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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360846

RESUMO

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.


Assuntos
Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Furanos/farmacologia , Fenantrenos/farmacologia , Quinonas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Paclitaxel/farmacologia
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361736

RESUMO

We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert-butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties (tert-butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1ß, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.


Assuntos
COVID-19/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/antagonistas & inibidores , Pirimidinas/farmacologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Animais , COVID-19/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos/imunologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Pirimidinas/química , Síndrome do Desconforto Respiratório/induzido quimicamente , SARS-CoV-2
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360933

RESUMO

Cisplatin is among the most widely used anticancer drugs used in the treatment of several malignancies, including oral cancer. However, cisplatin treatment often promotes chemical resistance, subsequently causing treatment failure. Several studies have shown that epidermal growth factor receptors (EGFRs) play a variety of roles in cancer progression and overcoming cisplatin resistance. Therefore, this study focused on EGFR inhibitors used in novel targeted therapies as a method to overcome this resistance. We herein aimed to determine whether the combined effects of cisplatin and cetuximab could enhance cisplatin sensitivity by inhibiting the epithelial-to-mesenchymal transition (EMT) process in cisplatin-resistant cells. In vitro analyses of three cisplatin-resistant oral squamous cell carcinoma cells, which included cell proliferation assay, combination index calculation, cell cytotoxicity assay, live/dead cell count assay, Western blot assay, propidium iodide staining assay, scratch assay, and qRT-PCR assay were then conducted. Our results showed that a cisplatin/cetuximab combination treatment inhibited cell proliferation, cell motility, and N-cadherin protein expression but induced E-cadherin and claudin-1 protein expression. Although the combination of cisplatin and cetuximab did not induce apoptosis of cisplatin-resistant cells, it may be useful in treating oral cancer patients with cisplatin resistance given that it controls cell motility and EMT-related proteins.


Assuntos
Cetuximab/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Combinação de Medicamentos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos
4.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360994

RESUMO

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Glicina/análogos & derivados , Radiossensibilizantes/farmacologia , Sulfonas/farmacologia , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Glicina/farmacologia , Humanos
5.
Nutrients ; 13(7)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34371964

RESUMO

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.


Assuntos
Alisma , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rizoma , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
FASEB J ; 35(9): e21742, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403506

RESUMO

Withdrawal from contact inhibition is necessary for epithelial cancer precursor cells to initiate cell growth and motility. Nevertheless, little is understood about the mechanism for the sudden initiation of cell growth under static conditions. We focused on cellular junctions as one region where breaking out of contact inhibition occurs. In well-differentiated endometrial cancer cells, Sawano, the ligand administration for tricellular tight junction protein LSR, which transiently decreased the robust junction property, caused an abrupt increase in cell motility and consequent excessive multilayered cell growth despite being under contact inhibition conditions. We observed that macropinocytosis essentially and temporarily occurred as an antecedent event for the above process at intercellular junctions without disruption of the junction apparatus but not at the apical plasma membrane. Collectively, we concluded that the formation of macropinocytosis, which is derived from tight junction-mediated signaling, was triggered for the initiation of cell growth in static precancerous epithelium.


Assuntos
Adesão Celular , Inibição de Contato , Pinocitose , Receptores de Lipoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Toxinas Bacterianas/farmacologia , Sítios de Ligação , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fenótipo , Pinocitose/efeitos dos fármacos , Transporte Proteico , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo
7.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328195

RESUMO

Oral squamous cell carcinoma (OSCC) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with OSCC due to unknown mechanisms. Galectin­3 (Gal­3) is a ß­galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal­3 in cetuximab­resistant (cet­R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal­3 inhibitor was used to treat cet­R tumors, and the tumor volume was monitored. The expression of Gal­3, phosphorylated (p)­ERK1/2 and p­Akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal­3 inhibitor on HSC3 tumor xenografts was also investigated. HSC3 cells were cultured in vitro to investigate the regulatory effects of Gal­3 on ERK1/2 and Akt via western blotting. In addition, the effects of the Gal­3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSC3 cells were investigated by performing Cell Counting Kit­8, colony formation, Transwell and apoptosis assays, respectively. In cet­R OSCC tumors, increased expression of Gal­3, p­ERK1/2 and p­Akt was observed. Further research demonstrated that Gal­3 regulated the expression of both ERK1/2 and Akt in HSC3 cells by promoting phosphorylation. Moreover, the Gal­3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet­R HSC3 cells. In addition, the Gal­3 inhibitor suppressed the growth of cet­R tumors. Collectively, the results indicated that the Gal­3 inhibitor and cetuximab displayed a synergistic inhibitory effect on OSCC tumors. In summary, the present study demonstrated that Gal­3 may serve an important role in cet­R OSCC. The combination of cetuximab and the Gal­3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.


Assuntos
Proteínas Sanguíneas/antagonistas & inibidores , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Galectinas/antagonistas & inibidores , Neoplasias Bucais/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Sanguíneas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Galectinas/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Arterioscler Thromb Vasc Biol ; 41(9): 2469-2482, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34320834

RESUMO

Objective: Critical limb ischemia is a major complication of diabetes characterized by insufficient collateral vessel development and proper growth factor signaling unresponsiveness. Although mainly deactivated by hypoxia, phosphatases are important players in the deregulation of proangiogenetic pathways. Previously, SHP-1 (Scr homology 2-containing phosphatase-1) was found to be associated with the downregulation of growth factor actions in the diabetic muscle. Thus, we aimed to gain further understanding of the impact of SHP-1 on smooth muscle cell (SMC) function under hypoxic and diabetic conditions. Approach and Results: Despite being inactivated under hypoxic conditions, high glucose level exposure sustained SHP-1 phosphatase activity in SMC and increased its interaction with PDGFR (platelet-derived growth factor receptor)-ß, thus reducing PDGF proangiogenic actions. Overexpression of an inactive form of SHP-1 fully restored PDGF-induced proliferation, migration, and signaling pathways in SMC exposed to high glucose and hypoxia. Nondiabetic and diabetic mice with deletion of SHP-1 specifically in SMC were generated. Ligation of the femoral artery was performed, and blood flow was measured for 4 weeks. Blood flow reperfusion, vascular density and maturation, and limb survival were all improved while vascular apoptosis was attenuated in diabetic SMC-specific SHP-1 null mice as compared to diabetic mice. Conclusions: Diabetes and high glucose level exposure maintained SHP-1 activity preventing hypoxia-induced PDGF actions in SMC. Specific deletion of SHP-1 in SMC partially restored blood flow reperfusion in the diabetic ischemic limb. Therefore, local modulation of SHP-1 activity in SMC could represent a potential therapeutic avenue to improve the proangiogenic properties of SMC under ischemia and diabetes.


Assuntos
Indutores da Angiogênese/farmacologia , Diabetes Mellitus Experimental/enzimologia , Angiopatias Diabéticas/enzimologia , Membro Posterior/irrigação sanguínea , Isquemia/enzimologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Animais , Glicemia/metabolismo , Estudos de Casos e Controles , Bovinos , Hipóxia Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/fisiopatologia , Ativação Enzimática , Humanos , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Transdução de Sinais
9.
ACS Appl Mater Interfaces ; 13(30): 35431-35443, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34304556

RESUMO

Stent implantation is the primary method used to treat coronary heart disease. However, it is associated with complications such as restenosis and late thrombosis. Despite surface modification being an effective way to improve the biocompatibility of stents, the current research studies are not focused on changes in the vascular microenvironment at the implantation site. In the present study, an adaptive drug-loaded coating was constructed on the surface of vascular stent materials that can respond to oxidative stress at the site of vascular lesions. Two functional molecules, epigallocatechin gallate (EGCG) and cysteine hydrochloride, were employed to fabricate a coating on the surface of 316L stainless steel. In addition, the coating was used as a drug carrier to load pitavastatin calcium. EGCG has antioxidant activity, and pitavastatin calcium can inhibit smooth muscle cell proliferation. Therefore, EGCG and pitavastatin calcium provided a synergistic anti-inflammatory effect. Moreover, the coating was cross-linked using disulfide bonds, which accelerated the release of the drug in response to reactive oxygen species. A positive correlation was observed between the rate of drug release and the degree of oxidative stress. Collectively, this drug-loaded oxidative stress-responsive coating has been demonstrated to significantly inhibit inflammation, accelerate endothelialization, and reduce the risk of restenosis of vascular stents in vivo.


Assuntos
Stents Farmacológicos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Reestenose Coronária/prevenção & controle , Cistamina/administração & dosagem , Cistamina/química , Liberação Controlada de Fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacologia , Coelhos , Ratos Sprague-Dawley , Aço Inoxidável/química
10.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210094

RESUMO

Cigarette smoking (CS) is one of the main factors related to avoidable diseases and death across the world. Cigarette smoke consists of numerous toxic compounds that contribute to the development of osteoporosis and fracture nonunion. Exposure to pulsed electromagnetic fields (PEMF) was proven to be a safe and effective therapy to support bone fracture healing. The aims of this study were to investigate if extremely low frequency (ELF-) PEMFs may be beneficial to treat CS-related bone disease, and which effect the duration of the exposure has. In this study, immortalized human mesenchymal stem cells (SCP-1 cells) impaired by 5% cigarette smoke extract (CSE) were exposed to ELF-PEMFs (16 Hz) with daily exposure ranging from 7 min to 90 min. Cell viability, adhesion, and spreading were evaluated by Sulforhodamine B, Calcein-AM staining, and Phalloidin-TRITC/Hoechst 33342 staining. A migration assay kit was used to determine cell migration. Changes in TGF-ß signaling were evaluated with an adenoviral Smad2/3 reporter assay, RT-PCR, and Western blot. The structure and distribution of primary cilia were analyzed with immunofluorescent staining. Our data indicate that 30 min daily exposure to a specific ELF-PEMF most effectively promoted cell viability, enhanced cell adhesion and spreading, accelerated migration, and protected TGF-ß signaling from CSE-induced harm. In summary, the current results provide evidence that ELF-PEMF can be used to support early bone healing in patients who smoke.


Assuntos
Cílios/metabolismo , Células-Tronco Mesenquimais/citologia , Fumaça/efeitos adversos , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cílios/efeitos dos fármacos , Cílios/imunologia , Campos Eletromagnéticos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais/efeitos dos fármacos , Tabaco
11.
Nat Commun ; 12(1): 4310, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262026

RESUMO

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Fotoquimioterapia/métodos , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/química , Indóis/farmacologia , Raios Infravermelhos , Macrófagos/química , Nanomedicina , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxaliplatina/administração & dosagem , Oxaliplatina/química , Oxaliplatina/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia
12.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209825

RESUMO

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC50 reduced by a half, induction of apoptotic effect, and improved ROS production (from 67 to 134%) at low concentrations. Nanoparticles guaranteed a pH-dependent DOXO release, with a more efficient release in acidic environments. Finally, a synergistic effect between nanoparticles and Doxorubicin was demonstrated, with the free curcumin showing additive activity. Although in vivo studies are required to support the findings of this study, these preliminary in vitro data can be considered a proof of principle for the design of an effective therapy for prostate cancer treatment.


Assuntos
Curcumina/farmacologia , Dextranos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Próstata/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Curcumina/administração & dosagem , Dextranos/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Nanopartículas , Células PC-3
13.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281166

RESUMO

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Oligopeptídeos/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cetuximab/farmacologia , Neoplasias Colorretais/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Oligopeptídeos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resposta a Proteínas não Dobradas/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204367

RESUMO

The constitutive expression or overactivation of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes results in aberrant metabolism of arachidonic acid and poor prognosis in melanoma. Our aim is to compare the in vitro effects of selective COX-1 (acetylsalicylic acid), COX-2 (meloxicam), 5-LOX (MK-886 and AA-861), 12-LOX (baicalein) and 15-LOX (PD-146176) inhibition in terms of proliferation (SRB assay), mitochondrial viability (MTT assay), caspase 3-7 activity (chemiluminescent assay), 2D antimigratory (scratch assay) and synthesis of eicosanoids (EIA) in the B16F10 cell line (single treatments). We also explore their combinatorial pharmacological space with dacarbazine and temozolomide (median effect method). Overall, our results with single treatments show a superior cytotoxic efficacy of selective LOX inhibitors over selective COX inhibitors against B16F10 cells. PD-146176 caused the strongest antiproliferation effect which was accompanied by cell cycle arrest in G1 phase and an >50-fold increase in caspases 3/7 activity. When the selected inhibitors are combined with the antineoplastic drugs, only meloxicam provides clear synergy, with LOX inhibitors mostly antagonizing. These apparent contradictions between single and combination treatments, together with some paradoxical effects observed in the biosynthesis of eicosanoids after FLAP inhibition in short term incubations, warrant further mechanistical in vitro and in vivo scrutiny.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase/química , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores de Lipoxigenase/química , Melanoma Experimental , Camundongos , Estrutura Molecular , Temozolomida/farmacologia
15.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34206998

