First Name:
Chirayu
Last Name:
Patel
Major Department:
Biology
Thesis Director:
Maryam Ahmed
Date of Thesis:
May 2014
Vesicular stomatitis virus (VSV) is currently being studied as a candidate oncolytic agent due to its ability to induce apoptosis in a variety of cancer cells. Previous studies have shown that matrix (M) protein mutants of VSV, such as rM51R-M virus, act as selective anti-cancer agents by targeting cancer cells while sparing normal cells. Our goal is to promote the use of VSV for the treatment of cervical cancers. The cervical cancer cell line Siha has been shown in previous studies to be permissive to infection and killing by VSV. We hypothesized that cervical cancer lines are sensitized to VSV due to blockage of the type-1 interferon (IFN) response by human papillomavirus (HPV) oncoproteins. However, our results indicated that Siha cells retained their ability to respond to type I IFN. Furthermore, in contrast to previous studies, we observed that Siha cells were sensitive to killing by both wild-type (wt) and M protein mutant VSV (rM51R-M virus) only when infected at high multiplicities of infection. In addition, cells were more sensitive to killing by rM51R-M virus than wt VSV. We tested another cervical cancer cell line, C4-II, for its sensitivity to VSV infection and results indicated that C4-II cells were more resistant to VSV infection in comparison to Siha cells. Additionally we investigated the mechanisms of resistance in different cervical cancer cell lines and developing combination therapeutic strategies with natural compounds such as curcumin, resveratrol, flavokavain B, echinacea, and quercetin, to augment VSV induced oncolysis of cervical cancers. In conclusion, our results show that cervical cancer cells exhibit resistance to VSV infection, perhaps due to the maintenance of intact antiviral responses.