title: NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis.
abstract: Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.
authors.affiliation: Affiliated Hospital of Nanjing University of TCM, Nanjing, China.
authors.forename: Haiwen
authors.initials: H
authors.lastname: Ni
authors.affiliation: Sino-EU Biomedical Innovation Center (SEBIC), OG Pharma Corporation, Nanjing, China.
authors.forename: Wanzhou
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Affiliated Hospital of Nanjing University of TCM, Nanjing, China.
authors.forename: Xiangtu
authors.initials: X
authors.lastname: Kong
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing,China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ouyang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000188:drug therapy*; D000072000:NF-KappaB Inhibitor alpha; D053978:Pentacyclic Triterpenes; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D053978:Pentacyclic Triterpenes; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014315:Triterpenes; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; C505407:CASP3 protein, human; D053148:Caspase 3; C050414:celastrol
references.citation: Oncogene. 2001 Nov 1;20(50):7342-51
references.pmid: 11704864
references.citation: Blood. 2008 Mar 15;111(6):2962-72
references.pmid: 18332230
references.citation: Nat Rev Cancer. 2005 Apr;5(4):297-309
references.pmid: 15803156
references.citation: Clin Adv Hematol Oncol. 2004 Mar;2(3):162-6
references.pmid: 16166946
references.citation: J Mol Med (Berl). 2010 Dec;88(12):1243-53
references.pmid: 20798912
references.citation: Mol Pharmacol. 2011 Jul;80(1):23-31
references.pmid: 21450930
references.citation: Mol Cancer Res. 2009 Dec;7(12):1946-53
references.pmid: 19934274
references.citation: Leukemia. 1997 Mar;11(3):342-5
references.pmid: 9067571
references.citation: BMC Cancer. 2009 Sep 25;9:343
references.pmid: 19778460
references.citation: Cancer Metastasis Rev. 2010 Sep;29(3):405-34
references.pmid: 20737283
references.citation: Expert Rev Anticancer Ther. 2008 Jul;8(7):1053-72
references.pmid: 18588451
references.citation: Br J Pharmacol. 2010 Oct;161(3):541-54
references.pmid: 20880395
references.citation: Eur J Cancer. 2006 Jul;42(11):1612-22
references.pmid: 16750621
references.citation: Biochim Biophys Acta. 2010 Apr;1805(2):167-80
references.pmid: 20079806
references.citation: Clin Cancer Res. 2009 Jan 15;15(2):425-30
references.pmid: 19147746
references.citation: Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
references.pmid: 20066113
references.citation: Cancer Lett. 2011 Apr 1;303(1):9-20
references.pmid: 21168266
references.citation: J Biol Chem. 2012 Sep 28;287(40):33781-95
references.pmid: 22872644
references.citation: Int J Cancer. 2009 Aug 15;125(4):952-60
references.pmid: 19462449
references.citation: Cancer Res. 2006 May 1;66(9):4758-65
references.pmid: 16651429
references.citation: J Neuroinflammation. 2010 Mar 08;7:17
references.pmid: 20211007
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2001 Oct;25(7):1341-57
references.pmid: 11513350
references.citation: Am J Transl Res. 2009;1(1):1-15
references.pmid: 19966933
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20684-9
references.pmid: 22143786
references.citation: Lancet. 2009 Jul 25;374(9686):324-39
references.pmid: 19541364
references.citation: Am J Hypertens. 2010 Aug;23(8):821
references.pmid: 20644533
references.citation: J Biol Chem. 2012 Aug 3;287(32):26702-14
references.pmid: 22711534
references.citation: Trends Pharmacol Sci. 2009 Jun;30(6):313-21
references.pmid: 19446347
references.citation: Hepatology. 2005 Sep;42(3):588-97
references.pmid: 16037944
references.citation: Clin Exp Pharmacol Physiol. 2012 Mar;39(3):311-20
references.pmid: 21834865
references.citation: Leukemia. 2009 Nov;23(11):1964-79
references.pmid: 19741722
references.citation: Br J Haematol. 2001 Nov;115(2):279-86
references.pmid: 11703322
references.citation: Carcinogenesis. 2002 Dec;23(12):2087-93
references.pmid: 12507932
references.citation: PLoS One. 2010 Dec 10;5(12):e14153
references.pmid: 21170316
references.citation: Cell Cycle. 2012 Jun 15;11(12):2248-52
references.pmid: 22617388
references.citation: Cancer Detect Prev. 2003;27(1):67-75
references.pmid: 12600419
references.citation: Br J Haematol. 2006 Mar;132(5):584-93
references.pmid: 16445831
references.citation: Cancer Lett. 2008 Jun 8;264(1):101-6
references.pmid: 18343027
references.citation: Blood. 2008 Apr 1;111(7):3793-801
references.pmid: 18202225
references.citation: Biosci Biotechnol Biochem. 2003 Sep;67(9):1883-7
references.pmid: 14519971
references.citation: J Cell Sci. 2002 Jan 1;115(Pt 1):141-51
references.pmid: 11801732
references.citation: Biochem Biophys Res Commun. 2012 Jul 6;423(3):467-72
references.pmid: 22683631
references.citation: Biochem Biophys Res Commun. 2010 Apr 9;394(3):439-42
references.pmid: 20226165
references.citation: Food Chem Toxicol. 2011 Feb;49(2):527-32
references.pmid: 21134410
references.citation: J Biol Chem. 1999 Sep 10;274(37):26071-8
references.pmid: 10473555
references.citation: Nat Rev Cancer. 2004 May;4(5):349-60
references.pmid: 15122206
references.citation: Blood. 2003 Feb 1;101(3):1053-62
references.pmid: 12393461
references.citation: Blood. 2000 Nov 1;96(9):2943-50
references.pmid: 11049970