RESUMO

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Serotonina/farmacologia , Animais , Carragenina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7
16.
Cell Prolif ; 54(8): e13087, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34255393

RESUMO

OBJECTIVES: Histatin 1(Hst 1) has been proved to promote wound healing. However, there was no specific study on the regulation made by Hst 1 of fibroblasts in the process of wound healing. This research comprehensively studied the regulation of Hst 1 on the function of fibroblasts in the process of wound healing and preliminary mechanism about it. MATERIALS AND METHODS: The full-thickness skin wound model was made on the back of C57/BL6 mice. The wound healing, collagen deposition and fibroblast distribution were detected on days 3, 5 and 7 after injury. Fibroblast was cultured in vitro and stimulated with Hst 1, and then, their biological characteristics and functions were detected. RESULTS: Histatin 1 can effectively promote wound healing, improve collagen deposition during and after healing and increase the number and function of fibroblasts. After healing, the mechanical properties of the skin also improved. In vitro, the migration ability of fibroblasts stimulated by Hst 1 was significantly improved, and the fibroblasts transformed more into myofibroblasts, which improved the function of contraction and collagen secretion. In fibroblasts, mTOR signalling pathway can be activated by Hst 1. CONCLUSIONS: Histatin 1 can accelerate wound healing and improve the mechanical properties of healed skin by promoting the function of fibroblasts. The intermolecular mechanisms need to be further studied, and this study provides a direction about mTOR signalling pathway.


Assuntos
Histatinas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Colágeno/metabolismo , Módulo de Elasticidade , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/transplante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Serina-Treonina Quinases TOR/metabolismo
17.
Chem Biol Interact ; 346: 109580, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280354

RESUMO

Dichloromethane (DCM), a widely used chlorinated solvent, is classified by IARC (2017) as probably carcinogenic to humans. Exposure to DCM has been associated with increased incidence of cholangiocarcinoma (CCA) in humans. This study aimed to investigate how DCM could contribute to CCA development by investigating the effects of DCM on DNA damage and cell transformation in cholangiocytes (MMNK-1) and on metastatic potential as measured by invasion and cell migration in malignant CCA cell lines (HuCCA-1 and RMCCA-1). MMNK-1 cells treated with the non-cytotoxic concentration of DCM (25 µM, 24 h) significantly increased the levels of mutagenic DNA adducts including 8-hydroxydeoxyguanosine, 8-OHdG, (1.84-fold, p < 0.01) and 8-nitroguanine (1.96-fold, p < 0.01) and enhanced cell transformation by 1.47-fold (p < 0.01). In addition, the expression of various genes involved in carcinogenesis, namely, NFE2L2 (antioxidative response), CXCL8 (inflammation), CDH1 (cell adhesion), MMP9 (tissue remodeling) and MKI67 (cell proliferation) were altered in cholangiocytes treated with DCM. When MMNK-1 cells were transformed by DCM, the expression of all the aforementioned genes was also increased. In malignant cell lines (HuCCA-1 and RMCCA-1), DCM treatment resulted in increased CXCL8 and MMP9 transcription and decreased CDH1 transcription accompanied by increased invasion and migration capabilities of these cells. Taken together, this study demonstrated that DCM exposure could be linked to the development of CCA.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Cloreto de Metileno/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Adutos de DNA/análise , Adutos de DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Cloreto de Metileno/química , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo
18.
Int J Biol Macromol ; 185: 592-603, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216661

