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1.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361085

RESUMO

A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure-activity relationship of sclerostin inhibitors for rational drug design.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Aptâmeros de Nucleotídeos/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Aptâmeros de Nucleotídeos/isolamento & purificação , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , Osteoporose/metabolismo , Osteoporose/patologia
2.
Biomed Res Int ; 2021: 5552226, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763472

RESUMO

Background: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in the world. Despite advances in surgical resection, radiotherapy, and chemotherapy, GBM continues to have a poor overall survival. CDDO (2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid), a synthetic triterpenoid, is an Nrf2 activator used to inhibit proliferation and induce differentiation and apoptosis in various cancer cells. One new trifluoroethylamide derivative of CDDO, RTA 404, has been found to have increased ability to cross the blood-brain barrier. However, it is not clear what effect it may have on tumorigenesis in GBM. Methods: This in vitro study evaluated the effects of RTA 404 on GBM cells. To do this, we treated GBM840 and U87 MG cell lines with RTA 404 and assessed apoptosis, cell cycle, cell locomotion, and senescence. DNA content and induction of apoptosis were analyzed by flow cytometry and protein expression by Western blot analysis. Results: RTA 404 significantly inhibited the proliferation of tumor cells at concentrations higher than 100 nM (p < 0.05) and reduced their locomotion ability. In addition, treatment with RTA 404 led to an accumulation of RTA 404-treated G 2/M phase cells and apoptosis. An analysis of the p21/AKT expression suggested that RTA 404 may not only help prevent brain cancer but it may also exert antitumor activities in established GBM cells. Conclusion: RTA404 can inhibit proliferation, cell locomotion, cell cycle progression, and induce apoptosis in GBM cells in vitro, possibly through its inhibition of N-cadherin and E-cadherin expression via its inhibition of the AKT pathway.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Glioma , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Humanos
3.
J Med Food ; 22(5): 444-450, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084542

RESUMO

Studies have identified the potential of chemopreventive effects of sulforaphane (SFN); however, the underlying mechanisms of its effect on breast cancer require further elucidation. This study investigated the anticancer effects of SFN that specifically induces G1/S arrest in breast ductal carcinoma (ZR-75-1) cells. The proliferation of the cancer cells after treatment with SFN was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA content and cell cycle status were analyzed through flow cytometry. Our results demonstrated the inhibition of growth in ZR-75-1 cells upon SFN exposure. In addition, SERTAD1 (SEI-1) caused the accumulation of SFN-treated G1/S-phase cells. The downregulation of SEI-1, cyclin D2, and histone deacetylase 3 suggested that in addition to the identified effects of SFN against breast cancer prevention, it may also exert antitumor activities in established breast cancer cells. In conclusion, SFN can inhibit growth of and induce cell cycle arrest in cancer cells, suggesting its potential role as an anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Proteínas Nucleares/genética , Transativadores/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D2/genética , Ciclina D2/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição , Verduras/química
4.
J Cell Mol Med ; 23(5): 3512-3519, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30912292

RESUMO

Cucurbitacin E (CuE), an active compound of the cucurbitacin family, possesses a variety of pharmacological functions and chemotherapy potential. Cucurbitacin E exhibits inhibitory effects in several types of cancer; however, its anticancer effects on brain cancer remain obscure and require further interpretation. In this study, efforts were initiated to inspect whether CuE can contribute to anti-proliferation in human brain malignant glioma GBM 8401 cells and glioblastoma-astrocytoma U-87-MG cells. An MTT assay measured CuE's inhibitory effect on the growth of glioblastomas (GBMs). A flow cytometry approach was used for the assessment of DNA content and cell cycle analysis. DNA damage 45ß (GADD45ß) gene expression and CDC2/cyclin-B1 disassociation were investigated by quantitative real-time PCR and Western blot analysis. Based on our results, CuE showed growth-inhibiting effects on GBM 8401 and U-87-MG cells. Moreover, GADD45ß caused the accumulation of CuE-treated G2/M-phase cells. The disassociation of the CDC2/cyclin-B1 complex demonstrated the known effects of CuE against GBM 8401 and U-87-MG cancer cells. Additionally, CuE may also exert antitumour activities in established brain cancer cells. In conclusion, CuE inhibited cell proliferation and induced mitosis delay in cancer cells, suggesting its potential applicability as an antitumour agent.


