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1.
iScience ; 27(3): 109256, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38455976

RESUMO

To address the challenge of solid tumor targeting in CAR-T therapy, we utilized the A56 antigen, which is uniquely expressed on a diverse range of cancer cells following the systemic administration of an oncolytic vaccinia virus (OVV). Immunohistochemical assays precisely confirmed exclusive localization of A56 to tumor tissues. In vitro studies demonstrated a distinct superiority of A56-dependent CAR-T cytotoxicity across multiple cancer cell lines. Building on these in vitro observations, we strategically administered A56 CAR-T cells, OVV, and hydroxyurea (HU) combination in HCT-116 tumor-bearing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, leading to a significant reduction in tumor size and an extended time to progression. Consequently, A56-targeting combinatorial immunotherapy provides the benefit of reducing inadvertent CAR-T effects on normal cells while preserving its effectiveness against cancer cells. Furthermore, our approach of implanting A56 via OVV on tumors facilitates a wide therapeutic application of CAR-T cells across various solid tumors.

2.
Korean J Physiol Pharmacol ; 24(4): 299-310, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32587124

RESUMO

Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aß accumulation, GSK-3ß, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased ß-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, ß-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aß1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

3.
Int Immunopharmacol ; 73: 461-470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170675

RESUMO

Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 µM cilostazol and 0.3 µM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 µM) and celecoxib (0.3 µM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1ß levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Celecoxib/uso terapêutico , Cilostazol/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catepsina K/genética , Celecoxib/farmacologia , Cilostazol/farmacologia , Citocinas/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas do Tecido Nervoso/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Células RAW 264.7 , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Superfície Celular/genética
4.
Eur J Pharmacol ; 857: 172454, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202803

RESUMO

Cerebrovascular dysfunction is crucially associated with cognitive impairment and a high prevalence of psychotic symptoms in the vascular dementia characterized by oxidative stress and multifactorial neurodegeneration. In this study, the significant decrease in BDNF expression in HT22 cells due to H2O2 (0.25 mM) was little affected by either aripiprazole (1 µM) or cilostazol (1 µM) alone, but significantly increased by cotreatment with both drugs. Even in the presence of H2O2, P-CK2α (Tyr 255), nuclear P-CREB (Ser 133), and nuclear P-ß-catenin (Ser 675) levels were significantly increased in a synergistic manner by aripiprazole plus cilostazol cotreatment. Aripiprazole and cilostazol cotreatment synergistically increased P-GSK-3ß (Ser 9) level. Nrf2/HO-1 expression was significantly elevated time- and concentration-dependently by either aripiprazole or cilostazol. In line with these, concurrent treatment with aripiprazole (1 µM) plus cilostazol (1 µM) significantly increased Nrf2 and HO-1 expression in a synergistic manner, accompanying with increased ARE luciferase activity, while each drug monotherapy showed little effects. Consequently, this cotreatment synergistically ameliorated the attenuated neurite outgrowth induced by H2O2 in the HT22 cells, and these were inhibited by K252A (inhibitor of BDNF receptor), TBCA (CK2 inhibitor), imatinib (ß-catenin inhibitor) and ZnPP (inhibitor of HO-1), indicating that BDNF, P-CK2α, ß-catenin and HO-1 activation are implicated in the enhanced neurite outgrowth. This study highlights that cotreatment with low concentrations of aripiprazole and cilostazol synergistically elicits neuroprotective effects by overcoming oxidative stress-evoked neurotoxicity associated with increased neurite outgrowth, providing a rationale for the use of this combinatorial treatment in vascular dementia.


Assuntos
Aripiprazol/farmacologia , Cilostazol/farmacologia , Hipocampo/citologia , Fármacos Neuroprotetores/farmacologia , Animais , Caseína Quinase II/metabolismo , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Interações Medicamentosas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/toxicidade , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Fosfoproteínas/metabolismo , beta Catenina/metabolismo
5.
Inflammopharmacology ; 27(6): 1205-1216, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31123968

