The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells.
Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM.
Zhang
Shuhong
S
Division of Hematology and Oncology, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Suvannasankha
Attaya
A
Crean
Colin D
CD
White
Valerie L
VL
Chen
Ching-Shih
CS
Farag
Sherif S
SS
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130
Int J Cancer. 2004 Nov 1;112(2):171-8
15352027
Neoplasia. 2005 Jul;7(7):646-57
16026644
Clin Cancer Res. 2008 Mar 15;14(6):1814-22
18347184
Clin Cancer Res. 2006 Sep 1;12(17):5199-206
16951239
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1241-6
14734806
Br J Haematol. 1998 Oct;103(1):168-75
9792305
Nat Rev Cancer. 2004 Feb;4(2):97-105
14964307
Mol Cancer Ther. 2004 Nov;3(11):1397-402
15542778
Leukemia. 2005 Oct;19(10):1729-38
16094421
Oncogene. 2002 Feb 21;21(9):1391-400
11857082
Immunol Rev. 2003 Aug;194:164-76
12846814
Blood. 2003 May 15;101(10):4055-62
12531799
J Immunol. 2008 Feb 1;180(3):1545-55
18209050
J Immunol. 1997 Sep 1;159(5):2212-21
9278309
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4386-91
9539746
Leuk Lymphoma. 2008 Mar;49(3):502-7
18297527
Haematologica. 2006 Feb;91(2):248-51
16461312
Crit Rev Immunol. 2005;25(1):31-58
15833082
Blood. 1995 Feb 15;85(4):863-72
7849308
J Immunol. 1998 Oct 15;161(8):3936-42
9780161
Epigenetics. 2008 May-Jun;3(3):164-71
18487953
Blood. 2003 Oct 1;102(7):2615-22
12816865
Immunity. 1999 Jan;10(1):105-15
10023775
Blood. 1991 Oct 15;78(8):1996-2004
1912582
Br J Haematol. 2001 Nov;115(2):287-97
11703323
Blood. 2004 Mar 1;103(5):1799-806
12969976
Blood. 2006 Mar 1;107(5):2094-7
16304046
Leuk Lymphoma. 2003 Jul;44(7):1209-14
12916874
J Biol Chem. 2001 Dec 14;276(50):47038-45
11602599
Biochem J. 1998 Sep 1;334 ( Pt 2):297-314
9716487
Mol Cancer Ther. 2009 Feb;8(2):366-75
19174558
Am J Hematol. 2001 Nov;68(3):170-8
11754398
Clin Cancer Res. 2002 Apr;8(4):945-54
11948098
Br J Cancer. 2005 Jul 11;93(1):70-80
15970928
Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):540-5
14695887
Arch Biochem Biophys. 2008 Sep 15;477(2):330-8
18593565
Mol Cancer Ther. 2007 Mar;6(3):987-94
17363492
Leukemia. 2004 Jul;18(7):1207-14
15116122
Cancer Biol Ther. 2007 Feb;6(2):185-91
17218782
J Biol Chem. 2001 Jun 1;276(22):19414-9
11259441
Biochem J. 2003 Aug 15;374(Pt 1):1-20
12773095
Surgery. 2005 Jul;138(1):1-7
16003308
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18030-5
15596714
Leukemia. 2007 Sep;21(9):1892-900
17637810
Blood. 2004 Jan 1;103(1):20-32
12969978
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3697-702
15738394
Cancer Res. 2006 Jun 1;66(11):5781-9
16740717
J Med Chem. 2005 Aug 25;48(17):5530-5
16107152