title: Simvastatin in combination with bergamottin potentiates TNF-induced apoptosis through modulation of NF-κB signalling pathway in human chronic myelogenous leukaemia.
abstract: Context Simvastatin (SV) and bergamottin (BGM) are known to exhibit diverse anti-cancer and anti-inflammatory activities. Objective Very little is known about the potential efficacy of combination of these two agents to potentiate TNF-induced apoptosis in human chronic myelogenous leukaemia (CML). Materials and methods In the present study, we investigated whether SV combined with BGM mediates its effect through suppression of NF-κB-signalling pathway. Results We found that the combination treatment enhanced cytotoxicity and potentiated the apoptosis induced by TNF as indicated by intracellular esterase activity, Annexin V staining and caspase activation. This effect of co-treatment correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1), cell survival (cIAP-1, Bcl-2, Bcl-xL and Survivin), invasion (MMP-9) and angiogenesis (VEGF); all known to be regulated by NF-κB. SV combined with BGM also produced TNF-induced cell-cycle arrest in S-phase and this arrest correlated with a concomitant increase in the levels of cyclin-dependent inhibitor p21 and p27. The combination therapy inhibited TNF-induced NF-κB activation, IκBα degradation and p65 translocation to the nucleus as compared with the treatment with individual agents alone. Besides, SV combined with BGM did not significantly potentiate apoptotic effect induced by TNF in p65(-)(/)(-) cells, as compared with wild-type fibroblasts. Discussion and conclusion Our results provide novel insight into the role of SV and BGM in potentially preventing and treating cancer through modulation of NF-κB signalling pathway and its regulated gene products.
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Yang
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.affiliation: a Department of Oriental Pathology , College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D011564:Furocoumarins / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D011564:Furocoumarins; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D019821:Simvastatin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C068337:bergamottin
keywords: Apoptosis; CML; TNF; bergamottin; simvastatin