title: Dihydroartemisinin induces apoptosis of cervical cancer cells via upregulation of RKIP and downregulation of bcl-2.
abstract: 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.
authors: Department of Obstetrics and Gynecology; The Fourth Affiliated Hospital; Harbin Medical University; Harbin City, Heilongjiang Province PR China.
authors: Chun-Jie
authors: CJ
authors: Hu
authors: Department of Orthopedics; The First Affiliated Hospital; Harbin Medical University; Harbin City; Heilongjiang Province PR China.
authors: Lei
authors: L
authors: Zhou
authors: Department of Obstetrics and Gynecology; The Fourth Affiliated Hospital; Harbin Medical University; Harbin City, Heilongjiang Province PR China.
authors: Yan
authors: Y
authors: Cai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D049488:Phosphatidylethanolamine Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C039060:artenimol
keywords: Raf kinase inhibitor protein; apoptosis; bcl-2; cervival cancer; dihydroartemisinin; metastasis; tumor