The Novel Histone Deacetylase Inhibitor RAS2410 (Resminostat) Interferes with Important Signalling Pathways and Induces Apoptosis in Multiple Myeloma Cells.

Abstract 4928

Inhibition of histone deacetylase (HDAC) is a promising target for novel, anti-myeloma agents. In this study we investigated the biologic effects of the novel HDAC inhibitor RAS2410 (also known as “4SC-201”, “resminostat”) on Multiple Myeloma (MM) cells in vitro. RAS2410 is a potent, direct inhibitor of HDACs 1, 3 and 6 (IC₅₀ = 43-72nM) representing the HDAC classes I and II. Accordingly, RAS2410 induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of RAS2410 abrogate cell growth and strongly induce apoptosis (IC₅₀ = 2.5-3μM in 3 out of 4 cell lines) in MM cell lines (NCI-H929, U-266, RPMI-8226, OPM-2) as well as in primary MM cells isolated from patients. At 1μM, RAS2410 induces G0/G1 cell cycle arrest in 3 out of 4 MM cell lines associated with decreased levels of cyclin D1, cdc25a, Cdk4, pRb and p53 as well as upregulation of p21. This cell cycle arrest is reflected by an inhibition of cell proliferation. RAS2410 decreases phosphorylation of 4EBP-1 and P70S6K indicating that RAS2410 induces apoptosis by interfering with Akt pathway signalling downstream of Akt. Treatment with RAS2410 results in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 are activated by RAS2410. Furthermore, additive and synergistic effects in terms of apoptosis induction are observed for combinations of RAS2410 with melphalan, doxorubicin and the proteasome inhibitors bortezomib and S2209. In conclusion, we have identified potent anti-myeloma activity for the novel HDACi RAS2410. This study has yielded further insight into the biological sequelae of HDAC inhibition in MM and provides the rationale for in vivo studies and clinical trials using RAS2410 to improve patient outcome in MM.