Dietary Polyphenols, Resveratrol and Pterostilbene Exhibit Antitumor Activity on an HPV E6-Positive Cervical Cancer Model: An in vitro and in vivo Analysis.

Kaushiki Chatterjee,Sumit Mukherjee,Jonathan Vanmanen,Jimmie E Fata,Probal Banerjee

doi:10.3389/fonc.2019.00352

Abstract

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.

Highlights

Human papilloma virus (HPV) is responsible for almost all cervical cancer incidences [1]
A short treatment cycle of 5 days was sufficient to see a significant antitumor potential of resveratrol and pterostilbene. We propose that this antitumor efficacy is dependent on two different mechanisms where resveratrol playing a vital role in arresting tumor growth evident by a significant reduction of proliferating cell nuclear antigen (PCNA) and pterostilbene largely causing cell death in tumors by activating apoptotic caspase-3
Based on the findings of our previous studies on HeLa cells showing the cytotoxic potential of resveratrol and pterostilbene [4], we wanted to determine their anticancer efficacy on HPVE6-positive mouse TC1 cells

Summary

Introduction

Human papilloma virus (HPV) is responsible for almost all cervical cancer incidences [1]. High risk HPV types are responsible for other types of invasive malignancies including head and neck cancers, oropharyngeal cancers, and other anogenital cancers. With current screening and vaccination programs, the rate of cervical cancer has decreased. Every year more than 500,000 new cases of cervical cancer are reported, with the majority originating from developing countries. All of the current treatment regimens for metastatic cervical cancer (radiation, surgery, and chemotherapy) [6] are associated with deleterious side effects [7,8,9]. Advancements in cancer prevention and treatment have failed in significantly decreasing cervical cancer mortality in developing countries, often because of the high costs associated with each. Due to a growing need for effective low-cost cervical cancer therapy with no detrimental side effects, naturally occurring dietary polyphenols, that have known anti-cancer properties, have continued to be of great interest

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