The HDAC6-selective inhibitor is effective against non-Hodgkin lymphoma and synergizes with ibrutinib in follicular lymphoma

Dong Hoon Lee, Go Woon Kim, So Hee Kwon

Research output: Contribution to journalArticle

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Abstract

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215. We first showed that FL is the most sensitive to HDAC6 inhibitor. We showed that combining A452 with ibrutinib led to the synergistic inhibition of cell growth and decreased viability of FL cells, as well as increased levels of apoptosis. Similar synergistic interactions occur in chronic lymphocytic leukemia (CLL) and germinal center diffuse large B-cell lymphoma cells (DLBCL). Enhanced cell death is associated with AKT and ERK1/2 inactivation and increased DNA damage (induction of γH2A.X and reduction of pChk1/2). In addition, A452 downregulates c-Myc, an effect significantly enhanced by ibruninib. Although ACY-1215 is less potent than A452, it displays synergism with ibrutinib. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215 in FL. These findings suggest that a combination of HDAC6-selective inhibitor and ibrutinib is a potent therapeutic strategy for NHL including FL.

Original languageEnglish
Pages (from-to)944-956
Number of pages13
JournalMolecular Carcinogenesis
Volume58
Issue number6
DOIs
Publication statusPublished - 2019 Jun 1

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Follicular Lymphoma
Histone Deacetylases
Non-Hodgkin's Lymphoma
Histone Deacetylase Inhibitors
Germinal Center
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
B-Cell Chronic Lymphocytic Leukemia
PCI 32765
Antineoplastic Agents
DNA Damage
Cell Death
Down-Regulation
Apoptosis
Drug Therapy
Therapeutics
Growth
Pharmaceutical Preparations
2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

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abstract = "Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215. We first showed that FL is the most sensitive to HDAC6 inhibitor. We showed that combining A452 with ibrutinib led to the synergistic inhibition of cell growth and decreased viability of FL cells, as well as increased levels of apoptosis. Similar synergistic interactions occur in chronic lymphocytic leukemia (CLL) and germinal center diffuse large B-cell lymphoma cells (DLBCL). Enhanced cell death is associated with AKT and ERK1/2 inactivation and increased DNA damage (induction of γH2A.X and reduction of pChk1/2). In addition, A452 downregulates c-Myc, an effect significantly enhanced by ibruninib. Although ACY-1215 is less potent than A452, it displays synergism with ibrutinib. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215 in FL. These findings suggest that a combination of HDAC6-selective inhibitor and ibrutinib is a potent therapeutic strategy for NHL including FL.",
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The HDAC6-selective inhibitor is effective against non-Hodgkin lymphoma and synergizes with ibrutinib in follicular lymphoma. / Lee, Dong Hoon; Kim, Go Woon; Kwon, So Hee.

In: Molecular Carcinogenesis, Vol. 58, No. 6, 01.06.2019, p. 944-956.

Research output: Contribution to journalArticle

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