Assuntos
Neoplasias Encefálicas/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Triterpenos/farmacologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Mitose/efeitos dos fármacos , Mitose/genética , Ligação Proteica/efeitos dos fármacos , Interferência de RNA
5.
J Mol Med (Berl) ; 96(12): 1407-1418, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374682

RESUMO

The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone and important component of the renin-angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1-7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1-7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1-7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1-7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1-7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1-7) post-treatment. Taken together, these data indicate that Ang-(1-7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. KEY MESSAGES: Ang-(1-7) inhibits cell proliferation, migration, and invasion by activating autophagy Ang-(1-7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway. Ang-(1-7) may provide a novel preventative treatment for NPC and recurrent NPC.


Assuntos
Angiotensina I/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Angiotensina I/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Fragmentos de Peptídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Cell Physiol ; 233(6): 4618-4625, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28833099

RESUMO

Simvastatin (SIM), a widely used cholesterol-lowering drug, also exhibits tumor-suppressive potentials in several types of malignancy. Colorectal cancer (CRC), the third most common malignant neoplasm, accounts for the second most leading cause of cancer-related deaths worldwide. In the present study, we investigated the anticancer effects of SIM on CRC using primary cancer cells lines (CPs: CP1 to CP5) isolated from five Taiwanese colorectal cancer patients as a model for colorectal cancer. We treated all five CPs with SIM for 24-72 hr and observed the respective cell viability by an MTT assay. SIM increased DNA content of the G1 phase, but did not induce apoptosis/necrosis in CPs as shown by flow cytometry with propidium iodide (PI)/annexin V double staining and PI staining. The expression of G1 phase-related proteins was analyzed by RT-PCR and Western blotting. SIM suppressed cell growth and induced cell cycle G1 -arrest by suppressing the expression of CDK4/cyclin D1 and CDK2/cyclin E1, but elevating the expression of glycogen synthase kinase 3ß in CPs. Our findings indicate that SIM may have antitumor activity in established colorectal cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Oncogênicas/metabolismo , Sinvastatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/genética , Ciclina E/genética , Quinase 2 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/genética , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Proteínas Oncogênicas/genética , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Sci ; 18(7)2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28644386

RESUMO

Capsaicin is a potential chemotherapeutic agent for different human cancers. In Southeast China, nasopharyngeal carcinoma (NPC) has the highest incidence of all cancers, but final treatment outcomes are unsatisfactory. However, there is a lack of information regarding the anticancer activity of capsaicin in NPC cells, and its effects on the signaling transduction pathways related to apoptosis and autophagy remain unclear. In the present study, the precise mechanisms by which capsaicin exerts anti-proliferative effects, cell cycle arrest, autophagy and apoptosis were investigated in NPC-TW01 cells. Exposure to capsaicin inhibited cancer cell growth and increased G1 phase cell cycle arrest. Western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) were used to measure capsaicin-induced autophagy via involvement of the class III PI3K/Beclin-1/Bcl-2 signaling pathway. Capsaicin induced autophagy by increasing levels of the autophagy markers LC3-II and Atg5, enhancing p62 and Fap-1 degradation and increasing caspase-3 activity to induce apoptosis, suggesting a correlation of blocking the PI3K/Akt/mTOR pathway with the above-mentioned anticancer activities. Taken together, these data confirm that capsaicin inhibited the growth of human NPC cells and induced autophagy, supporting its potential as a therapeutic agent for cancer.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Capsaicina/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Carcinoma/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Nasofaringe/efeitos dos fármacos , Nasofaringe/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
Int J Med Sci ; 14(5): 462-469, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28539822

RESUMO

Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, for which radiotherapy and/or chemotherapy are the primary treatment methods. Many herbs are known to have potential uses in chemotherapy; however, the mechanisms underlying the observed antitumor activity of Ajuga bracteosa (AB) against NPC remain unclear. We explored the antitumor effects of AB, which was shown specifically to induce mitotic delay in pharyngeal (Detroit 562) and nasopharyngeal (Hone-1) cancer cells. Proliferation of cancer cells after exposure to aqueous extract of A. bracteosa (AEAB) was assessed using the MTT assay. DNA content and cell cycle arrest induction were analyzed using flow cytometry. The expression of checkpoint kinase 2 (CHK2), cell division control protein 2 (CDC2), and cyclin B1 was investigated using qRT-PCR and Western blot analysis. Results indicated the inhibition of cancer cell growth following exposure to AEAB. In addition, AEAB induced the accumulation of G2/M-phase cells in cancer cell through the disassociation of CDC2/cyclin B1 complex. Our findings suggested that, in addition to the known effects of AEAB in NPC prevention, it may have antitumor activities against NPC cells. In conclusion, AEAB inhibits the growth of and induces mitotic delay in cancer cells, supporting its use as an anticancer agent.


