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1.
Biochim Biophys Acta Gen Subj ; 1868(9): 130650, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38830560

RESUMO

Glioblastoma (GBM), a highly aggressive malignant tumor of the central nervous system, is mainly treated with radiotherapy. However, since irradiation may lead to the acquisition of migration ability by cancer cells, thereby promoting tumor metastasis and invasion, it is important to understand the mechanism of cell migration enhancement in order to prevent recurrence of GBM. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor activated by high mobility group box 1 (HMGB1). In this study, we found that RAGE plays a role in the enhancement of cell migration by γ-irradiation in human GBM A172 cells. γ-Irradiation induced actin remodeling, a marker of motility acquisition, and enhancement of cell migration in A172 cells. Both phenotypes were suppressed by specific inhibitors of RAGE (FPS-ZM1 and TTP488) or by knockdown of RAGE. The HMGB1 inhibitor ethyl pyruvate similarly suppressed γ-irradiation-induced enhancement of cell migration. In addition, γ-irradiation-induced phosphorylation of STAT3 was suppressed by RAGE inhibitors, and a STAT3 inhibitor suppressed γ-irradiation-induced enhancement of cell migration, indicating that STAT3 is involved in the migration enhancement downstream of RAGE. Our results suggest that HMGB1-RAGE-STAT3 signaling is involved in radiation-induced enhancement of GBM cell migration, and may contribute to GBM recurrence by promoting metastasis and invasion.

2.
Nat Commun ; 14(1): 8095, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38092728

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.


Assuntos
Carcinoma Neuroendócrino , Niacina , Masculino , Camundongos , Animais , Nicotinamida Fosforribosiltransferase/metabolismo , Niacina/farmacologia , Niacina/metabolismo , NAD/metabolismo , Citocinas/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Linhagem Celular Tumoral
3.
In Vivo ; 37(6): 2464-2472, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37905640

RESUMO

BACKGROUND/AIM: The COVID-19 pandemic led to the rapid spread of the use of ultraviolet C (UVC) sterilizers in many public facilities. Considering the harmful effects of prolonged exposure to UVC, manufacturing of safe skin care products is an important countermeasure. In continuation of our recent study of water-soluble herbal extracts, the present study aimed at searching for anti-UVC components from fat-soluble herbal extracts. MATERIALS AND METHODS: Human dermal fibroblast and melanoma cells were exposed to UVC (1.193 W/m2) for 3 min. Viable cell number was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell-cycle analysis was performed using a cell sorter. UVC-protective activity was quantified by the selective index (SI), i.e., the ratio of the 50% cytotoxic concentration for unirradiated cells to the concentration that restored viability of UVC-treated cells by 50%. RESULTS: Only lemongrass extract, among 12 fat-soluble herbal extracts, showed significant anti-UVC activity, comparable to that of lignified materials and tannins, but exceeding that of N-acetyl-L-cysteine and resveratrol. Lemongrass extract was highly cytotoxic, producing a subG1 cell population. During prolonged incubation in culture medium, the anti-UVC activity of lemongrass extract, sodium ascorbate and vanillic acid declined with an approximate half-life of <0.7, 5.4-21.6, and 27.8-87.0 h, respectively. CONCLUSION: Removal of cytotoxic principle(s) from lemongrass extract is crucial to producing long-lasting UVC-protective effects.


Assuntos
Cymbopogon , Extratos Vegetais , Humanos , Extratos Vegetais/farmacologia , Pandemias , Pele , Raios Ultravioleta/efeitos adversos
4.
Anticancer Res ; 43(8): 3429-3439, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37500171

RESUMO

BACKGROUND/AIM: Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT. MATERIALS AND METHODS: The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis. RESULTS: Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G2/M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG1 arrest, in a synergistic fashion. CONCLUSION: The combination G2/M blockers and mild-HT can potentially be used for the treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas , Hipertermia Induzida , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Apoptose , Neoplasias Bucais/tratamento farmacológico , Docetaxel/farmacologia , Docetaxel/uso terapêutico
5.
Medicines (Basel) ; 10(7)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37505064

