Treatment of recurrent and metastatic
cervical cancer remains a challenge, especially in developing countries, which lack efficient screening programs. In recent years,
artemisinin and its derivatives, such as
dihydroartemisinin (DHA), which were traditionally used as
anti-malarial agent, have been shown to inhibit
tumor growth with low toxicity to normal cells. In this study, we investigated mechanisms underlying the anti-
tumor effect of DHA in
cervical cancer. We evaluated the role of DHA on the expression of bcl-2 and
Raf kinase inhibitor protein (RKIP), which is a suppressor of
metastasis. The MTT assay was used to compare the proliferation of untreated and DHA-treated Hela and Caski
cervical cancer cells. Flow cytometry was used to determine the percentage of cells at each stage of the cell cycle in untreated and DHA-treated cells. We used RT-PCR and western blots to determine the expression of bcl-2 and RKIP
mRNA and
proteins. We evaluated the effect of DHA treatment in nude mice bearing Hela or Caski
tumors. DHA-treated cells showed a time- and dose-dependent inhibition of proliferation and a significant increase in apoptosis. The expression of RKIP was significantly upregulated and the expression of bcl-2 was significantly downregulated in DHA-treated cells compared with control cells. DHA treatment caused (1) a significant inhibition of
tumor growth and (2) a significant increase in the apoptotic index in nude mice bearing Hela or Caski
tumors. Our data suggest that DHA inhibits
cervical cancer growth via upregulation of RKIP and downregulation of bcl-2.