title: Oncolytic adenovirus armed with human papillomavirus E2 gene in combination with radiation demonstrates synergistic enhancements of antitumor efficacy.
abstract: High-risk human papillomavirus (hr-HPV) E6 and E7 oncogenes are associated with resistance to radiotherapy in cervical cancer. Efforts have been taken to employ HPV E2, a crucial negative transcriptional modulator of HPV E6 and E7 oncogenes, and also an apoptosis-inducing agent, for therapeutic intervention. Despite being conceptually attractive, the potency and feasibility of current hr-HPV E2-based therapies remain limited. Here, we designed a novel recombinant adenovirus, named M5, with a 27-bp deletion in E1A conserved region-2 by which to realize tumor-specific replication, and a total HPV type 16 (HPV16) E2 gene complementary DNA inserted into the E3 coding region. In this design, M5 exploited the adenovirus E3 promoters to express HPV16 E2 gene in a viral replication-dependent manner and preferentially silenced the hr-HPV E6 and E7 oncogenes in HPV-positive cervical cancer cells. In vitro and in vivo assays confirmed that M5 exhibited potent antitumoral efficacy. Moreover, the effects of combined treatment with M5 and radiation treatment resulted in synergistically enhanced potency (P<0.01). The increase in killing efficacy of M5 was also found in HPV-negative cervical cancer cells, for which the pro-apoptotic activity of HPV16 E2 was thus responsible. Our results indicated that the use of M5 that locally delivers HPV16 E2 to cancers has broad therapeutic windows and that the combination therapy with radiation for cervical cancer will be the more effective way of improving survival.
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Xia
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Sima
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Z
authors.initials: Z
authors.lastname: Han
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.forename: A
authors.initials: A
authors.lastname: Luo
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Meng
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Shen
authors.forename: D
authors.initials: D
authors.lastname: Ma
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral