Therapeutic Potential of Regorafenib—A Multikinase Inhibitor in Pulmonary Hypertension

Veeroju, Swathi; Kojonazarov, Baktybek; Weiß, Astrid; Ghofrani, Hossein Ardeschir; Weißmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Novoyatleva, Tatyana; Schermuly, Ralph T.

doi:10.3390/ijms22031502

Cited by 6 publications

(6 citation statements)

References 78 publications

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“…Regorafenib, as a multitargeted tyrosine kinase inhibitor, is gradually being discovered to have potential curative effects in animal models of pulmonary emphysema, pulmonary hypertension, autoimmune arthritis, and Alzheimer’s disease . Given its established antitumor properties, exploring regorafenib’s utility in noncancerous diseases is of significant scientific interest.…”

Section: Discussionmentioning

confidence: 99%

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

Zhou,

Su,

Luo

et al. 2024

ACS Omega

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Osteolytic diseases such as osteoporosis and neoplastic bone metastases are caused by the excessive activation of osteoclasts. Inhibiting the excessive activation of osteoclasts is a crucial strategy for treating osteolytic diseases. This study investigated the roles and mechanisms of regorafenib, a tyrosine kinase inhibitor, on osteoclasts and osteolytic diseases. We first identified the potential targets and mechanisms of regorafenib on osteoclast-related osteolytic diseases using network pharmacological analysis and molecular docking techniques. Then, we verified its role and mechanism on osteoclasts via cellular and animal experiments. Network pharmacology analysis identified 89 common targets shared by regorafenib and osteoclast-related osteolytic diseases. Enrichment analysis suggested that regorafenib may act on osteoclast-related osteolytic diseases by modulating targets such as AKT1, CASP3, MMP9, and MAPK3, regulating biological processes such as cell proliferation, apoptosis, and phosphorylation regulation, and influencing signaling pathways such as MAPK, PI3K/AKT, and osteoclast differentiation. The molecular docking results indicated that regorafenib and AKT1, CASP3, MMP9, MAPK3, and MAPK14 were stably docked. Cell experiments demonstrated that regorafenib significantly inhibited osteoclast differentiation and bone resorption in RAW 264.7 cells and bone marrow macrophages in a dose-dependent manner, with up to 50% reduction at 800 nM concentration without exhibiting cytotoxic effects. Furthermore, Western blot and RT-qPCR results demonstrated that regorafenib inhibited osteoclast differentiation by blocking the transduction of RANKL-induced NF-κB, p38, ERK, and NFAT signaling pathways. In vivo studies using an ovariectomized mouse model showed that regorafenib significantly improved bone volume fraction (BV/TV), bone surface to total volume (BS/TV), and number of trabeculae (TB.N), as well as reduced trabecular separation (Tb.Sp) compared to the OVX groups (P < 0.05). TRAcP staining results revealed a reduction in the number of osteoclasts with regorafenib treatment (P < 0.01). These results indicate that regorafenib exerts its protective effects against osteoclast-related osteolytic disease by inhibiting the RANKL-induced NF-κB, NFAT, ERK, and p38 signaling pathways. This study proves that regorafenib may serve as a potential therapeutic agent for osteoclast-related osteolytic diseases.

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Section: Discussionmentioning

confidence: 99%

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

Zhou,

Su,

Luo

et al. 2024

ACS Omega

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“…Treatment with regorafenib resulted in amelioration of senescence and lung function in the model of PPE-induced emphysema. Previous studies have reported on the efficacy of regorafenib in animal models of Alzheimer's disease and bleomycin-induced fibrosis [30][31][32] . The role of regorafenib in the attenuation of senescence may provide an explanation for its beneficial effects in these disease models.…”

Section: Discussionmentioning

confidence: 99%

“…Regorafenib, which is also an inhibitor of multiple RTKs, is approved for the treatment of patients with metastatic colorectal and hepatocellular carcinoma and gastrointestinal stromal tumors 28 , 29 . The beneficial effects of regorafenib have been reported in recent studies in animal models of Alzheimer’s disease, bleomycin-induced fibrosis, and pulmonary hypertension, suggesting its broad application potential 30 – 32 .…”

Section: Introductionmentioning

confidence: 94%

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

Park

Lee

et al. 2023

Exp Mol Med

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Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema.

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“…Rats were euthanized after transthoracic echocardiography, and then the heart and lung were rapidly removed for further analysis. RV hypertrophy was measured by calculating the ratio of the RV to left ventricle (LV) plus septum (S) (RV/LV + S)[ 32 ]. The RV tissues and the lung tissues were removed immediately and fixed in a 10% formalin solution.…”

Section: Methodsmentioning

confidence: 99%

Chronic Sigma 1 receptor activation alleviates right ventricular dysfunction secondary to pulmonary arterial hypertension

et al. 2022

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Sigma 1 receptor (S1R) has shown a preferable protective effect on left ventricular function, but whether it protects right ventricular (RV) function is still elusive.This study aimed to determine the effects of S1R on RV dysfunction secondary to pulmonary arterial hypertension.Sixty wild-type male Sprague–Dawley rats were randomly divided into the control group, the fluvoxamine group, the pulmonary arterial hypertension group and the pulmonary arterial hypertension combined with fluvoxamine group. Monocrotaline (60 mg/kg) was administered to induce pulmonary arterial hypertension, and fluvoxamine was given for 21 consecutive days to activate S1R after one week of monocrotaline administration. Echocardiographic, serologic, and histologic parameters, qRT-PCR, and western blotting were conducted after 4 weeks of monocrotaline administration.The expression of S1R was decreased in the right ventricle in pulmonary arterial hypertension. TAPSE, and the FAC of the right ventricle were significantly decreased, and RV EDP and the plasma concentration of N-terminal pro-B-type natriuretic peptide was increased in the pulmonary arterial hypertension group, but fluvoxamine partly restored those abnormalities (all P < 0.05). Moreover, pulmonary arteriole remodeling, and fibrosis and hypertrophy in the RV were shown in the pulmonary arterial hypertension group; interestingly, fluvoxamine recovered RV structural remodeling (all P < 0.05) but neither alleviated pulmonary arteriole remodeling nor reduced pulmonary artery pressure. Furthermore, S1R activation protects RV function by upgrading the NRF 2/HO 1-mediated antioxidant stress pathway. In conclusion, chronic S1R activation ameliorates structural remodeling and RV dysfunction secondary to pulmonary arterial hypertension without altering pulmonary artery pressure.

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Therapeutic Potential of Regorafenib—A Multikinase Inhibitor in Pulmonary Hypertension

Cited by 6 publications

References 78 publications

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

Regorafenib Attenuates Osteoclasts Differentiation by Inhibiting the NF-κB, NFAT, ERK, and p38 Signaling Pathways

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

Chronic Sigma 1 receptor activation alleviates right ventricular dysfunction secondary to pulmonary arterial hypertension

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