Biomaterial Database

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma. 2021

Mitsuhito Hirano, and Yoichi Imai, and Yuta Kaito, and Takahiko Murayama, and Kota Sato, and Tadao Ishida, and Junichi Yamamoto, and Takumi Ito, and Muneyoshi Futami, and Masaki Ri, and Hiroshi Yasui, and Tamami Denda, and Yukihisa Tanaka, and Yasunori Ota, and Masanori Nojima, and Yasuhiko Kamikubo, and Noriko Gotoh, and Shinsuke Iida, and Hiroshi Handa, and Arinobu Tojo

Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

BACKGROUND Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. METHODS We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. RESULTS The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. CONCLUSIONS The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

UI	MeSH Term	Description	Entries
D007167	Immunotherapy	Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection.	Immunotherapies
D008297	Male		Males
D009101	Multiple Myeloma	A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.	Myeloma, Plasma-Cell,Kahler Disease,Myeloma, Multiple,Myeloma-Multiple,Myelomatosis,Plasma Cell Myeloma,Cell Myeloma, Plasma,Cell Myelomas, Plasma,Disease, Kahler,Multiple Myelomas,Myeloma Multiple,Myeloma, Plasma Cell,Myeloma-Multiples,Myelomas, Multiple,Myelomas, Plasma Cell,Myelomas, Plasma-Cell,Myelomatoses,Plasma Cell Myelomas,Plasma-Cell Myeloma,Plasma-Cell Myelomas
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D056572	Histone Deacetylase Inhibitors	Compounds that inhibit HISTONE DEACETYLASES. This class of drugs may influence gene expression by increasing the level of acetylated HISTONES in specific CHROMATIN domains.	HDAC Inhibitor,HDAC Inhibitors,Histone Deacetylase Inhibitor,Deacetylase Inhibitor, Histone,Deacetylase Inhibitors, Histone,Inhibitor, HDAC,Inhibitor, Histone Deacetylase,Inhibitors, HDAC,Inhibitors, Histone Deacetylase
D020533	Angiogenesis Inhibitors	Agents and endogenous substances that antagonize or inhibit the development of new blood vessels.	Angiogenesis Factor Inhibitor,Angiogenesis Inhibitor,Angiogenetic Antagonist,Angiogenetic Inhibitor,Angiogenic Antagonist,Angiogenic Antagonists,Angiogenic Inhibitor,Angiostatic Agent,Angiostatic Agents,Anti-Angiogenetic Agent,Anti-Angiogenic Drug,Anti-Angiogenic Drugs,Antiangiogenic Agent,Neovascularization Inhibitor,Neovascularization Inhibitors,Angiogenesis Factor Inhibitors,Angiogenetic Antagonists,Angiogenetic Inhibitors,Angiogenic Inhibitors,Antagonists, Angiogenic,Anti-Angiogenesis Effect,Anti-Angiogenesis Effects,Anti-Angiogenetic Agents,Antiangiogenesis Effect,Antiangiogenesis Effects,Antiangiogenic Agents,Inhibitors, Angiogenesis,Inhibitors, Angiogenetic,Inhibitors, Angiogenic,Inhibitors, Neovascularization,Agent, Angiostatic,Agent, Anti-Angiogenetic,Agent, Antiangiogenic,Agents, Angiostatic,Agents, Anti-Angiogenetic,Agents, Antiangiogenic,Antagonist, Angiogenetic,Antagonist, Angiogenic,Antagonists, Angiogenetic,Anti Angiogenesis Effect,Anti Angiogenesis Effects,Anti Angiogenetic Agent,Anti Angiogenetic Agents,Anti Angiogenic Drug,Anti Angiogenic Drugs,Drug, Anti-Angiogenic,Drugs, Anti-Angiogenic,Effect, Anti-Angiogenesis,Effect, Antiangiogenesis,Effects, Anti-Angiogenesis,Effects, Antiangiogenesis,Factor Inhibitor, Angiogenesis,Factor Inhibitors, Angiogenesis,Inhibitor, Angiogenesis,Inhibitor, Angiogenesis Factor,Inhibitor, Angiogenetic,Inhibitor, Angiogenic,Inhibitor, Neovascularization,Inhibitors, Angiogenesis Factor