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

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.

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

“…34 Upregulation of p16 INK4a is associated with apoptosis in MM cells. 35 Nevertheless, our results showing the direct transcriptional repression of CUL4A by Blimp-1 extend the current understandings of the mode of action of anti-myeloma drugs. We hypothesized that Blimp-1 and Aiolos cooperatively suppress apoptosis genes in MM cells, which ensures the survival of those cells.…”

The pan‐histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells

“…Histone deacetylases (HDAC) are enzymes that determine the acetylating status of histones, affecting chromatin structure and gene expression and have become a potential therapeutic target in MM therapy (Zhang et al, 2010). HDAC inhibitors (HDACi) were initially developed as agents that alter epigenetic changes by histone hyperacetylation which in turn leads to chromatin remodelling and expression of repressed genes (Villar-Garea & Esteller, 2004).…”

“…In addition to their action on histones, substrates for HDACs include many other cellular proteins including p53, which requires acetylation for its activation (Tang et al, 2008;Batty et al, 2009). Furthermore, HDACs can modulate a wide variety of cellular functions including transcriptional reactivation and expression of genes responsible for cell proliferation, apoptosis, cytoskeleton and angiogenesis (Villar-Garea & Esteller, 2004;Marsoni et al, 2008;Zhang et al, 2010).…”

A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas

“…AR-42 (Arno Therapeutics) is an orally bioavailable, hydroxamate-tethered phenylbutyrate derived small molecule that targets and inhibits Class I and IIB HDAC enzymes[12,13], and has antitumor activity in in vitro and in vivo models of solid tumors[14–18] and numerous B-cell malignancies including chronic lymphocytic leukemia (CLL), Burkitt’s lymphoma, mantle cell lymphoma (MCL), and MM[19–21]. Similar to other pan-HDACi like vorinostat and panobinostat, AR-42 suppresses tumor cell growth via a broad spectrum of mechanisms.…”

“…Similar to other pan-HDACi like vorinostat and panobinostat, AR-42 suppresses tumor cell growth via a broad spectrum of mechanisms. However, in comparison to vorinostat, AR-42 has been shown to be four- to seven-fold more potent and associated with increased cell killing of multiple MM cell lines (U266, H929, RPMI 8226, ARH-77, and IM-9) and primary MM cells via targeting of the gp130/STAT3 pathway, modulation of downstream cell survival pathways including downregulation of Akt and NF-KB signaling, and enhanced cleavage of caspase-3, 8, and 9; a distinct effect on caspase activity not observed with vorinostat treatment of myeloma or prostate cancer preclinical models[16,19,21,22]. It has also been demonstrated that AR-42 has more potent in vitro and in vivo activity than vorinostat in multiple preclinical lymphoma models, including the Raji Burkitt lymphoma, JeKo-1 mantle cell lymphoma, and Eu-Tcl1 murine models.…”