Date of Degree

2-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Jimmie E. Fata

Committee Members

Greg Phillips

Abdeslem Elidrissi

Krishnaswami Raja

Edward Kennelly

Shawon Debnath

Subject Categories

Alternative and Complementary Medicine | Cancer Biology | Neoplasms | Other Chemicals and Drugs | Virus Diseases

Keywords

HPV E6 positive cervical cancer, resveratrol, pterostilbene, cell cycle arrest, apoptosis, in vivo

Abstract

Cervical cancer remains as one of the most prevalent cancers effecting women globally. Lack of awareness and affordable prophylactic and therapeutic options in developing countries drive the need for alternative low-cost approaches. Dietary polyphenols have gained increased attention as possible anti-cancer agents. Our study aims to investigate whether two natural structural analogs, resveratrol and pterostilbene, exhibit anti-HPV (Human papillomavirus) activity in cervical cancer. To determine the efficacy of these polyphenols, extensive in vitro and in vivo analyses were carried out. For the in vitro studies we utilized human HeLa cells (HPV18 positive) and murine TC1 cells (HPV 16 oncogene positive). Both these plant polyphenols show efficacy against these cell lines with low IC50 values in the µM range. In HeLa cells we looked at E6 protein expression, downstream p53 expression and activation of caspase 3 as a means to understand the mechanism of action. Both resveratrol and pterostilbene showed efficacy against HeLa by eliciting S-phase growth arrest, decreasing mitotic activity and impairing it’s clonogenicity. These findings were significant, with pterostilbene often being more effective than resveratrol. Results point to a possible mechanism in HPV18 which involves the downregulation of HPV E6 oncogene, stabilization of functional p53 and activation of the apoptotic pathway. Further in vitro analysis on TC1 cells confirmed the cytotoxic potential of both resveratrol and pterostilbene and their ability to downregulate E6 oncoprotein. Our in vivo studies on TC1 tumors established in mice elucidated that both compounds substantially decrease tumor load with E6 and VEGF protein downregulation. Intriguingly, the tumor reduction induced by pterostilbene is caused by apoptosis via activation of caspase 3, whereas, the efficacy of resveratrol is a due to growth arrest indicated by suppressed PCNA expression. Thus, our results show the antineoplastic potential of resveratrol and pterostilbene against both HPV18 and HPV16 cervical cancers. These findings show their robust anti-tumor potential and warrants the need for future clinical trials utilizing these food- derived compounds as nontoxic therapeutic agents.

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