Assuntos
Ajuga/química , Carcinoma/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase do Ponto de Checagem 2/genética , Ciclina B1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patologia , Extratos Vegetais/química , Água/química
9.
Cell Death Discov ; 3: 17014, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28487767

RESUMO

Cervical cancer is the most common malignancy in women, for which conization or hysterectomy are the main therapy. Curcubitacin E (Cu E) is a natural compound-based drug which from the Guadi (climbing stem of Cucumic melo L). Previously shown to be an anti-tumor as well as a potent chemopreventive agent against several types of tumors. The present study, investigated anti-proliferation and apoptosis induced by Cu E in cervical cancer cell lines (HeLa and Ca Ski). The results indicate that the cytotoxicity is associated with accumulation in apoptosis but not necrosis. Cu E produced apoptosis as well as the up-regulation the expression of death receptor 5 (DR5). In addition, the DR5 gene activation in apoptosis, both effects increased proportionally with the dose of Cu E; however, mitosis delay was also dependant on the amount of Cu E treatment in the cancer cells. These results indicate that Cu E may delay cancer cell growth by apoptosis via upregulation of DR5 gene expression.

10.
Cell Biol Int ; 41(3): 345-352, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28035725

RESUMO

Cyclophosphamide is indicated for the treatment of cancerous diseases such as breast cancer and cervical cancer. Recent studies have shown that cyclophosphamide may induce cancer metastasis, but the cause of this unexpected adverse effect is not fully understood. In this study, we investigate the effect of cyclophosphamide on cancer cell migration and its correlation to chemokine (C-X-C motif) receptor 4 (CXCR4), a biomarker for cancer metastasis. Two human cancer cell lines with significant difference in endogenous CXCR4 expression, the breast cancer cell line, MDA-MB-231, and the melanoma cell line, MDA-MB-435S, were treated with various concentrations of cyclophosphamide, followed by the assessment of CXCR4 expression and cell migration. We found that the migration ability of MDA-MB-231 cells was enhanced with increasing concentrations of cyclophosphamide, which induced the cell-surface expression of CXCR4, but had no effect on the overall amount of CXCR4. In MDA-MB-435S cells, in which CXCR4 was barely detectable, cyclophosphamide was unable to activate cell-surface CXCR4, and did not promote cell migration. Studies on the mRNA expression profile of matrix metalloproteinases (MMPs) in MDA-MB-231 cells further indicate that MMP9 and MMP13 may be involved in the action of cyclophosphamide. The protein expression of both MMP9 and MMP13 was increased in the presence of cyclophosphamide. Results from this study provide the molecular basis for the possible pathway of cyclophosphamide to induce cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Ciclofosfamida/toxicidade , Metaloproteinases da Matriz/biossíntese , Receptores CXCR4/biossíntese , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos
11.
Int J Mol Sci ; 17(9)2016 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-27626412

RESUMO

Globally, cervical cancer is the most common malignancy affecting women. The main treatment methods for this type of cancer include conization or hysterectomy procedures. Sulforaphane (SFN) is a natural, compound-based drug derived from dietary isothiocyanates which has previously been shown to possess potent anti-tumor and chemopreventive effects against several types of cancer. The present study investigated the effects of SFN on anti-proliferation and G2/M phase cell cycle arrest in cervical cancer cell lines (Cx, CxWJ, and HeLa). We found that cytotoxicity is associated with an accumulation of cells in the G2/M phases of the cell-cycle. Treatment with SFN led to cell cycle arrest as well as the down-regulation of Cyclin B1 expression, but not of CDC2 expression. In addition, the effects of GADD45ß gene activation in cell cycle arrest increase proportionally with the dose of SFN; however, mitotic delay and the inhibition of proliferation both depend on the dosage of SFN used to treat cancer cells. These results indicate that SFN may delay the development of cancer by arresting cell growth in the G2/M phase via down-regulation of Cyclin B1 gene expression, dissociation of the cyclin B1/CDC2 complex, and up-regulation of GADD45ß proteins.


