Abstract 5571: Antitumor activity of a novel natural therapeutic agent against triple negative breast cancer.

Purpose: Triple-negative breast cancer (TNBC), representing up to 20% of all breast cancer cases, is a highly diverse group of cancer that is associated with an aggressive phenotype, with affected patients having a poorer prognosis. Its treatment has been challenging due to its heterogeneity and the absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. Nuclear factor kappa-B (NF-κB), a transcription factor, has been shown to be significantly increased in TNBC, consistent with the aggressiveness of these tumors. Thus, inactivation of the NF-κB pathway, could serve as therapeutic targets for treatment of TNBC. Panepoxydone (PP), a compound isolated from Lentinus crinitus (an edible mushroom), has been shown to interfere with NF-κB mediated signal transduction by inhibiting the phosphorylation of IκBα. Here we evaluate the antitumor activity of panepoxydone in several breast cancer cell lines. Experimental Design: Estrogen receptor positive (MCF-7) and three triple negative breast cancer cell line subtypes (MDAMB-231, MDAMB-468 and MDAMB-453) were treated with increasing concentrations of panepoxydone or DMSO (final concentration, 0.2%). Results: Significant antitumor activity was seen in all the breast cancer cell lines, with differential responses noted in a cell-line specific manner. Whereas treatment with PP resulted in significant cytotoxicity, along with decreased invasion and migration in all the cell lines tested, with IC50 of 4-15 μM, MDAMB-453 cells were the most sensitive, whereas MDAMB-231 were almost 4-fold less sensitive. PP treatment also induced apoptosis in a cell-line specific manner, with minimal effect noted in MCF7 and MDAMB-231 cells, but a 35.8% and 40.8% increase in apoptotic cells noted in MDAMB-453 and MDAMB-468 cells, respectively. Differential response to PP treatment was also noted in the decreased expression of the apoptosis-related proteins Bcl-2, survivin, and cyclin D1, with MDAMB-453 again having at least a 3-fold greater decrease in expression when compared to the other TNBC cell lines. The antitumor effect of PP, appeared in part, to be related to its ability to inhibit phosphorylated IκBα, with accumulation of IκBα noted in a dose-dependent manner in all the cell lines. This resulted in reduced translocation of NF-kB from cytoplasm to nucleus as analyzed via immunofluorescence. Conclusion: Altogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. Additional studies are required to further elucidate the antitumor effect of panepoxydone, but these studies provide support for the further evaluation of PP as a therapeutic agent in the treatment of TNBC. Citation Format: Ritu Arora, Bernard D. Gary, Steven McClellan, Yaguang Xi, Gary Piazza, Eddie Reed, Laurie Owen, Windy Dean-Colomb. Antitumor activity of a novel natural therapeutic agent against triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5571. doi:10.1158/1538-7445.AM2013-5571