The synergistic therapeutic effect of cisplatin with Human papillomavirus E6/E7 short interfering RNA on cervical cancer cell lines in vitro and in vivo

Hun Soon Jung; Ozgur Cem Erkin; Mi Jeong Kwon; Seok Hyung Kim; Jae In Jung; Yu-Kyoung Oh; Song Wook Her; Woong Ju; Yoon-La Choi; Sang Yong Song; Joong Kyu Kim; Young Deug Kim; Ga Yong Shim; Young Kee Shin

doi:10.1002/ijc.26197

The synergistic therapeutic effect of cisplatin with Human papillomavirus E6/E7 short interfering RNA on cervical cancer cell lines in vitro and in vivo

Int J Cancer. 2012 Apr 15;130(8):1925-36. doi: 10.1002/ijc.26197. Epub 2011 Aug 8.

Authors

Hun Soon Jung¹, Ozgur Cem Erkin, Mi Jeong Kwon, Seok Hyung Kim, Jae In Jung, Yu-Kyoung Oh, Song Wook Her, Woong Ju, Yoon-La Choi, Sang Yong Song, Joong Kyu Kim, Young Deug Kim, Ga Yong Shim, Young Kee Shin

Affiliation

¹ Laboratory of Molecular Pathology, College of Pharmacy, Seoul National University, Seoul, South Korea.

PMID: 21630254
DOI: 10.1002/ijc.26197

Abstract

Human papillomavirus (HPV) types 16 and 18 are the major etiologic factors in the development of cervical epithelial neoplasia. Our study was designed to validate antiviral short interfering RNA (siRNA) targeting the E6 and E7 oncogenes as a potential chemosensitizer of cisplatin (cis-diaminedichloroplatinum II; CDDP) in cervical carcinoma. Specifically, the therapeutic efficacy of combination of CDDP and E6/E7-specific siRNA was assessed in an in vivo cervical cancer xenograft models. The combination of CDDP and E6/E7-specific siRNA had greater efficacy than the combination of CDDP and E6-specific siRNA especially in terms of inducing cellular senescence. Through in vitro and in vivo experiments, the mechanism of synergy between these two treatments was revealed, demonstrating that the combination of E6/E7-specific siRNA and CDDP therapy was significantly superior to either modality alone. In vitro, long-term exposure of HeLa cells to the combination of CDDP and E6/E7-specific siRNA induced apoptosis and cellular senescence. In vivo, E6/E7-specific siRNA potentiated the antitumor efficacy of CDDP via induction of apoptosis, senescence and antiangiogenesis. Our results suggest that E6/E7-specific siRNA may be an effective sensitizer of CDDP chemotherapy in cervical cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alphapapillomavirus / genetics
Alphapapillomavirus / physiology
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Cell Line, Tumor
Cisplatin / pharmacology
Cisplatin / therapeutic use*
Combined Modality Therapy
Cyclin-Dependent Kinase Inhibitor p21 / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Female
Gene Expression Regulation, Neoplastic
HeLa Cells
Host-Pathogen Interactions / genetics
Humans
Mice
Mice, Nude
Oncogene Proteins, Viral / genetics
Oncogene Proteins, Viral / metabolism
Papillomavirus E7 Proteins / genetics
Papillomavirus E7 Proteins / metabolism
RNA Interference*
RNA, Small Interfering / genetics*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Burden / drug effects
Tumor Burden / genetics
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / therapy*
Uterine Cervical Neoplasms / virology
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Cyclin-Dependent Kinase Inhibitor p21
DNA-Binding Proteins
E6 protein, Human papillomavirus type 16
E6 protein, Human papillomavirus type 18
E7 protein, Human papillomavirus type 18
Oncogene Proteins, Viral
Papillomavirus E7 Proteins
RNA, Small Interfering
Repressor Proteins
oncogene protein E7, Human papillomavirus type 16
Cisplatin