SP-8356, a (1S)-(–)-verbenone derivative, exerts in vitro and in vivo anti-breast cancer effects by inhibiting NF-κB signaling

Mander, Sunam; Kim, Dong Hwi; Nguyen, Huyen Thi; Yong, Hyo Jeong; Pahk, Kisoo; Kim, Eun Yeong; Lee, Kiho; Seong, Jae Young; Kim, Won Ki; Hwang, Jong Ik

doi:10.1038/s41598-019-41224-y

Cited by 16 publications

(24 citation statements)

References 41 publications

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“…Also, (1S,5R)-6,6-dimethyl-4-((E)-4-methylstyryl) bicyclo[3.1.1]hept-3-en-2-one (LMT-335) not only reduced OGD/R-induced injury by decreasing intracellular oxidative/nitrosative stress, it also potently inhibited N-methyl-D-aspartic acid-evoked excitotoxicity in rat cortical neurons [9]. Recently, it has been reported that SP-8356 exerted anti-breast cancer activities both in vitro (cell cycle arrestment and cancer cell migration inhibition) and in vivo (inhibition of tumor growth and metastasis in a mouse xenograft model of triple-negative breast cancer), through regulation of nuclear factor kappa B signaling and metastasis-associated gene expression [10].…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

Zhou

Kim

et al. 2020

Molecules

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(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(−)-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life; after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation; this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low.

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Section: Introductionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

Zhou

Kim

et al. 2020

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“…Secretion of CypA is upregulated by inflammatory stimuli [18] and reactive oxygen species [41]. Accordingly, we propose that the anti-inflammatory and anti-oxidative activities of SP-8356 reported by our group [19,21] are associated with reduction of the CypA level in atheroaclerotic plaques. Recently, elevated CypA levels were reported to have a prognostic impact on all-cause death, coronary revascularization and rehospitalization of patients with coronary artery disease [42].…”

Section: Discussionmentioning

confidence: 66%

“…In addition, we recently found that SP-8356 binds to CD147 and reduces neointimal hyperplasia through inhibition of MMP-9 activity [20]. We also found that SP-8356 has an anti-tumor effect through inhibition of CD147/MMP-9 pathway [21]. In the present study, we further examined whether binding of SP-8356 to CD147 can disrupt its interaction with CypA with consequent suppressive effects on plaque progression.…”

Section: Introductionmentioning

confidence: 71%

“…CD147-CypA interaction can promote nuclear factor kappa B (NF-κB) nuclear translocation thereby upregulating leukocyte adhesion and migration, which eventually leads to accelerating plaque progression [18]. In our previous study, we found that SP-8356 binds to CD147 and inhibits NF-κB nuclear translocation thereby limiting the proliferation rate of breast cancer cells [21]. Thus, the inhibitory effect of SP-8356 on CD147-CypA interaction-evoked NF-κB nuclear translocation may be at least in part involved in the anti-atherosclerotic effect of SP-8356.…”

Section: Discussionmentioning

confidence: 99%

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SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice

Pahk

Joung

Song

et al. 2019

IJMS

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Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6, 6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.Keywords: atherosclerosis; plaque; plaque vulnerability; cluster of differentiation 147 (CD147); matrix metalloproteinase; matrix metalloproteinase-9 (MMP-9) Int.

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“…Recently, we reported that a novel synthetic small-molecule drug SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1] hept-3-en-2-one) directly binds to CD147 thereby inhibiting neointimal hyperplasia and stabilizing plaque vulnerability in animal models through the inhibition of MMP-9 activity [14,15] . Furthermore, we also found that SP-8356 possesses anti-tumor effect through the inhibition of CD147/MMP-9 pathway [16]. In the present study, we studied the inhibitory pharmacological effect of SP-8356 on corneal fibrosis known to be mediated by CD147/MMP-9.…”

Section: Introductionmentioning

confidence: 82%

A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea

Joung

Noh

Jung

et al. 2020

IJMS

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The corneal fibrotic responses to corneal damage often lead to severe corneal opacification thereby resulting in severe visual impairment or even blindness. The persistence of corneal opacity depends heavily on the activity of corneal myofibroblast. Myofibroblasts are opaque and synthesize a disorganized extracellular matrix (ECM) and thus promoting opacification. Cluster of differentiation 147 (CD147), a member of the immunoglobulin superfamily, is known to play important roles in the differentiation process from fibroblast to myofibroblast in damaged cornea and may therefore be an effective target for treatment of corneal opacity. Here, we examined the therapeutic efficacy of novel CD147 inhibiting verbenone derivative SP-8356 ((1S,5R)-4-(3,4dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) on corneal fibrosis. Topical SP-8356 significantly reduced corneal haze and fibrosis in the alkali-burned cornea. In detail, SP-8356 inhibited both alpha-smooth muscle actin (α-SMA) expressing myofibroblast and its ECM-related products, such as matrix-metalloproteinase-9 and collagen type III and IV. Similar to SP-8356, topical corticosteroid (prednisolone acetate, PA) also reduced the ECM-related products and opacification. However, prednisolone acetate failed to decrease the population of α-SMA-positive corneal myofibroblast. In conclusion, SP-8356 is capable enough to prevent corneal haze by preventing pathological fibrosis after severe corneal damage. Therefore, SP-8356 could be a potentially promising therapeutic drug for corneal fibrosis.

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SP-8356, a (1S)-(–)-verbenone derivative, exerts in vitro and in vivo anti-breast cancer effects by inhibiting NF-κB signaling

Cited by 16 publications

References 41 publications

Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice

A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea

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