RESUMO

Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

6.
In Vivo ; 37(4): 1540-1551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37369486

RESUMO

BACKGROUND/AIM: COVID-19 pandemic caused the rapid dissemination of ultraviolet C (UVC) sterilization apparatuses. Prolonged exposure to UVC, however, may exert harmful effects on the human body. The aim of the present study was to comprehensively investigate the anti-UVC activity of a total of 108 hot-water soluble herb extracts, using human dermal fibroblast and melanoma cell lines, for the future development of skin care products. MATERIALS AND METHODS: Exposure time to UVC was set to 3 min, and cell viability was determined using the MTT assay. Anti-UVC activity was determined using the selective index (SI), a ratio of 50% cytotoxic concentration for unirradiated cells to 50% effective concentration that restored half of the UVC-induced decrease of viability. RESULTS: Dermal fibroblasts at any population doubling level were more resistant to UVC irradiation than melanoma cells. Both 49 herb extracts recommended by Japan Medical Herb Association (JAMHA) and 59 additional herb extracts showed comparable anti-UVC activity. SI values of selected herbs (Butterbur, Cloves, Curry Tree, Evening Primrose, Rooibos, Stevia, Willow) were several-fold lower than those of vitamin C and vanillin. Their potent anti-UVC activity was maintained for at least 6 h post irradiation, but declined thereafter to the basal level, possibly due to cytotoxic ingredients. CONCLUSION: UVC sensitivity may be related to the growth potential of target cells. Removal of cytotoxic ingredients of herb extracts may further potentiate and prolong their anti-UVC activity.


Assuntos
COVID-19 , Melanoma , Humanos , Pandemias , Linhagem Celular , Pele , Raios Ultravioleta/efeitos adversos , Melanoma/tratamento farmacológico , Extratos Vegetais/farmacologia
7.
In Vivo ; 36(6): 2689-2699, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36309360

RESUMO

BACKGROUND/AIM: The rapid spread of COVID-19 resulted in the revision of the value of ultraviolet C (UVC) sterilization in working spaces. This study aimed at re-evaluating the anti-UVC activity of four groups of natural products against human melanoma COLO679 and human normal dermal fibroblast (HDFa) cells, based on chemotherapeutic index. MATERIALS AND METHODS: Various cell lines were exposed to UVC for 3 min in the presence of increasing concentrations of test compounds and viable cell numbers were determined with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The anti-UVC activity was quantified by the ratio of the 50% cytotoxic concentration (determined without irradiation) to the 50% effective concentration (which abolished by 50% the UVC-induced loss of viability). Apoptosis was quantified as the subG1 population proportion following cell-cycle analysis. RESULTS: Among four groups of major natural products, six phenylpropanoids showed the highest anti-UVC activity, followed by the lignified products and alkaline products that contain lignin and its degradation products. On the other hand, tannins and flavonoids showed lower activity due to their higher cytotoxicity. UVC-sensitive COLO679 cells lack dectin-1 protein expression. CONCLUSION: These data suggest the prominent anti-UVC activity of lignin degradation products, and the possible involvement of dectin-1 expression in UVC-sensitivity.


Assuntos
Produtos Biológicos , COVID-19 , Melanoma , Humanos , Lignina/farmacologia , Raios Ultravioleta , Produtos Biológicos/farmacologia
8.
Food Sci Nutr ; 10(5): 1461-1468, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35592293

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease with accompanying perceptive disorder. We previously reported that decreasing levels of brain-derived neurotrophic factor (BDNF) promoted beta-amyloid (Aß)-induced neuronal cell death in neuron-like differentiated SH-SY5Y (ndSH-SY5Y) human neuroblastoma cells in an AD mimic cell model. We investigated the neuroprotective effects of passion fruit seed extract (PFSE) and one of the main stilbene compounds, piceatannol, in an AD cell model using ndSH-SY5Y cells. Both PFSE and piceatannol were found to protect Aß-induced neurite fragmentation in the cell model (protection efficacy; 34% in PFSE and 36% in piceatannol). In addition, both PFSE and piceatannol suppress Aß-induced neuronal cell death in the cell model (inhibitory effect; 27% in PFSE and 32% in piceatannol). Our study is the first to report that piceatannol-rich PFSE can repress Aß-induced neuronal cell death by protecting against neurite fragmentation in the AD human cell model. These findings suggest that piceatannol-rich PFSE can be considered a potentially neuroprotective functional food for both prevention and treatment of AD.

9.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408786

RESUMO

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)-receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.


Assuntos
Neoplasias do Colo , Proteína HMGB1 , Anti-Inflamatórios/farmacologia , Neoplasias do Colo/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína HMGB1/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Microambiente Tumoral
10.
Biochimie ; 192: 13-21, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34536557

RESUMO

Tyrosinase (TYR) is a key enzyme for melanin production. We previously showed that hinokitiol, a naturally occurring seven-membered ring terpenoid, potently inhibits human TYR activity. Interestingly, hinokitiol was recently reported to decrease expression of TYR and microphthalmia-associated transcription factor (MITF), which is a main transcription factor of the TYR gene, in murine melanoma cells. However, the mechanisms by which hinokitiol decreases the intracellular levels of TYR and MITF have not been fully elucidated. Here, we investigated the underlying mechanisms of the decreases using cultured human melanoma cells. As a result, hinokitiol treatment decreased TYR protein level in a time- and dose-dependent manner in G361 human melanoma cells, while MITF protein level was decreased only at higher concentrations after 3 days treatment. Notably, the mRNA levels of TYR and MITF were slightly increased by hinokitiol treatment. Therefore, we focused on the degradation of TYR and MITF in endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Importantly, co-treatment of ERAD inhibitor with hinokitiol restored the protein levels of TYR and MITF to approximately 30% and 20% of total those in untreated control cells, respectively. Hinokitiol affected the ER homeostasis as well as degradation of TYR and MITF in two human melanoma cell lines, G361 and HT-144, but the changes of ER-stress markers under the hinokitiol treatment were different in the two human melanoma cell lines. Taken together, these observations indicate that hinokitiol may induce ER stress and trigger the degradation of unfolded newly synthesizing TYR and MITF via the ERAD pathway.


Assuntos
Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Melanoma/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Monoterpenos/farmacologia , Proteínas de Neoplasias/metabolismo , Tropolona/análogos & derivados , Linhagem Celular Tumoral , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Tropolona/farmacologia
11.
Anticancer Res ; 41(12): 5959-5971, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34848450

RESUMO

BACKGROUND/AIM: We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs). MATERIALS AND METHODS: Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1high cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined. RESULTS: GLO 1high, PKCλhigh, and ALDH1A3high tumors were enriched in stage I/II/III/IV samples, associated with the HER2 and TNBC subtypes according to receptor status, and associated with the HER2-enriched and basal-like subtypes according to PAM50. Inhibition of either GLO 1 (TLSC702) or PKCλ (ANF) suppressed tumor-sphere formation and enhanced death in ALDH1high cells. TLSC702 also effectively inhibited tumor-sphere formation and induced death in PKCλ knockout ALDH1high cells. CONCLUSION: GLO 1 and PKCλ are important for the survival of ALDH1-positive breast CSCs, and may represent potential therapeutic targets for the treatment of ALDH1-positive breast CSCs.


Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Neoplasias da Mama/metabolismo , Isoenzimas/metabolismo , Lactoilglutationa Liase/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteína Quinase C/metabolismo , Família Aldeído Desidrogenase 1/genética , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologia , Transcriptoma
12.
Arch Biochem Biophys ; 711: 109029, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34517011

RESUMO

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.


Assuntos
Anti-Inflamatórios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores Toll-Like/metabolismo , Trimebutina/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Quimiocinas/metabolismo , Feminino , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Receptor para Produtos Finais de Glicação Avançada/deficiência , Receptor para Produtos Finais de Glicação Avançada/genética , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Trimebutina/uso terapêutico
13.
Medicines (Basel) ; 8(6)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199423

RESUMO

Background: ß-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were used to investigate whether ß-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of ß-thujaplicin on X-linked inhibitor of apoptosis protein (XIAP) in NCI-H460 cells and a fluorescence polarization binding assay was used to evaluate the binding-inhibitory activity of ß-thujaplicin against XIAP-BIR3. Results: ß- and γ-thujaplicins decreased the viability of NCI-H460 cells in a dose-dependent manner; they also sensitized the cells to TRAIL-induced cell growth inhibition and apoptosis. ß-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, ß-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, ß-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site. Conclusions: These findings indicate that ß-thujaplicin could enhance TRAIL-induced apoptosis in NCI-H460 cells via XIAP inhibition and degradation. Thus, the tropolone scaffold may be useful for designing novel nonpeptidic small-molecule inhibitors of XIAP and developing new types of anticancer drugs.

14.
Oncol Lett ; 22(1): 547, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34093768

RESUMO

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III-IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08-5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.

15.
Medicines (Basel) ; 8(4)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805209

RESUMO

Background: High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Methods: Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4' position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.

16.
Bioorg Med Chem Lett ; 40: 127918, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711442

RESUMO

Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability.


