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Identification of SYK Inhibitor, R406 As a Novel Senolytic Agent

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Identification of SYK Inhibitor, R406 As a Novel Senolytic Agent www.aging-us.com AGING 2020, Vol. 12, No. 9 Research Paper Identification of SYK inhibitor, R406 as a novel senolytic agent Hyun-Ji Cho1,2, Eun Jae Yang3, Joon Tae Park4, Jae-Ryong Kim5, Eok-Cheon Kim5, Kyong-Jin Jung5, Sang Chul Park1,6,7, Young-Sam Lee1,3 1Well Aging Research Center, DGIST, Daegu 42988, Korea 2Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 42472, Korea 3Department of New Biology, DGIST, Daegu 42988, Korea 4Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea 5Department of Biochemistry and Molecular Biology, Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu 42415, Korea 6Department of Molecular Medicine, Chonnam National University Medical School, Gwangju 58128, Korea 7The Future Life and Society Research Center, Chonnam National University, Gwangju 58128, Korea Correspondence to: Hyun-Ji Cho, Young-Sam Lee; email: [email protected], [email protected] Keywords: cellular senescence, senolytics, apoptosis, FAK, p38 Abbreviations: ATCC: American Type Culture Collection; HUVEC: human umbilical vein endothelial cells; DMEM: Dulbecco’s modified Eagle’s medium; FBS: fetal bovine serum Received: October 29, 2019 Accepted: March 24, 2020 Published: May 7, 2020 Copyright: Cho et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity. INTRODUCTION cycle, resistance to apoptosis, increasing activity of senescence-associated β-galactosidase (SA-β-gal), and Aging is a progressive physiological change over time secretion of a set of various cytokines involving chronic and is mainly associated with the decline of biological inflammation and structure remodeling, known as functions and senescence in an organism [1]. The loss senescence-associated secretory phenotypes (SASPs) of biological function in cells, the basic units of tissue [2, 3, 6–9]. Although the transient appearance of and organ, can be caused by cellular stresses, including cellular senescence plays an essential role in tissue genomic instability, impaired proteostasis, and remodeling, efficient immune clearance during dysfunctional subcellular organelles, all of which embryonic development, and after an injury [10–12], a provoke the cessation of cell division and cellular loss of proliferation capacity and SASP secretion in senescence [2–5]. Senescent cells have a variety of chronic senescent cells per se affects the repair of characteristics such as the irreversible arrest of the cell impaired tissues. Therefore, cellular senescence is www.aging-us.com 8221 AGING suggested to be strongly linked with age-associated did not significantly change the level of Bcl-2 family tissue damage and diseases. Recent evidence also points in senescent cells. Alternatively, R406 inhibited the to close linkage between cellular senescence and tissue phosphorylation of focal adhesion kinase (FAK) as well dysfunction. Transplanting senescent cells induced as p38 mitogen-activated protein kinase (MAPK), which physical dysfunction in young mice [13]. In contrast, both regulate cell survival. Our results demonstrate that the clearance of p16Ink4a-positive senescent cells extends R406 is a new class of senolytics that targets multiple lifespan in an aging-induced transgenic mouse model, regulatory pathways for senescent cell survival. INK-ATTAC mice [14], and a mouse model of a human progeroid syndrome, Ercc1-/ mice [15]. RESULTS Senotherapeutics, which are small molecules targeting R406 reduces cell viability in senescent HDFs cellular senescence for delaying age-related processes or diseases, have been developed mainly for two uses: In our previous studies, we evaluated the ability to restore one is senomorphic medicines, which suppress cellular senescent fibroblasts in the RS model using HTS with a senescence and induce reverse senescence phenotypes, library containing 355 kinase inhibitors [24, 25]. From and the other is senolytic drugs, which induce these results, we selected candidates for their senolytic cytotoxicity selectively in senescent cells [16]. The activity based on inducing