The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Shuhong Zhang, Attaya Suvannasankha, Colin D. Crean, Valerie L. White, Ching Shih Chen, Sherif S. Farag

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31 Scopus citations

Abstract

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 LC50 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 G1 and G2 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.

Original languageEnglish (US)
Pages (from-to)204-213
Number of pages10
JournalInternational Journal of Cancer
Volume129
Issue number1
DOIs
StatePublished - Jul 1 2011

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Keywords

  • apoptosis
  • cell cycle
  • multiple myeloma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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