Sapna Sharma1, Ruma Baksi2, Milee Agarwal3. 1. Department of Pharmacology and Toxicology, NIPER-Ahmedabad, C/o B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Thaltej-Gandhinagar Highway, Ahmedabad 380054, Gujarat, India. 2. Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Thaltej-Gandhinagar Highway, Ahmedabad 380054, Gujarat, India. 3. Department of Pharmacology and Toxicology, NIPER-Ahmedabad, C/o B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Thaltej-Gandhinagar Highway, Ahmedabad 380054, Gujarat, India; Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Thaltej-Gandhinagar Highway, Ahmedabad 380054, Gujarat, India. Electronic address: milee.agarwal@yahoo.com.
Abstract
BACKGROUND: Increase in expression of eIF4E (Eukaryotic translation initiation factor 4E) protein is mediated by oncogenic proteins of Human Papilloma Virus (HPV). Increased expression of eIF4E plays an important role in HPV induced carcinogenesis. Ribavirin and Indinavir are known inhibitors of eIF4E activity. METHODS: The effect of the drugs on HeLa cells was assessed by in vitro assays including cell viability using MTT and Neutral red assay, apoptotic potential using Caspase-3, Caspase-8 and Caspase-9 activity assays and MMP-2 and MMP-9 secretion by determination of Gelatinase activity. The in vivo effect of Ribavirin treatment on tumor volume was assessed in human xenograft in immunocompromised C57BL/6 mice. RESULTS: In vitro analyses indicate that Ribavirin and Indinavir reduce viability of HeLa cells, induce apoptosis and decrease secretion of MMPs. Treatment with Ribavirin at a dose of 50mg/kg and 100mg/kg daily led to significant decrease in tumor volume in vivo. CONCLUSION: The study thus provides evidence that Ribavirin and Indinavir can be explored as therapy against HPV-18 induced cervical cancer.
BACKGROUND: Increase in expression of eIF4E (Eukaryotic translation initiation factor 4E) protein is mediated by oncogenic proteins of Human Papilloma Virus (HPV). Increased expression of eIF4E plays an important role in HPV induced carcinogenesis. Ribavirin and Indinavir are known inhibitors of eIF4E activity. METHODS: The effect of the drugs on HeLa cells was assessed by in vitro assays including cell viability using MTT and Neutral red assay, apoptotic potential using Caspase-3, Caspase-8 and Caspase-9 activity assays and MMP-2 and MMP-9 secretion by determination of Gelatinase activity. The in vivo effect of Ribavirin treatment on tumor volume was assessed in human xenograft in immunocompromised C57BL/6 mice. RESULTS: In vitro analyses indicate that Ribavirin and Indinavir reduce viability of HeLa cells, induce apoptosis and decrease secretion of MMPs. Treatment with Ribavirin at a dose of 50mg/kg and 100mg/kg daily led to significant decrease in tumor volume in vivo. CONCLUSION: The study thus provides evidence that Ribavirin and Indinavir can be explored as therapy against HPV-18 induced cervical cancer.
Authors: Betty Tyler; Nicolas Skuli; Joshua Casaos; Sakibul Huq; Tarik Lott; Raphael Felder; John Choi; Noah Gorelick; Michael Peters; Yuanxuan Xia; Russell Maxwell; Tianna Zhao; Chenchen Ji; Thomas Simon; Julie Sesen; Sarah J Scotland; Richard E Kast; Jeffrey Rubens; Eric Raabe; Charles G Eberhart; Eric M Jackson; Henry Brem Journal: Oncotarget Date: 2018-01-03