Abstract A74: Modulation of oxidative stress and exosome activity by phytoagent deoxyelephantopin (DET) and its derivative treatment in suppressing triple negative breast cancer cell functions

Abstract

Abstract Breast cancer is one of the frequently diagnosed and life-threatening cancer diseases in women worldwide, especially, the triple negative breast cancer (ER-/PR-/HER2- TNBC) is a clinically challenging breast cancer disease due to lack of efficient targeted therapeutics. Recently, the development of phytocompounds derived from traditional medicinal herbs into potential chemotherapeutic or chemopreventive agent for human cancer management has aroused a great interest. In our previous study, we identified deoxyelephantopin (DET), a major germacranolide sesquiterpene lactone from a traditional medicinal herb Elephantopus scaber L., which could significantly suppress TS/A (ER+) mammary cancer cell growth, motility and metastasis in vitro andin vivo; however, a relatively less suppressive effect was observed in human TNBC cell line, MDA-MB-231. We thus designed and created a DET derivative (designated DETD) by semi-organic synthesis, which exhibited a 4-fold less in IC50 value than DET in inhibiting MDA-MB-231 cell proliferation. To address the modes of action of both authentic DET and novel DETD compounds against TNBC, we established and used mass spectrometry (MS)-based quantitative proteomics, direct binding assay of DET-near infrared (NIR) fluorescent compound conjugate, and mammary tumor model to gain the mechanistic insight. Our data showed that DET and DETD can markedly induce the reactive oxygen species (ROS) production in early stage of treatment, that may further promote nonautophagic cell death through cytoplasmic vacuoles production. Furthermore, we observed the release of exosome vesicles from MDA-MB-231 cells was elevated by DET or DETD treatment compared to the vehicle control. Quantitative investigation of exosomal proteome showed that DET and DETD responsive exosomal proteins were involved in the regulation of EIF2 signaling, mTOR signaling, regulation of eIF4 and p70S6K signaling, CDK5 signaling, and inhibition of angiogenesis. Of note, the immunofluorescence cell staining showed that DET-NIR was co-localized with exosomes of MDA-MB-231 cells, on the other hand, several nuclear exosomal proteins of mouse TNBC 4T1 cells could interact directly with DET. Together results of this study suggest that DET and DETD compounds may serve as a good candidate in treatment of TNBC disease, through modulation of oxidative stress and specific exosomal proteins in cancer cells. Citation Format: Jeng-Yuan Shiau, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Wai-Leng Lee, Jacquelyn Gervay-Hague, Lie-Fen Shyur. Modulation of oxidative stress and exosome activity by phytoagent deoxyelephantopin (DET) and its derivative treatment in suppressing triple negative breast cancer cell functions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A74.