Resveratrol and Pterostilbene Exhibit Anticancer Properties Involving the Downregulation of HPV Oncoprotein E6 in Cervical Cancer Cells

Nutrients. 2018 Feb 21;10(2):243. doi: 10.3390/nu10020243.

Abstract

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.

Keywords: HPV E6; cell cycle; cervical cancer; p53; pterostilbene; resveratrol.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Cycle Checkpoints / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Female
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Polyphenols / pharmacology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Resveratrol
  • Stilbenes / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 16
  • E6 protein, Human papillomavirus type 18
  • Oncogene Proteins, Viral
  • Polyphenols
  • Repressor Proteins
  • Stilbenes
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • pterostilbene
  • CASP3 protein, human
  • Caspase 3
  • Resveratrol