Abstract 1701: A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells

Abstract

Abstract Chemotherapy is a mainstay in the treatment of breast cancer. FDA approved, Doxorubicin (Dox) is considered to be the most effective chemotherapeutic agent for the treatment of solid tumors like breast cancer. However, resistance to Dox impairs successful treatment. The increased expression of multidrug-resistance P-glycoprotein (P-gp) pump that constantly efflux drugs, such as Dox, is a well documented mechanism of resistance. Flavonoids as a class have been implicated in the inhibition of ABC transporters such as BCRP, P-gp and MRP-1, have potent anxiolytic activity, protect against anthracycline induced cardiotoxicity, and improve general health. Our current study proposes to examine the efficacy of a synthetic flavonoid, SF as a chemotherapeutic agent alone and in combination with Dox in a xenograft nude mouse model and to delineate the specific molecular targets involved. Treatment with a combination of Dox and SF lead to significant cell death in the Dox resistant, MCF-7/Dox cells as compared to treatment with Dox alone. In vivo studies using a xenograft nude mouse model corroborated these findings. Also, mice treated with SF alone and in combination with Dox showed improved overall health. SF also inhibited P-gp pump activity and increased Dox sequestration in cancer cells, leading to chemosensitization. Moreover, SF alone or in combination with Dox caused remarkable de-phosphorylation of constitutively active FAK(Focal Adhesion Kinase) in MCF-7/Dox cells. In conclusion, our study beings forth an excellent prototype candidate, SF- as an anti-tumor agent with little to no toxicity and provides new insights into previously uncharacterized mechanisms for the anti-cancer activity of SF alone and in combination with Dox in resistant breast cancer cells. The desirable traits of endowed pleiotropic activities, safety, synergistic action with therapeutic agents make SF attractive for clinical use. Citation Format: Amrita Datta, Barbara J. Rider, Zakaria Y. Abd Elmageed, Hogyoung Kim, Debasis Mondal, Asim B. Abdel Mageed. A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2014-1701