title: The synergistic therapeutic effect of cisplatin with Human papillomavirus E6/E7 short interfering RNA on cervical cancer cell lines in vitro and in vivo.
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.
authors.affiliation: Laboratory of Molecular Pathology, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hun Soon
authors.initials: HS
authors.lastname: Jung
authors.forename: Ozgur Cem
authors.initials: OC
authors.lastname: Erkin
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kwon
authors.forename: Seok Hyung
authors.initials: SH
authors.lastname: Kim
authors.forename: Jae In
authors.initials: JI
authors.lastname: Jung
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Song Wook
authors.initials: SW
authors.lastname: Her
authors.forename: Woong
authors.initials: W
authors.lastname: Ju
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Song
authors.forename: Joong Kyu
authors.initials: JK
authors.lastname: Kim
authors.forename: Young Deug
authors.initials: YD
authors.lastname: Kim
authors.forename: Ga Yong
authors.initials: GY
authors.lastname: Shim
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Shin
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin