HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma

Hye Rim Won, Dong Hoon Lee, Soo Keun Yeon, Hyun Wook Ryu, Go Woon Kim, So Hee Kwon

Research output: Contribution to journalArticle

Abstract

Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose-limiting toxicities in patients with multiple myeloma (MM). The present study investigated the interaction between the HDAC6 inhibitor, A452, and immunomodulatory drugs (IMiDs) on dexamethasone (Dex)-sensitive and -resistant MM cells compared with the current clinically tested HDAC6 inhibitor, ACY-1215. It was shown that the combination of the HDAC6-selective inhibitor, A452, with either of the IMiDs tested (lenalidomide or pomalidomide) led to the synergistic inhibition of cell growth, a decrease in the viability of MM cells and in an increase in the levels of apoptosis. Furthermore, enhanced cell death was associated with the inactivation of AKT and extracellular signal-regulated kinase (ERK)1/2. Of note, A452 in combination with IMiDs induced synergistic MM cytotoxicity without altering the expression of cereblon and thereby, the synergistic downregulation of IKAROS family zinc finger (IKZF)1/3, c-Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD-L1. More importantly, this combination treatment was effective in the Dex-resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY-1215. Taken together, these findings suggest that a combination of the HDAC6-selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.

Original languageEnglish
Pages (from-to)499-512
Number of pages14
JournalInternational journal of oncology
Volume55
Issue number2
DOIs
Publication statusPublished - 2019 Jan 1

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Multiple Myeloma
Pharmaceutical Preparations
Dexamethasone
Histone Deacetylase Inhibitors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Zinc Fingers
Therapeutic Uses
Antineoplastic Agents
Cell Death
Up-Regulation
Therapeutics
Down-Regulation
Apoptosis
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Won, Hye Rim ; Lee, Dong Hoon ; Yeon, Soo Keun ; Ryu, Hyun Wook ; Kim, Go Woon ; Kwon, So Hee. / HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma. In: International journal of oncology. 2019 ; Vol. 55, No. 2. pp. 499-512.
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HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma. / Won, Hye Rim; Lee, Dong Hoon; Yeon, Soo Keun; Ryu, Hyun Wook; Kim, Go Woon; Kwon, So Hee.

In: International journal of oncology, Vol. 55, No. 2, 01.01.2019, p. 499-512.

Research output: Contribution to journalArticle

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T1 - HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma

AU - Won, Hye Rim

AU - Lee, Dong Hoon

AU - Yeon, Soo Keun

AU - Ryu, Hyun Wook

AU - Kim, Go Woon

AU - Kwon, So Hee

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AB - Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose-limiting toxicities in patients with multiple myeloma (MM). The present study investigated the interaction between the HDAC6 inhibitor, A452, and immunomodulatory drugs (IMiDs) on dexamethasone (Dex)-sensitive and -resistant MM cells compared with the current clinically tested HDAC6 inhibitor, ACY-1215. It was shown that the combination of the HDAC6-selective inhibitor, A452, with either of the IMiDs tested (lenalidomide or pomalidomide) led to the synergistic inhibition of cell growth, a decrease in the viability of MM cells and in an increase in the levels of apoptosis. Furthermore, enhanced cell death was associated with the inactivation of AKT and extracellular signal-regulated kinase (ERK)1/2. Of note, A452 in combination with IMiDs induced synergistic MM cytotoxicity without altering the expression of cereblon and thereby, the synergistic downregulation of IKAROS family zinc finger (IKZF)1/3, c-Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD-L1. More importantly, this combination treatment was effective in the Dex-resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY-1215. Taken together, these findings suggest that a combination of the HDAC6-selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.

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