title: The effect of 17-allylamino-17-demethoxygeldanamycin alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.
abstract: The effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an hsp90 inhibitor, alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma (ATC) was evaluated. In 8505C and CAL62 cells, after treatment of 17-AAG, cell viability decreased, and the percentage of dead cells increased. 17-AAG did not cause cleavage of caspase-3 protein, and change expression of IAPs. Pretreatment of z-VAD-fmk did not alter cell viability and the percentage of dead cells. In 17-AAG-treated cells, knockdown of p53 rescued growth inhibition, while cycloheximide attenuated cell death. When cells were treated with both 17-AAG and paclitaxel, all of the combination index values were higher than 1, indicating antagonism between 17-AAG and paclitaxel. In 17-AAG- and paclitaxel-treated cells, compared with paclitaxel alone-treated cells, the protein levels of hsp90, hsp70, and hsc70 increased. In conclusion, our results suggest that 17-AAG induces non-apoptotic cell death requiring de novo protein synthesis in ATC cells. Moreover, these results demonstrate that 17-AAG antagonizes paclitaxel with concomitant alterations in hsp90 client proteins in ATC cells.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Si Hyoung
authors.initials: SH
authors.lastname: Kim
authors.forename: Jun Goo
authors.initials: JG
authors.lastname: Kang
authors.forename: Chul Sik
authors.initials: CS
authors.lastname: Kim
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Ihm
authors.forename: Moon Gi
authors.initials: MG
authors.lastname: Choi
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004359:Drug Therapy, Combination; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D053148:Caspase 3; D017239:Paclitaxel
references.citation: J Clin Endocrinol Metab. 2006 Jun;91(6):2389-95
references.pmid: 16537683
references.citation: Cell. 1997 Jul 11;90(1):65-75
references.pmid: 9230303
references.citation: Mol Cancer Ther. 2006 May;5(5):1197-208
references.pmid: 16731752
references.citation: Invest New Drugs. 2012 Dec;30(6):2201-9
references.pmid: 22227828
references.citation: Cancer Lett. 2005 Jun 16;224(1):123-32
references.pmid: 15911108
references.citation: Cancer Chemother Pharmacol. 1998;42(4):273-9
references.pmid: 9744771
references.citation: J Clin Endocrinol Metab. 2008 Nov;93(11):4331-41
references.pmid: 18713817
references.citation: Leukemia. 2002 Apr;16(4):455-62
references.pmid: 11960322
references.citation: Thyroid. 2011 Jul;21(7):735-44
references.pmid: 21568723
references.citation: Exp Hematol. 2006 Dec;34(12):1670-9
references.pmid: 17157164
references.citation: Thyroid. 2011 Nov;21(11):1183-9
references.pmid: 21936674
references.citation: Curr Cancer Drug Targets. 2003 Oct;3(5):349-58
references.pmid: 14529386
references.citation: Cancer Res. 2001 May 15;61(10):4003-9
references.pmid: 11358818
references.citation: Endocr Relat Cancer. 2007 Sep;14(3):839-45
references.pmid: 17914112
references.citation: Pediatr Res. 2005 Mar;57(3):430-7
references.pmid: 15659698
references.citation: Thyroid. 2000 Jul;10(7):587-94
references.pmid: 10958311
references.citation: J Clin Endocrinol Metab. 2003 Jul;88(7):3346-53
references.pmid: 12843186
references.citation: Mol Cancer Res. 2009 Oct;7(10):1645-54
references.pmid: 19825993
references.citation: Trends Mol Med. 2002;8(4 Suppl):S55-61
references.pmid: 11927289
references.citation: Cell Death Differ. 2004 Oct;11(10):1066-75
references.pmid: 15195070
references.citation: Expert Opin Biol Ther. 2002 Jan;2(1):3-24
references.pmid: 11772336
references.citation: J Clin Endocrinol Metab. 2004 Jun;89(6):2982-8
references.pmid: 15181088
references.citation: J Biol Chem. 2004 Oct 15;279(42):43990-7
references.pmid: 15302866
references.citation: Cancer Lett. 2013 May 28;332(2):275-85
references.pmid: 21078542