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// 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.

The global health threat of antimicrobial resistance has created a pressing need to develop practical alternatives to conventional antibiotic agents. Peptide mimetic synthetic amphiphilic polymers are known to non-specifically disrupt the bacterial cell surface thus leading to highly hindered bacterial resistance development. We investigated the antibacterial activities of a terpolymer macromolecular architecture with a combination of 6-carbon and 2-carbon spacer arms (distance from polymer backbone to pendent cationic center) interspersed with counits with hydrophobic side groups. A random copolymer with a combination of 6-carbon spacer arm repeat units (60 mol%) and 2-carbon spacer arm (40 mol%) units is moderately active against bacteria and shows very low hemolytic activity. Incorporation of comonomer units with alkyl side groups, by replacing different levels of 2-carbon spacer arm counit, led to substantial increments in antibacterial activities without detrimental effects on hemolytic activities leading to highly selective (bacteria over red blood cells) antibacterial activity. Time-kill studies revealed rapid bactericidal activity of the terpolymer against both Staphylococcus aureus and Escherichia coli with 100% killing efficiency achieved within 1 h of polymer treatment, corresponding to a 5-log reduction of bacterial colony forming units. These results indicate the high potential of this amphiphilic terpolymer architecture in the development of alternatives to antibiotics.

Human papilloma virus (HPV)-induced cervical cancer is one of the most frequent cancers in women residing in underdeveloped countries. Natural compounds like polyphenols continue to be of scientific interest as non-toxic effective alternative treatments. Our previous work showed the efficacy of two polyphenols, resveratrol, and pterostilbene on human HeLa cells. Here we explored the in vitro anti-cancer activity and in vivo anti-tumor potential of these two structurally similar compounds on HPV oncogene E6 and E7 positive murine TC1 cells. In vitro analysis confirmed the cytotoxic potential of both resveratrol and pterostilbene compounds with each having a low IC50 value and each showing the ability to downregulate viral oncogene E6. Further in vivo studies on TC1 tumors developing in mice indicated that treatment with either resveratrol or pterostilbene can significantly inhibit tumor development, with both compounds capable of downregulating E6 and VEGF tumor protein levels. Interestingly, the decrease in tumor size in pterostilbene was associated with tumor cell apoptosis, as indicated by an upregulation of activated caspase-3 whereas in resveratrol-treated mice it was accompanied by arrest of cell cycle, as indicated by a downregulation of PCNA. Thus, resveratrol and pterostilbene can serve as potential antineoplastic agents against HPV E6+ tumors and may suppress tumor growth via two different mechanisms.

Cervical cancer is one of the most common cancers in women living in developing countries. Due to a lack of affordable effective therapy, research into alternative anticancer compounds with low toxicity such as dietary polyphenols has continued. Our aim is to determine whether two structurally similar plant polyphenols, resveratrol and pterostilbene, exhibit anticancer and anti-HPV (Human papillomavirus) activity against cervical cancer cells. To determine anticancer activity, extensive in vitro analyses were performed. Anti-HPV activity, through measuring E6 protein levels, subsequent downstream p53 effects, and caspase-3 activation, were studied to understand a possible mechanism of action. Both polyphenols are effective agents in targeting cervical cancer cells, having low IC50 values in the µM range. They decrease clonogenic survival, reduce cell migration, arrest cells at the S-phase, and reduce the number of mitotic cells. These findings were significant, with pterostilbene often being more effective than resveratrol. Resveratrol and to a greater extent pterostilbene downregulates the HPV oncoprotein E6, induces caspase-3 activation, and upregulates p53 protein levels. Results point to a mechanism that may involve the downregulation of the HPV E6 oncoprotein, activation of apoptotic pathways, and re-establishment of functional p53 protein, with pterostilbene showing greater efficacy than resveratrol.