Abstract 2102: Investigational agent 5F 203 modulates apoptotic regulatory gene expression and induces lysosomal membrane permeabilization in breast cancer cells.

Abstract

Abstract Despite advances in targeted therapeutic agents for women with breast cancer that either express estrogen receptor (ER) alpha or over-expresses human epidermal growth factor receptor 2 (Her2), nearly 40,000 women die each year due to this malignancy. An investigational anticancer agent 2-(4-amino-3-methylphenyl)-5-benzothiazole (5F 203) potently inhibits the growth of breast cancer cells irrespective of either ER or Her2 status. In our current studies we used the Annexin V/PI assay to determine that 5F 203 induced a dose-dependent increase in the percentage of ER/Her2-positive T47D cells and ER/Her2-negative MDA-MB-468 breast cancer cells in early apoptosis. Cell death was not entirely caspase-dependent as pretreatment with pan-caspase inhibitor z-VAD-fmk only partially suppressed apoptosis. A pathway specific PCR-array revealed the ability for 5F 203 to increase the mRNA expression of pro-apoptotic genes bcl-2-antagonist/killer 1 (BAK1) and lymphotoxin alpha (LTA). Using the Acridine Orange assay, we found that 5F 203-mediated cell death was associated with lysosomal membrane permeabilization in both T47D and MDA-MB-468 cells. Additionally, we determined using the Cathepsin B assay that 5F 203 promoted the release of cathepsin B from the lysosomes in both breast cancer cell types. These data indicate 5F 203 upregulates BAK1 and LTA expression and promotes lysosomal cell death triggering the release of cathepsin B in breast cancer cells to confer its anticancer action. Citation Format: Eileen J. Brantley, Gabriell Thorne, Devin Daly, Dain Zylstra, Lancelot McLean. Investigational agent 5F 203 modulates apoptotic regulatory gene expression and induces lysosomal membrane permeabilization in breast cancer cells. [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 2102. doi:10.1158/1538-7445.AM2013-2102