A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2002-

Antineoplastic Agents/*pharmacology ; Benzamides/*pharmacology ; Epstein-Barr Virus Infections/*drug therapy ; HSP90 Heat-Shock Proteins/*antagonists & inhibitors ; Isoindoles/*pharmacology ; Nasopharyngeal Neoplasms/*drug therapy; Acetylation ; Animals ; Carcinoma ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Epstein-Barr Virus Infections/metabolism ; Epstein-Barr Virus Infections/pathology ; Female ; HSP90 Heat-Shock Proteins/metabolism ; Histone Deacetylase 6 ; Histone Deacetylases/metabolism ; Humans ; Hyaluronan Receptors/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/metabolism ; Nasopharyngeal Neoplasms/pathology ; Nasopharyngeal Neoplasms/virology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Protein Processing, Post-Translational ; Protein Stability ; SOXB1 Transcription Factors/metabolism ; Spheroids, Cellular/drug effects ; Spheroids, Cellular/metabolism ; Tubulin/metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.
Results: Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.
Conclusion: AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC.

Genes Dev. 2012 Apr 1;26(7):641-50. (PMID: 22474259)
Cell. 2006 Aug 25;126(4):663-76. (PMID: 16904174)
Mol Cancer Ther. 2012 Aug;11(8):1799-808. (PMID: 22714264)
J Biomed Biotechnol. 2011;2011:875824. (PMID: 21076528)
Hum Pathol. 2006 May;37(5):593-605. (PMID: 16647958)
Cancer Genet Cytogenet. 1998 Mar;101(2):83-8. (PMID: 9494607)
Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40. (PMID: 17667954)
Drug Discov Today. 2008 Jan;13(1-2):38-43. (PMID: 18190862)
Nat Rev Cancer. 2010 Jan;10(1):51-7. (PMID: 20029423)
In Vivo. 2005 Jan-Feb;19(1):237-45. (PMID: 15796181)
Drug Resist Updat. 2009 Feb-Apr;12(1-2):17-27. (PMID: 19179103)
Int J Cell Biol. 2012;2012:594681. (PMID: 22500174)
Nat Genet. 2010 Jul;42(7):599-603. (PMID: 20512145)
Nat Rev Cancer. 2005 Oct;5(10):761-72. (PMID: 16175177)
EMBO J. 2002 Dec 16;21(24):6820-31. (PMID: 12486003)
Photochem Photobiol. 2009 Sep-Oct;85(5):1207-17. (PMID: 19496992)
Head Neck. 2003 Oct;25(10):864-72. (PMID: 12966511)
Expert Opin Ther Targets. 2012 Mar;16 Suppl 1:S63-8. (PMID: 22313344)
Invest New Drugs. 2010 Jun;28(3):326-33. (PMID: 19756373)
Int J Colorectal Dis. 2011 Oct;26(10):1279-85. (PMID: 21670985)
Oral Oncol. 2011 Feb;47(2):83-91. (PMID: 21167769)
Chin J Cancer. 2011 Mar;30(3):204-12. (PMID: 21352698)
Cell Div. 2009 Jun 23;4:11. (PMID: 19549334)
Nature. 2003 Sep 25;425(6956):407-10. (PMID: 14508491)
Anticancer Drugs. 2010 Jun;21(5):471-7. (PMID: 20124988)
Cancer Sci. 2012 Mar;103(3):522-7. (PMID: 22181674)
Nat Rev Cancer. 2011 Apr;11(4):254-67. (PMID: 21390059)
Ann Oncol. 2010 Oct;21 Suppl 7:vii308-12. (PMID: 20943634)
Cancer Cell. 2004 May;5(5):423-8. (PMID: 15144950)
J Med Chem. 2010 Aug 26;53(16):5956-69. (PMID: 20662534)
Nat Cell Biol. 2009 Apr;11(4):377-9. (PMID: 19337320)
Head Neck. 2008 Jul;30(7):946-63. (PMID: 18446839)
Trends Cell Biol. 2012 Apr;22(4):211-9. (PMID: 22245068)
Mol Carcinog. 2012 Dec;51(12):963-72. (PMID: 22006341)
Nat Rev Mol Cell Biol. 2003 Jan;4(1):33-45. (PMID: 12511867)
Ann Oncol. 2003 Aug;14(8):1169-76. (PMID: 12881371)
Trends Cell Biol. 2008 Jun;18(6):291-7. (PMID: 18472263)
J Natl Cancer Inst. 2010 Oct 20;102(20):1536-46. (PMID: 20858887)
Semin Cancer Biol. 2002 Dec;12(6):431-41. (PMID: 12450729)
Blood. 2008 Sep 1;112(5):1886-93. (PMID: 18591380)
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7. (PMID: 7568133)
Chin J Cancer. 2012 Apr;31(4):169-77. (PMID: 22200179)
Nat Rev Cancer. 2010 Aug;10(8):537-49. (PMID: 20651736)
PLoS One. 2012;7(12):e52426. (PMID: 23285037)
Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):202-7. (PMID: 18538504)
ACS Chem Biol. 2006 Jun 20;1(5):279-84. (PMID: 17163756)
Nat Rev Cancer. 2008 Jun;8(6):438-49. (PMID: 18500245)
PLoS One. 2010 Jun 11;5(6):e11076. (PMID: 20552022)
J Cancer Res Clin Oncol. 2012 Apr;138(4):675-86. (PMID: 22237455)
Semin Cancer Biol. 2008 Aug;18(4):260-7. (PMID: 18467123)
Cancer Chemother Pharmacol. 2008 Jun;62(1):59-64. (PMID: 17762933)
Cell. 2003 Jun 13;113(6):703-16. (PMID: 12809602)
Nature. 2002 May 23;417(6887):455-8. (PMID: 12024216)
Acta Biochim Biophys Sin (Shanghai). 2009 May;41(5):414-28. (PMID: 19430707)
Nature. 2010 Mar 18;464(7287):374-9. (PMID: 20237562)

0 (Antineoplastic Agents)
0 (Benzamides)
0 (CD44 protein, human)
0 (HSP90 Heat-Shock Proteins)
0 (Hyaluronan Receptors)
0 (Isoindoles)
0 (SOX2 protein, human)
0 (SOXB1 Transcription Factors)
0 (Tubulin)
EC 3.5.1.98 (HDAC6 protein, human)
EC 3.5.1.98 (Histone Deacetylase 6)
EC 3.5.1.98 (Histone Deacetylases)
Q7Y33N57ZZ ((2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone)

Date Created: 20131026 Date Completed: 20140708 Latest Revision: 20211025

20231215

PMC3834878

10.1186/1476-4598-12-128

24156782