M-134, a novel HDAC6-selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis
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ARTICLE
M‑134, a novel HDAC6‑selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis when combined with tofacitinib Daekwon Bae1,3 · Youngil Choi3 · Jiyoung Lee2 · Nina Ha3 · Donghyeon Suh3 · Jiyeon Baek3 · Jinsol Park3 · Woochan Son2 Received: 11 July 2020 / Revised: 6 October 2020 / Accepted: 27 October 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background Although tofacitinib has shown highly significant efficacy for rheumatoid arthritis (RA), there are still a considerable number of patients that are non-responders owing to its limited effectiveness and various adverse effects. Thus, alternative options with better efficacy and lower toxicity are desired. Here, M-134, a recently developed HDAC6 inhibitor, was examined for its therapeutic potential when combined with tofacitinib in a rat model of RA. Methods The single or combined administration of M-134 and tofacitinib was examined in complete Freund’s adjuvantinduced arthritis (AIA) or collagen-induced arthritis (CIA) rodent models. To evaluate the therapeutic and adverse effects, the following factors were observed: macroscopic or microscopic scoring of all four paws; the expression of ICAM-1, VCAM-1, and IP-10 in the joints and that of various cytokines and chemokines in the plasma; the weight of the thymus and the liver; and changes in hematological enzymes. Results Combination treatment showed strong synergistic effects as measured by the clinical score and histological changes, without adverse effects such as weight loss in the thymus and increased liver enzymes (ALT and AST). Additionally, it also reduced ICAM-1, VCAM-1, and IP-10 expression in the joints, and M-134 increased the efficacy of tofacitinib by regulating various cytokines, such as interleukin (IL)-1β, IL-17, and TNF-α, in the serum of AIA rats. Differences in the cytokine expression for each drug were found in the CIA model. Conclusions M-134 and tofacitinib combination therapy is a potential option for the treatment of RA through the regulation of cytokines, chemokines, and adhesion molecules. Keywords Rheumatoid arthritis · Histone deacetylase 6 inhibitor · Tofacitinib · Combined treatment · Animal model
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43440-020-00188-x) contains supplementary material, which is available to authorized users. * Woochan Son [email protected] 1
Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
2
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
3
Department of Pharmacology, CKD Research Institute, CKD Pharmaceutical Co, Yongin, Republic of Korea
Abbreviations AIA Adjuvant-induced arthritis CIA Collagen-induced arthritis HDAC Histone deacetylase IL Interleukin JAK Janus kinase RA Rheumatoid arthritis T
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