title: Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells with little or no adverse effects on normal cells. TRAIL is relatively safe for clinical applications. However, TRAIL resistance is widely found in cancer cells leading to limitations in utilizing TRAIL as a therapeutic agent for cancer treatment. Recently, artesunate, an effective and safe anti-malarial drug, was also described as a promising candidate for cancer therapy. It would be of importance to determine whether combination treatment of TRAIL together with artesunate could overcome drug-resistance of tumors. Here, we demonstrate the first evidence that artesunate effectively enhances TRAIL-mediated cytotoxicity by suppressing pro-survival proteins, such as survivin, XIAP and Bcl-XL. Upon treatment with artesunate, the levels of survival proteins were strongly suppressed in HeLa cells. The down-regulation of these survival proteins could be regulated by repressing activation of NF-κB and Akt. Artesunate also inhibited TRAIL-induced transcriptional activity of NF-κB. In addition, this substance significantly enhanced both extrinsic and intrinsic apoptosis, which were induced by TRAIL. Taken together, the results of the present study suggest that artesunate exhibits an ability to overcome TRAIL resistance and combination treatment of TRAIL together with artesunate may be an effective strategy for cancer therapy.
authors.affiliation: Faculty of Pharmaceutical Sciences, Ubonratchathani University, Ubonratchathani 34190, Thailand.
authors.forename: Oranuch
authors.initials: O
authors.lastname: Thanaketpaisarn
authors.forename: Pornthip
authors.initials: P
authors.lastname: Waiwut
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D000077332:Artesunate; D053148:Caspase 3; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand