Abstract 2201: Downregulation of NF-kB by nanoconjugates to overcome drug resistance in ovarian tumors

Abstract

Ovarian cancer is the fifth leading cause of cancer deaths in women. Globally, around 140k women die from ovarian cancer per year. Recurrence can lead to development of resistance to first line agents such as platinum analogs, taxanes, and doxorubicin. Several studies have shown that decrease of NF-κB expression will inhibit P-glycoprotein maturation and thereby overcome drug resistance. In this context, it is well known that Disulfiram (DSF), a FDA approved drug for anti-alcoholism, have been identified as moderate inhibitor of NF-κB activity. It is also shown that DSF possess mild anti-cancer effects via increased permeability of the outer membrane of mitochondria resulting in leakage of proteins, such as cytochrome C, generation of ROS that simulates the ROS-MAPK pathway leading to apoptosis, and inhibition of P-glycoprotein. As such DSF is not a strong therapeutic agent; however, in combination with copper it showed excellent therapeutic benefit. This effect is mainly attributed to metabolite diethyldithio-carbamate -a proteasome inhibitor that was produced upon complexation of DSF with copper. However, delivery of DSF-Cu complex was not successful in clinical setting. We hypothesized gold nanoparticles can serve as potential delivery vehicle to selectively transfer Cu-DSF to turmor without toxicity. Indeed, cellular studies in drug sensitive (OVCAR) and Adriamycin resistant p-glycoprotein expressing (NCI-ADR/RES) ovarian cancer cells indicated that the gold nanoconjugate exhibit significant cytotoxicity and the IC-50 values was decreased 2.5 fold times compared to the Cu-DSF complex. NF-κB expression was decreased by two folds compared to native Cu-DSF complex. Detailed cellular and mechanistic studies along with the evaluation of [Au(DSF-Cu)NP] in human multi-drug resistant (NCI-ADR/RES) mouse xenografts will be presented. Citation Format: Ajit P. Zambre, Sarjukumar Panchal, Alyssa Worland, Sarah Chapman, Matthew Leevy, Anandhi Upendran, Raghuraman Kannan. Downregulation of NF-kB by nanoconjugates to overcome drug resistance in ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2201. doi:10.1158/1538-7445.AM2017-2201