cytotoxicity, increasing ROS combination of dasatinib and quercetin are the first levels, or both (Supplementary Table 1). Next, we senolytic agents effective in the removal of ionizing selected out second candidate compounds by reviewing radiation-induced senescent cells in vitro and alleviating the publications on the chosen drugs initially regarding age-related symptoms in the progeroid Ercc1−/Δ mouse cell physiologies (e.g., senolytic effect, apoptosis, and cell model in vivo [17]. Emerging evidence has death) and side effects in pre-clinical studies (e.g., high demonstrated that senolytic agents alleviate various age- toxicity, diarrhea, fever, rash, etc.). Then, based on the related conditions in mice, including age-associated CCK-1 assay, we assessed the differential cytotoxicity of vascular phenotypes [18], metabolic dysfunction [19], the remaining candidates depending on the state of and osteoarthritis [20], and even affect senescence- cellular senescence in HDFs (Supplementary Figure 1). related dysfunctions in human [21]. Among these, R406, an FDA-approved Syk inhibitor, was found to exhibit higher cytotoxicity in senescent HDFs Major classes of senolytic drugs typically focus on than in non-senescent cells over the tested range of inhibiting pro-survival pathways or triggering pro- concentration (from 1 to 20 μM; Figure 1A). Nintedanib, apoptosis signaling in senescent cells. The combination a tyrosine kinase inhibitor, also showed senolytic effects of dasatinib and quercetin, which reduced p21, PAI-2, at lower concentrations (from 1 to 5 μM) but was toxic in and BCL-xL [17], and Navitoclax (ABT263), which higher concentration (20 μM), regardless of the senescent targets the Bcl-2 family [22], belong to this class of state (Figure 1B). Other drug candidates were not suitable senolytics. In other classes, the mimicry of forkhead box as senolytic drugs due to either non-selective cytotoxicity protein O4 (FOXO4) peptide selectively disrupted the (NVP-BHG712, an Ephrin type-B receptor 4 inhibitor; p53-FOXO4 interaction, which induced p53-dependent AZD, an ALK inhibitor; CCT129202, an aurora kinase apoptosis in senescent cells [23]. Recently, a HSP90 inhibitor; and axitinib, a tyrosine kinase inhibitor; Figure inhibitor was identified as a novel class of senolytic drugs 1C–1F); or were drugs that had no cytotoxic effect that downregulated the phosphorylation of PI3K/AKT, an (bosutinib, an Src inhibitor; and selumetinib, a MEK anti-apoptotic factor [15]. Despite intensified efforts to inhibitor; Supplementary Figure 2A and 2B). In addition, develop drugs targeting senescent cells, however, the we further confirmed R406-induced cytotoxicity by number of senolytic agents is still limited in comparison Hoechst 33342 staining, because CCK-1-based cell with the number of drugs against other age-related viability assay could reflect cell metabolic activity, which diseases like cancer or fibrosis. Finding a novel might be influenced by kinase inhibitors. Similar to the senotherapeutic would expand the spectrum of efficacy CCK-1 assay, the fluorescence levels of senescent HDFs on various types and stages of cellular senescence. were reduced by R406 in a dose dependent manner (Supplementary Figure 2C). Our results demonstrated that In this study, using high-throughput screening (HTS) to R406 has cytotoxicity selectively in senescent fibroblasts measure the variation of cell proliferation and reactive in the RS model and, subsequent experiments were oxygen species (ROS) levels, we identified a novel performed using R406 concentration of 10 μM. senolytic agent R406, also known as tamatinib. This agent was effective in the replicative senescence (RS) model of R406 induces apoptotic cell death diploid human dermal fibroblasts (HDFs). R406 induced the caspase-9-mediated intrinsic apoptotic pathway, Senescent cells demonstrate elevated expression of anti- similar to other known senolytic drugs; however, R406 apoptotic and pro-survival factors [15, 17, 22]. Typical www.aging-us.com 8222 AGING senolytic agents inhibit cell viability by modulating compared with only 11% in the R406-treated non- expression of these factors, particularly Bcl-2 family senescent cells.
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