title: Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo.
abstract: Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Because many neoplastic cells (including cervical cancer cells) overexpress the transferrin receptor to increase their iron uptake, we hypothesized that iron-dependent, antimalarial drugs such as artemisinin might prove useful in treating HPV-infected or transformed cells. We tested three different artemisinin compounds and found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic effects on HPV-immortalized and transformed cervical cells in vitro with little effect on normal cervical epithelial cells. DHA-induced cell death involved activation of the mitochondrial caspase pathway with resultant apoptosis. Apoptosis was p53 independent and was not the consequence of drug-induced reductions in viral oncogene expression. Due to its selective cytotoxicity, hydrophobicity, and known ability to penetrate epithelial surfaces, we postulated that DHA might be useful for the topical treatment of mucosal papillomavirus lesions. To test this hypothesis, we applied DHA to the oral mucosa of dogs that had been challenged with the canine oral papillomavirus. Although applied only intermittently, DHA strongly inhibited viral-induced tumor formation. Interestingly, the DHA-treated, tumor-negative dogs developed antibodies against the viral L1 capsid protein, suggesting that DHA had inhibited tumor growth but not early rounds of papillomavirus replication. These findings indicate that DHA and other artemisinin derivatives may be useful for the topical treatment of epithelial papillomavirus lesions, including those that have progressed to the neoplastic state.
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Disbrow
authors.forename: Astrid C
authors.initials: AC
authors.lastname: Baege
authors.forename: Katie A
authors.initials: KA
authors.lastname: Kierpiec
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.forename: Jose A
authors.initials: JA
authors.lastname: Centeno
authors.forename: Clare A
authors.initials: CA
authors.lastname: Thibodeaux
authors.forename: Dan
authors.initials: D
authors.lastname: Hartmann
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009061:Mouth Mucosa / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D030361:Papillomavirus Infections / Q000517:prevention & control / Q000821:virology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D037621:Artemisinins; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C039060:artenimol