Coadministration of Paclitaxel and Curcumin in Nanoemulsion Formulations To Overcome Multidrug Resistance in Tumor Cells Srinivas Ganta and Mansoor Amiji* Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern UniVersity, 110 Mugar Life Sciences Building, Boston, Massachusetts 02115 Received November 23, 2008; Revised Manuscript Received January 24, 2009; Accepted March 11, 2009 Abstract: Development of multidrug resistance (MDR) against a variety of conventional and novel chemotherapeutic agents is a significant challenge in effective cancer therapy. Over the last several years, we have focused on a multimodal therapeutic strategy to overcome tumor MDR by enhancing the delivery efficiency to the tumor mass and lowering the apoptotic threshold by modulation of the intracellular signaling mechanisms. In this study, we have examined augmentation of therapeutic efficacy upon coadministration of paclitaxel (PTX) and curcumin (CUR), an inhibitor of nuclear factor kappa B (NFκB) as well as a potent down-regulator of ABC transporters, in wild-type SKOV3 and drug resistant SKOV3 TR human ovarian adenocarcinoma cells. PTX and CUR were encapsulated in flaxseed oil containing nanoemulsion formulations. The results showed that the encapsulated drugs were effectively delivered intracellular in both SKOV3 and SKOV3 TR cells. CUR administration was shown to inhibit NFκB activity and down regulate P-glycoprotein expression in resistant cells. Combination PTX and CUR therapy, especially when administered in the nanoemulsion formulations, was very effective in enhancing the cytotoxicity in wild-type and resistant cells by promoting the apoptotic response. Overall, this cotherapy strategy has significant promise in the clinical management of refractory diseases, especially in ovarian cancer. Keywords: Multidrug resistance; paclitaxel; curcumin; nanoemulsions; combination therapy; SKOV3 ovarian adenocarcinoma cells 1. Introduction Development of multidrug resistance (MDR) is one of the most challenging aspects of cancer chemotherapy, as resis- tance develops with both conventional cytotoxic agents and the recently developed targeted biological therapies. 1 In ovarian cancer, for instance, more than 70% of initially diagnosed patients are resistant to taxane therapy, and eventually all of them will be resistant upon relapse. Although clinical resistance is often manifested as refractory disease to standard chemotherapeutic regimens, there are several pathways by which tumor cells develop resistance due to microenvironment selection pressures. The most frequently occurring causes of MDR include the overex- pression of ATP-binding cassette (ABC) super family of transporters, which are trans-membrane proteins that acts as a drug-efflux pump by actively removing drugs from the cells and producing intracellular drug levels below the effective concentrations necessary for cytotoxicity. 2 P-glycoprotein (P- gp), breast cancer resistance protein (ABCG2), and multidrug resistance associated protein (MRP-1) are the major trans- porter proteins belonging to the ABC super family that have been linked with MDR. 1 P-gp is encoded by the MDR-1 gene * Corresponding author. Mailing address: Northeastern University, Pharmaceutical Sciences Department, 110 Mugar Life Sciences Building, 360 Huntington Ave., Boston, MA 02115. Tel: 617- 373-3137. Fax: 617-373-8886. E-mail: m.amiji@neu.edu. (1) Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. ReV. Drug DiscoVery 2006, 5 (3), 219–234. (2) Ejendal, K. F. K.; Hrycyna, C. A. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr. Protein Pept. Sci. 2002, 3, 503–511. articles 928 MOLECULAR PHARMACEUTICS VOL. 6, NO. 3, 928–939 10.1021/mp800240j CCC: $40.75  2009 American Chemical Society Published on Web 03/11/2009