Abstract 4067: Pluronic micelle-encapsulated Disulfiram targets cancer stem-like cells and reverses pan-resistance in acquired resistant breast cancer cell lines

Abstract

Abstract Background: Chemoresistance is the major obstacle for the success of cancer treatment. The advanced breast cancer (BC) is commonly pan-resistant to different anticancer drugs. BC contains a small population of cancer stem cells (CSCs). CSCs express stem cell markers (CD24low/CD44high, ALDH+, CD133+) and are resistant to a wide range of anticancer drugs. Therefore, CSCs may be responsible for the pan-chemoresistance in advanced BC. We have recently developed several acquired chemoresistant BC cell lines. In this study, we investigated CSC traits in these cell lines and examined the cross-resistance of these cell lines to a panel of anticancer drugs. Disulfiram (DS), an antialcoholism drug, shows high cytotoxicity in several different types of cancer cell lines in vitro. It also targets CSCs and reverses pan-chemoresistance. However, the clinical application of DS in cancer treatment is limited by its very short half-life in the bloodstream. In order to increase the bio-stability of DS in the bloodstream, we recently developed a pluronic micelle-encapsulated DS (PM-DS). In this study, we examined the cytotoxicity of a newly developed (PM-DS) in the resistant cell lines. The effect of PM-DS on CSC traits in the resistant BC cell lines was also examined. Cell lines and Methods: Cell lines: MDA-MB-231, MCF7 and T47D and acquired resistant BC cell lines [gemcitabine (MDA-MB-231GEM100), 5-fluouracil (MCF7FU10) and doxorubicin (T47DDOX100nM)]; Methodologies: MTT assay, Western blot, CSC markers detection (ALDH, CD24low/CD44high, CD133), embryonic stem cell markers detection (Nanog, Sox2, Oct 4). Results: The resistant cell lines are highly cross-resistant to 6 conventional anticancer drugs e.g doxorubicin, gemcitabine, docetaxel, cisplatin, 5-fluouracil and vincristine. In comparison with the parental cells, the resistant cell lines have significantly longer doubling time. Significantly higher population of resistant cells expresses high levels of CSC markers e.g. ALDH+, CD24low/CD44high, and CD133+ and embryonic stem cell markers (OCT4, Sox2 and Nanog). DS was successfully encapsulated in pluronic micelles with a high entrapment efficiency of about 90% and our in vitro release studies showed that DS was slowly released from the micelles. Our formulation PM-DS has a relatively small size of about 200nm with high drug loading content (90μgDS/1mgPM). PM-DS was highly toxic to chemoresistant cell lines. It also targeted CSC population and enhanced cytotoxicity of anticancer drugs in the resistant cell lines. Conclusions: The acquired resistant BC cell lines are highly cross-resistant to 6 different kinds of anticancer drugs. CSCs may be responsible for the cross-chemoresistance. PM-DS targets CSC population and reverses the acquired pan-chemoresistance in acquired resistant BC cell lines. Key words: Disulfiram, micelles, breast cancer, stem-like cells. Citation Format: EREBI P. TAWARI, Peng Liu, Zhipeng Wang, Vinodh Kannappan, Christopher Mcconville, Angel Armesilla, John Darling, Juan Irache, Krassimira Yoncheva, Weiguang Wang, Petar Petrov. Pluronic micelle-encapsulated Disulfiram targets cancer stem-like cells and reverses pan-resistance in acquired resistant breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2015-4067