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 irondependent, 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. (Cancer Res 2005; 65(23): 10854-61)

Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer

“…DHA was also able to inhibit ovarian cancer cell (HO8910PM) growth and metastasis, following ovarian orthotopic transplantation, in vivo, probably via inhibiting proliferation, which is supported by our findings in vitro, and also consistent with other reports in papilloma virusexpressing epithelial (28), lung cancer (29), pancreas cancer (30) and hepatoma (23) in vivo. The dosage of DHA from our current experiment is 50 mg/kg, which is about the mid-range of dosages used in the literature.…”

Anticancer activity of botanical compounds in ancient fermented beverages (Review)

“…The anticancer properties of the herb's principal active compound, artemisinin, were subsequently discovered, and still remain to be fully elucidated (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). Efferth and colleagues (54) have proposed that artemisinin's anticancer mechanism of action is via the endoperoxide linkage of the compound.…”

Immunochemical Analysis of the Antimalarial Drugs Artemisinin and Artesunate

“…Recent studies have shed light on the mechanisms underlying the anticancer activities of AM, and synthetic approaches to preparing AM derivatives that display better efficacy and tolerability profiles have been conducted by several groups [13][14][15][16][17][18][19][20]. The expanded medicinal applications of AM-related compounds may increase the demand for AM in the future.…”