RESUMO

Cilostazol (an inhibitor of phosphodiesterase type III) has potent anti-inflammatory effects, and celecoxib (a COX-2 specific inhibitor) has been reported to improve the unsatisfactory profile of NSAIDs. This study investigated the synergistic anti-arthritic potential of a multitarget-based cotreatment, in which cilostazol was used as an add-on therapy for celecoxib, using the synovial fibroblasts of RA patients (RASFs). Increased COX-2 protein expression and PGE2 synthesis by LPS (1 µg/ml) were significantly and synergistically attenuated by cotreatment with 3 µM cilostazol and 30 µM celecoxib, whereas monotherapy with either cilostazol or celecoxib showed little effects. IL-10 mRNA levels in LPS-treated RASFs were moderately increased by pretreating cilostazol (1-10 µM) or celecoxib (10-50 µM) monotherapy, but 3 µM of cilostazol add-on for 30 µM celecoxib treatment synergistically increased IL-10 mRNA levels and IL-10 release to culture media. Cilostazol and celecoxib cotreatment similarly showed synergistic increase in SOCS3 mRNA levels. Accordingly, LPS-induced increases in IL-1ß and IL-6 mRNA and TNF-α release were significantly and synergistically diminished by cilostazol and celecoxib cotreatment. Moreover, synovial cell proliferation was significantly suppressed by cotreatment. Summarizing, cotreatment with cilostazol and celecoxib exhibited a synergistic increase in IL-10 production and SOCS3 expressions, thereby resulted in synergistic decreases in IL-1ß mRNA, IL-6 mRNA expression and TNF-α synthesis in association with synergistic decreases in COX-2 and PGE2 protein expression in the RA synovial fibroblasts. In conclusion, these observations suggest low concentrations of cilostazol and celecoxib cotreatment may ensure a synergistic anti-arthritic potential.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Celecoxib/farmacologia , Cilostazol/farmacologia , Citocinas/antagonistas & inibidores , Interleucina-10/biossíntese , Proteína 3 Supressora da Sinalização de Citocinas/biossíntese , Líquido Sinovial/imunologia , Artrite Reumatoide/imunologia , Ciclo-Oxigenase 2/genética , Dinoprostona/biossíntese , Sinergismo Farmacológico , Fibroblastos/imunologia , Humanos , Interleucina-10/genética , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Líquido Sinovial/citologia
6.
Behav Brain Res ; 365: 133-140, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-30851315

RESUMO

Cerebrovascular dysfunction is associated with cognitive impairment in vascular dementia patients. This study aimed to explore augmented improvement of cognition and memory by aripiprazole add-on for cilostazol treatment in vascular dementia model. Male C57BL/6 mice were subjected to BCAS, and spatial probe and memory retention were examined using the Morris water maze (MWM) test. In the present study, the escape latency on the first day after 3rd week was 21.4 ± 4.0 s in sham-operated mice, and 76.3 ± 4.2 s in the vehicle-treated BCAS mice. In the spatial probe tests in the 3rd week, aripiprazole (1 mg/kg/day) showed time-dependently amelioration in spatial learning and memory impairments in contrast to 0.5 mg/kg/day. After treatment with 20 mg/kg/day of cilostazol for 3 weeks, the escape latency significantly decreased to 26.6 ± 5.8 s on the first day and further shortened to 21.6 ± 6.8 s on the fourth day. When the BCAS mice were concurrently treated with 0.5 mg/kg/day aripiprazole plus 20 mg/kg/day of cilostazol for 3 weeks, the escape latency was more shortened from 20.4 ± 1.2 s (1st day) to 14.9 ± 1.7 s on the 4th day of the 3-week trials. Furthermore, decreased spatial memory retention in BCAS mice was significantly alleviated by aripiprazole plus cilostazol cotreatment, indicating the benefit of aripiprazole add-on therapy. In line with these, significantly increased mBDNF and P-CREB levels and reduced apoptosis were identified in the BCAS mouse brain dentate gyrus by cotreatment as contrasted to each monotherapy. These results may provide the synergistic therapeutic avenues for augmented improvement of cognition and memory by cotreatment with aripiprazole plus cilostazol in cases of vascular dementia.


Assuntos
Aripiprazol/farmacologia , Cognição/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Aripiprazol/metabolismo , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Estenose das Carótidas/fisiopatologia , Cilostazol/metabolismo , Cilostazol/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Aprendizagem Espacial/efeitos dos fármacos
7.
Toxicol Appl Pharmacol ; 260(1): 89-94, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22326992

RESUMO

Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways.


Assuntos
Homocisteína/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Homocisteína/administração & dosagem , Macrófagos/metabolismo , Macrófagos Peritoneais/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
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