RESUMO

This paper presents a new thermal sensitive hydrogel system based on cystamine-functionalised sodium alginate-g-pluronic F127 (ACP). The introduction of cystamine to the alginate backbone not only creates a covalent bond with pluronic F127 but also provides intrinsic anti-bacterial activity for the resultant hydrogel. The amount of water uptake inside the hydrogel remained ~200% for 6 days and the degradation was completed in 12 days in physiological media. The ACP copolymer solution could form a hydrogel at body temperature (~37 °C) and could return to the solution phase if the temperature decreased below 25o °C. Fibroblast encapsulated in situ in the ACP hydrogel maintained their viability (≥90% based on the live/dead assay) for 7 days, demonstrating the good biocompatibility of the ACP hydrogel for long-term cell cultivation. In addition, three-dimensional (3D) culture showed that fibroblast attached to the hydrogels and successfully mimicked the porous structure of the ACP hydrogel after 5 days of culture. Fibroblast cells could migrate from the cell-ACP clusters and form a confluent cell layer on the surface of the culture dish. Altogether, the obtained results indicate that the thermal-responsive ACP hydrogel synthesised in this study may serve as a cellular delivery platform for diverse tissue engineering applications.


Assuntos
Alginatos/farmacologia , Antibacterianos/farmacologia , Cistamina/química , Poloxâmero/química , Alginatos/química , Antibacterianos/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hidrogéis/química , Injeções , Termodinâmica , Engenharia Tecidual
19.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281292

RESUMO

Cancer is one of the deadliest illness globally. Searching for new solutions in cancer treatments is essential because commonly used mixed, targeted and personalized therapies are sometimes not sufficient or are too expensive for common patients. Sugar fatty acid esters (SFAEs) are already well-known as promising candidates for an alternative medical tool. The manuscript brings the reader closer to methods of obtaining various SFAEs using combined biological, chemical and enzymatic methods. It presents how modification of SFAE's hydrophobic chains can influence their cytotoxicity against human skin melanoma and prostate cancer cell lines. The compound's cytotoxicity was determined by an MTT assay, which followed an assessment of SFAEs' potential metastatic properties in concentrations below IC50 values. Despite relatively high IC50 values (63.3-1737.6 µM) of the newly synthesized SFAE, they can compete with other sugar esters already described in the literature. The chosen bioactives caused low polymerization of microtubules and the depolymerization of actin filaments in nontoxic levels, which suggest an apoptotic rather than metastatic process. Altogether, cancer cells showed no propensity for metastasis after treating them with SFAE. They confirmed that lactose-based compounds seem the most promising surfactants among tested sugar esters. This manuscript creates a benchmark for creation of novel anticancer agents based on 3-hydroxylated fatty acids of bacterial origin.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Poli-Hidroxialcanoatos/química , Poli-Hidroxialcanoatos/farmacologia , Açúcares/química , Açúcares/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/química , Ésteres/farmacologia , Feminino , Humanos , Filamentos Intermediários/efeitos dos fármacos , Filamentos Intermediários/ultraestrutura , Masculino , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206484

RESUMO

Triple-negative breast cancer (TNBC) presents an important clinical challenge, as it does not respond to endocrine therapies or other available targeting agents. FOXM1, an oncogenic transcriptional factor, has reported to be upregulated and associated with poor clinical outcomes in TNBC patients. In this study, we investigated the anti-cancer effects of FDI-6, a FOXM1 inhibitor, as well as its molecular mechanisms, in TNBC cells. Two TNBC cell lines, MDA-MB-231 and HS578T, were used in this study. The anti-cancer activities of FDI-6 were evaluated using various 2D cell culture assays, including Sulforhodamine B (SRB), wound healing, and transwell invasion assays together with 3D spheroid assays, mimicking real tumour structural properties. After treatment with FDI-6, the TNBC cells displayed a significant inhibition in cell proliferation, migration, and invasion. Increased apoptosis was also observed in the treated cells. In addition, we found that FDI-6 lead to the downregulation of FOXM1 and its key oncogenic targets, including CyclinB1, Snail, and Slug. Interestingly, we also found that the FDI-6/Doxorubicin combination significantly enhanced the cytotoxicity and apoptotic properties, suggesting that FDI-6 might improve chemotherapy treatment efficacy and reduce unwanted side effects. Altogether, FDI-6 exhibited promising anti-tumour activities and could be developed as a newly effective treatment for TNBC.


Assuntos
Antineoplásicos/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Piridinas/farmacologia , Tiofenos/farmacologia , Antineoplásicos/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/química , Tiofenos/química , Neoplasias de Mama Triplo Negativas/metabolismo
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