Abstract
Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.
Highlights
Despite progress due to development of proteasome inhibitors and immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), novel combination treatment strategies are needed to further improve multiple myeloma (MM) patient outcome
Anti-c-Myc, anti-acetylated lysine, anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), anti-caspase-8, anti-caspase-9, anti-cleaved-caspase-3, anti-poly (ADP-ribose) polymerase (PARP), anti-X-linked inhibitor of apoptosis protein (XIAP), Bcl[2], anti-cIAP2, anti-α-tubulin, phospho-STAT3, HDAC6, IKZF1, IKZF3 and IRF4 Abs were obtained from Cell Signaling Technology (Danvers, MA, USA)
IMiDs and Histone deacetylases (HDACs) inhibitors downregulate c-Myc expression c-Myc has a crucial role in MM pathogenesis, and previous studies
Summary
Despite progress due to development of proteasome inhibitors (bortezomib, carfilzomib) and immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), novel combination treatment strategies are needed to further improve multiple myeloma (MM) patient outcome. Recent studies have shown cereblon to be a primary target of IMiDs:[1,2,3] IMiDs bind to cereblon, an E3 ubiquitin ligase which facilitates ubiquitination of IKZF1 (Ikaros) and IKZF3 (Aiolos) followed by proteasomal degradation. IMiDs downregulate IKZF1/3 within several hours, which is abrogated by proteasome inhibitors. It has shown that IMiDs downregulate c-Myc, and IRF4,3,8 which has a central role in MM pathogenesis.[6] These studies show that IMiDs inhibit multiple key molecules that mediate MM cell proliferation, survival and drug resistance in the context of the bone marrow (BM) microenvironment
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