Assuntos
Butiratos/química , Inibidores Enzimáticos/química , Lactoilglutationa Liase/antagonistas & inibidores , Tiazóis/química , Apoptose/efeitos dos fármacos , Benzeno/química , Butiratos/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Glutationa/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ligação Proteica , Aldeído Pirúvico/química , Relação Estrutura-Atividade , Tiazóis/metabolismo
17.
Biochem Biophys Res Commun ; 533(4): 1155-1161, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33041002

RESUMO

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.


Assuntos
Proteína HMGB1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Trimebutina/farmacologia , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Janus Quinases/antagonistas & inibidores , Macrófagos , Camundongos , Papaverina/química , Papaverina/farmacologia , Células RAW 264.7 , Trimebutina/química , Fator de Necrose Tumoral alfa/metabolismo
18.
Molecules ; 25(16)2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32785052

RESUMO

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole-piperidine (3a)- and azaindole-piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Indóis/química , Cinética , Simulação de Acoplamento Molecular , Nicotinamida Fosforribosiltransferase/metabolismo , Piperazina/química , Piperidinas/química
19.
Biol Pharm Bull ; 43(7): 1073-1080, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612070

RESUMO

Alzheimer's disease (AD) is pathologically characterized by accumulation of amyloid ß (Aß) and hyperphosphorylated tau, and thereby induction of neuronal cell death. The Aß-induced neuronal cell death has been shown to occur by several modes, such as apoptosis, necrosis, and necroptosis. Interestingly, in AD patients, the brain and serum levels of brain-derived neurotrophic factor (BDNF) have been reported to be significantly decreased. However, the relationship between Aß and BDNF in the onset of AD remains to be fully understood. Here, we used neuron-like differentiated human neuroblastoma SH-SY5Y (ndSH-SY5Y) cells to study the neurotoxicity of self-aggregated Aß1-42 peptide under different concentrations of BDNF in the culture medium. Importantly, decreasing levels of BDNF caused a considerable suppression in the extension of neurite length. Furthermore, only under low levels of BDNF, the aggregated Aß was revealed to induce neurite fragmentation and neuronal cell death in ndSH-SY5Y cells. Notably, the aggregated Aß and low levels of BDNF-induced neuronal cell death was characterized at least as caspase-6 dependent cell death and necroptosis. These results indicate that our ndSH-SY5Y cell system, cultured under decreasing levels of BDNF and aggregated Aß, has the potential to be applied in the analysis of the molecular mechanisms of the progressive neurodegenerative processes of AD and the discovery of neuroprotective drug candidates.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neurônios/metabolismo , Agregação Patológica de Proteínas/metabolismo , Doença de Alzheimer/patologia , Morte Celular , Linhagem Celular Tumoral , Humanos , Modelos Biológicos , Neurônios/patologia
20.
Oncol Rep ; 44(1): 283-292, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32377740

RESUMO

trans­Resveratrol (Rsv) is a natural compound contained in red wine and grape skins that has various beneficial effects for organisms such as lengthening of their life span. Rsv induces expression of the human TP53 and HELB genes, which are involved in the regulation of DNA maintenance. In the present study, a luciferase expression vector containing 309 bp of the 5' upstream end of the human MCM4 gene was transfected into HeLa S3 cells. A luciferase assay revealed that Rsv treatment increased the minichromosome maintenance 4 (MCM4) gene promoter activity by GC­box and GGAA (TTCC) motifs. Electro phoretic mobility shift assay revealed that the specific binding factor (complex) contains PU.1 (SPI1). Quantitative reverse transcription­polymerase chain reaction analysis indicated that MCM4 gene expression was transiently induced by Rsv. Moreover, western blotting revealed that the SP1/PU.1 ratio markedly increased after Rsv treatment, indicating that a balance or profile of these transcription factors may control Rsv­inducible initiation of transcription. These observations indicated that the beneficial effects of Rsv can be attributed to induction of the chromosomal DNA maintenance factor encoding gene expression.


Assuntos
Componente 4 do Complexo de Manutenção de Minicromossomo/genética , Proteínas Proto-Oncogênicas/metabolismo , Resveratrol/farmacologia , Transativadores/metabolismo , Linhagem Celular Tumoral , Células HL-60 , Humanos , Componente 4 do Complexo de Manutenção de Minicromossomo/metabolismo , Regiões Promotoras Genéticas , Transcrição Gênica/efeitos dos fármacos , Transfecção
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