title: Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo.
abstract: The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV-derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated β-galactosidase (SA-β-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas.
authors.affiliation: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. hunsoonjung@abionbio.com.|ABION Inc. R&D Center, 9th Floor, HanWha Biz Metro Bldg, 242 Digital-ro, Guro-gu, Seoul 152-733, Korea. hunsoonjung@abionbio.com.
authors.forename: Hun Soon
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. nirmalpharma@gmail.com.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Rajasekaran
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. yodasong@hanmail.net.
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Song
authors.affiliation: ABION Inc. R&D Center, 9th Floor, HanWha Biz Metro Bldg, 242 Digital-ro, Guro-gu, Seoul 152-733, Korea. todnos@abionbio.com.
authors.forename: Young Deug
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. sungyoul@snu.ac.kr.
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Radiology, Kangwon National University Hospital, Kangwon-do 200-722, Korea. choihjmd@gmail.com.
authors.forename: Hyuck Jae
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, Korea. ysk@amc.seoul.kr.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: The Center for Anti-cancer CDx, N-Bio, Seoul National University, Seoul 151-742, Korea. jscmd@naver.com.
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. yla.choi@samsung.com.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.affiliation: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. ykeeshin@snu.ac.kr.|The Center for Anti-cancer CDx, N-Bio, Seoul National University, Seoul 151-742, Korea. ykeeshin@snu.ac.kr.|Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 151-742, Korea. ykeeshin@snu.ac.kr.
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Shin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors*; D050725:Papillomavirus E7 Proteins / Q000037:antagonists & inhibitors; D030361:Papillomavirus Infections / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents
keywords: Concurrent Chemoradiation therapy (CCRT); E6; E7; cervical cancer; radiosensitizer; radiotherapy; siRNA