. However, rhTRAIL-induced apoptosis is not as effective in a majority of breast cancers due to the up-regulation of anti-apoptotic proteins, down-regulation of pro-apoptotic proteins, and/or down-regulation of death receptors (DRs) 4 and 5. A combinatorial approach of rhTRAIL with the “mother nature”-derived compound ursolic acid (UA) has been applied to sensitize rhTRAIL-resistant triple negative breast carcinoma. UA is derived from the leaves and berries of various plants and found in the coatings of fruits and does not exhibit toxicity to normal, non-transformed cells. UA has been revealed to possess the ability to up-regulate DR5 and diminish the expression of anti-apoptotic proteins survivin and FLIP in cancer cells and thereby, making UA an encouraging choice to be utilized as a sensitizing agent. The aim of this study was to determine the capacity of UA to sensitize rhTRAIL-resistant triple negative breast cancer (TNBC) BT-20 and HCC1937 cells to rhTRAIL-induced apoptosis and elucidate the underlying mechanisms for UA's sensitization. The combinatorial treatment of UA and rhTRAIL augmented the induction of apoptosis when compared to single agent UA and rhTRAIL treatments as detected by Annexin V/PI assays and through by the execution of the extrinsic pathway as marked by the activation of caspase 8, activation of the executioner caspases 3 and 7, and eventual PARP cleavage (a hallmark of apoptosis). The underlying mechanisms for UA's sensitization of rhTRAIL-resistant TNBCs were established to be through the down-regulation of the anti-apoptotic protein FLIP and through the up-regulation of DR4 and DR5. Overall, these findings reveal that UA is an efficacious sensitizing agent for rhTRAIL-resistant TNBCs. Citation Format: Jasmine Manouchehri, Michael Kalafatis. Ursolic acid sensitizes rhTRAIL-resistant triple negative breast carcinoma to rhTRAIL-induced apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1863.