The HDAC6 inhibitor ACY‑1215 enhances the anticancer activity of oxaliplatin in colorectal cancer cells
Open accessAbstract
ACY‑1215, also known as ricolinostat, is a leading histone deacetylase 6 inhibitor, which is currently being tested in clinical trials for hematological malignancies. Previous studies have reported that ACY‑1215 is not potent enough as a monotherapy for the treatment of colorectal cancer (CRC), which generally requires combination therapy for successful treatment. Therefore, the present study aimed to determine whether the synergistic interaction detected between ACY‑1215 and anticancer agents in hematological cancers could occur in solid tumors. The results of the present study indicated that ACY‑1215 exerted a potent synergistic anti-proliferative effect when used in combination with anticancer agents in CRC cells. The combination of ACY‑1215 and oxaliplatin was more potent than either drug alone, as indicated by an increase in apoptotic cells and their effects on the apoptotic pathway; ACY‑1215 and oxaliplatin cotreatment activated caspase‑3 and poly (ADP ribose) polymerase, increased B‑cell lymphoma (Bcl)‑2 homologous antagonist/killer expression, and decreased Bcl‑extra large protein, phosphorylated-extracellular signal-regulated kinase and phosphorylated-protein kinase B expression. In addition, combined treatment of ACY‑1215 and anticancer agents induced synergistic upregulation of programmed death‑ligand 1. These findings suggested that a therapeutic strategy that combines ACY‑1215 and oxaliplatin warrants attention for the treatment of solid tumors, including CRC.
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A selective inhibitor of HDAC6 was reported to enhance chemotherapeutic effects of 5-FU or oxaliplatin in CRC cells.
“Additionally, a selective inhibitor of HDAC6 was reported to enhance the chemotherapeutic effects of 5-FU or oxaliplatin in CRC cells [167,168].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [168]
Cites
Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564 · cited 1× · see citing works
“HDAC inhibitors (HDACis) kill tumor cells via numerous mechanisms, including DNA repair inhibition, cell-cycle checkpoint disruption and the induction of apoptosis (28,29).”
Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally
Zhang, Y., Kwon, S., Yamaguchi, T., Cubizolles, F., Rousseaux, S., Kneissel, M., Cao, C., Li, N., Cheng, H.-L., Chua, K., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01154-06 · Cited by 559 · cited 9× · see citing works
“At present, two HDACis, vorinostat and romidepsin, have been approved by the United States Food and Drug Administration for the treatment of cutaneous T cell lymphoma.”
InfluentialSelf-citationOptimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2)
Witter, D. J., Harrington, P., Wilson, K. J., Chenard, M., Fleming, J. C., Haines, B., Kral, A. M., Secrist, J. P., & Miller, T. A. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.11.047 · Cited by 93 · cited 1× · see citing works
“The pan-HDAC inhibitor, SAHA, was used as a positive control for HDAC inhibition (23).”
A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth
Kaliszczak, M., Trousil, S., Åberg, O., Perumal, M., Nguyen, Q.-D., & Aboagye, E. O. (2013) · British Journal of Cancer · doi:10.1038/bjc.2012.576 · Cited by 66 · see citing works
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Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer
Haynes, J., & Manogaran, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051988 · Cited by 82 · see citing works
“Additionally, a selective inhibitor of HDAC6 was reported to enhance the chemotherapeutic effects of 5-FU or oxaliplatin in CRC cells [167,168].”
Tan, Y., Zhang, S., Zhu, H., Chu, Y., Zhou, H., Liu, D., & Huo, J. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2018.11.48 · Cited by 35 · see citing works
- Authors
- Lee, D. H., Won, H.-R., Ryu, H.-W., Han, J. M., & Kwon, S. H.
- Affiliations
- Yonsei University (KR)
- Venue
- International Journal of Oncology
- Publisher
- Spandidos Publications
- Published
- 2018-05-11
- Volume
- 53
- Issue
- 2
- Pages
- 844-854
- ISSN
- 1019-6439 (ISSN-L)
- 1791-2423
- OpenAlex
- W2799987494
- Cited by
- 38
- References
- 4
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 8 · 2018: 1
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea (2016R1D1A1A02937071)
- Ministry of Education, Science and Technology (2016R1D1A1A02937071)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- ACY-1215, ricolinostat, HDAC6 inhibitors, oxaliplatin, colorectal cancer, combination therapy, drug synergy, apoptosis, caspase-3, poly(ADP-ribose) polymerase, Bcl-2, ERK, PI3K/Akt, PD-L1
- MeSH terms
- Oxaliplatin, Antineoplastic Agents, Cell Survival, Drug Synergism, Humans, Hydroxamic Acids, Organoplatinum Compounds, Poly(ADP-ribose) Polymerases, Pyrimidines, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, HT29 Cells, HCT116 Cells, Cell Proliferation, Caspase 3, Histone Deacetylase Inhibitors, B7-H1 Antigen
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