Unique synergistic formulation of curcumin, epicatechin gallate and resveratrol, tricurin, suppresses HPV E6, eliminates HPV+ cancer cells, and inhibits tumor progression

// Sumit Mukherjee 1, 3, 5, * , Priya Ranjan Debata 5, 8, * , Rahman Hussaini 5 , Kaushiki Chatterjee 2, 4 , Juliet N.E. Baidoo 1, 3 , Samay Sampat 5 , Anita Szerszen 6 , Joseph P. Navarra 7 , Jimmie Fata 2 , Elena Severinova 6, 9 , Probal Banerjee 1, 5 and Mario R. Castellanos 6 1 Department of Chemistry, The College of Staten Island (CUNY), New York, NY, USA 2 CUNY Doctoral Program in Biology, CUNY Graduate Center, New York, NY, USA 3 CUNY Doctoral Program In Biochemistry, CUNY Graduate Center, New York, NY, USA 4 Department of Biology, The College of Staten Island (CUNY), New York, NY, USA 5 Center of Developmental Neuroscience, The College of Staten Island (CUNY), New York, NY, USA 6 Division of Research, Department of Medicine, Staten Island University Hospital (Northwell Health), New York, NY, USA 7 College of Pharmacy and Health Sciences, St. John’s University, New York, NY, USA 8 Current Address: Department of Zoology North Orissa University Baripada, Mayurbhanj, Odisha, India 9 Current Address: Cell Biology and Molecular Medicine, Rutgers University, Newark, NJ, USA * These authors contributed equally to this work Correspondence to: Probal Banerjee, email: probal.banerjee@csi.cuny.edu , probalbanerjee@yahoo.com Keywords: curcumin, cervical cancer, human papillomavirus, synergism, combination index Received: May 31, 2016 Accepted: September 02, 2016 Published: March 29, 2017 ABSTRACT Curcumin (from curry) (C) is highly potent against cervical cancer cells (CCC), but poor bioavailability has limited its clinical use. Similar natural polyphenols resveratrol (from grapes) (R), and epicatechin gallate (from green tea) (E) also display activity against CCC. By treating CCC (HeLa) with C, E, or R, or combinations of these compounds, we computed combination indices and observed a strong synergism among C, E, and R at the unique molar ratio 4:1:12.5. This combination, named as TriCurin, rapidly down regulated HPV18 E6 and NF-kB expression while concomitantly inducing the tumor suppressor protein p53 in HeLa cells. In the mouse c-Ha-ras and HPV16 E6, E7-expressing TC-1 CCC, both C and TriCurin elicited suppression of E6, induction of both p53 and acetyl-p53 (activated p53), and activation of caspase-3, but the TriCurin-evoked changes were several-fold greater than that produced by curcumin (4.7-fold for E6 inhibition, and 2-fold, 6-fold, and 1.7-fold for the induction of p53, acetyl-p53, and active caspase-3, respectively). Consequently, TriCurin was more potent in killing TC-1 and HeLa cells. Intralesional TriCurin treatment of tumors generated in mice by subcutaneously implanting the TC-1 CCC caused an 80–90% decrease in tumor growth. The ability of C to eliminate HeLa cells was significantly stabilized when delivered as TriCurin than when delivered alone. Topical application of TriCurin dispersed in a cream base afforded efficient transfer of C across the skin. Subcutaneous TriCurin injection yielded no adverse effect in tumor-naive healthy mice. Thus, TriCurin is a safe and promising therapeutic agent against HPV-associated disease.