Efficacy of Topically Administered Dihydroartemisinin in Treating Papillomavirus-Induced Anogenital Dysplasia in Preclinical Mouse Models
Laura C. Gunder,
Simon Blaine-Sauer,
Hillary R. Johnson,
Myeong-Kyun Shin,
Andrew S. Auyeung,
Wei Zhang,
Glen E. Leverson,
Ella T. Ward-Shaw,
Renee E. King,
Stephanie M. McGregor,
Kristina A. Matkowskyj,
Paul F. Lambert,
Evie H. Carchman
Affiliations
Laura C. Gunder
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, 600 Highland Ave, Madison, WI 53792, USA
Simon Blaine-Sauer
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, USA
Hillary R. Johnson
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, 600 Highland Ave, Madison, WI 53792, USA
Myeong-Kyun Shin
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, USA
Andrew S. Auyeung
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, 600 Highland Ave, Madison, WI 53792, USA
Wei Zhang
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 3170 UW Medical Foundation Centennial Building (MFCB), 1685 Highland Avenue, Madison, WI 53705, USA
Glen E. Leverson
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, 600 Highland Ave, Madison, WI 53792, USA
Ella T. Ward-Shaw
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, USA
Renee E. King
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, USA
Stephanie M. McGregor
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 3170 UW Medical Foundation Centennial Building (MFCB), 1685 Highland Avenue, Madison, WI 53705, USA
Kristina A. Matkowskyj
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 3170 UW Medical Foundation Centennial Building (MFCB), 1685 Highland Avenue, Madison, WI 53705, USA
Paul F. Lambert
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Ave, Madison, WI 53705, USA
Evie H. Carchman
Department of Surgery, School of Medicine and Public Health, University of Wisconsin, 600 Highland Ave, Madison, WI 53792, USA
The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice.