Assuntos
Anticarcinógenos/farmacologia , Ciclina B1/genética , Quinases Ciclina-Dependentes/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias do Colo do Útero/genética , Antígenos de Diferenciação/genética , Proteína Quinase CDC2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico
12.
Nanoscale Res Lett ; 11(1): 247, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27173676

RESUMO

The carbon-based nanomaterial graphene can be chemically modified to associate with various molecules such as chemicals and biomolecules and developed as novel carriers for drug and gene delivery. In this study, a nonviral gene transfection reagent was produced by functionalizing graphene oxide (GO) with a polycationic polymer, polyethylenimine (PEI), to increase the biocompatibility of GO and to transfect small interfering RNA (siRNA) against C-X-C chemokine receptor type 4 (CXCR4), a biomarker associated with cancer metastasis, into invasive breast cancer cells. PEI-functionalized GO (PEI-GO) was a homogeneous aqueous solution that remained in suspension during storage at 4 °C for at least 6 months. The particle size of PEI-GO was 172 ± 4.58 and 188 ± 5.00 nm at 4 and 25 °C, respectively, and increased slightly to 262 ± 17.6 nm at 37 °C, but remained unaltered with time. Binding affinity of PEI-GO toward siRNA was assessed by electrophoretic mobility shift assay (EMSA), in which PEI-GO and siRNA were completely associated at a PEI-GO:siRNA weight ratio of 2:1 and above. The invasive breast cancer cell line, MDA-MB-231, was transfected with PEI-GO in complex with siRNAs against CXCR4 (siCXCR4). Suppression of the mRNA and protein expression of CXCR4 by the PEI-GO/siCXCR4 complex was confirmed by real-time PCR and western blot analysis. In addition, the metastatic potential of MDA-MB-231 cells was attenuated by the PEI-GO/siCXCR4 complex as demonstrated in wound healing assay. Our results suggest that PEI-GO is effective in the delivery of siRNA and may contribute to targeted gene therapy to suppress cancer metastasis.

13.
Oncotarget ; 7(23): 34172-9, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27129156

RESUMO

Human umbilical cord mesenchymal stem cells (hUCMSCs) derived from the umbilical cord matrix have been reported to be used as anti-tumor gene carrier for attenuation of tumor growth, which extends the half-life and lowers the unexpected cytotoxicity of the gene in vivo. Interferon-ß (IFNß) is known to possess robust anti-tumor effects on different types of cancer cell lines in vitro. The present study was aimed to investigate the anti-tumor effect of IFNß gene-transfected hUCMSCs (IFNß-hUCMSCs) on breast cancer cells with emphasis on triple negative breast carcinoma. Our findings revealed that the co-culture of IFNß-hUCMSCs with the human triple negative breast carcinoma cell lines MDA-MB-231 or Hs578T significantly inhibited growth of both carcinoma cells. In addition, the culture medium conditioned by these cells also significantly suppressed the growth and induced apoptosis of both carcinoma cells. Further investigation showed that the suppressed growth and the apoptosis induced by co-culture of IFNß-hUCMSCs or conditioned medium were abolished by pretreating anti-IFNß neutralizing antibody. These findings indicate that IFNß-hUCMSCs triggered cell death of breast carcinoma cells through IFN-ß production, thereby induced apoptosis and suppressed tumor cell growth. In conclusion, we demonstrated that IFNß-hUCMSCs inhibited the growth of breast cancer cells through apoptosis. With potent anti-cancer activity, it represents as an anti-cancer cytotherapeutic modality against breast cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Terapia Genética/métodos , Interferon beta/farmacologia , Células-Tronco Mesenquimais , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Sangue Fetal , Humanos , Transfecção
14.
Int J Mol Sci ; 17(2)2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26840297

RESUMO

Melatonin is found in animals as well as plants. In animals, it is a hormone that anticipates the daily onset of darkness and regulates physiological functions, such as sleep timing, blood pressure, and reproduction. Melatonin has also been found to have anti-tumor properties. Malignant cancers are the most common cause of death, and the mortality rate of ovarian tumor is the highest among gynecological diseases. This study investigated the anti-tumor effects of melatonin on the ovarian cancer lines, OVCAR-429 and PA-1. We observed the accumulation of melatonin-treated cells in the G1 phase due to the down-regulation of CDK 2 and 4. Our results suggest that in addition to the known effects on prevention, melatonin may also provide anti-tumor activity in established ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Melatonina/farmacologia , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/genética , Feminino , Humanos
15.
Clin Exp Pharmacol Physiol ; 43(2): 251-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26541904

RESUMO

Previous researchers have claimed that metronomic low-dose/dense chemotherapy can enhance the therapeutic effectiveness of cisplatin treatment in the control of cancer. Therefore, the aim of this study was to explore the effectiveness of metronomic drug delivery with regards to its effects on adaptive immunity in a murine model of ectopic cervical cancer. The effectiveness of long-term low-dose/dense cisplatin treatment in HPV E7-expressing TC-1 cells was evaluated via morphological observations. Tumour mass and survival curves were used to determine the antitumour effect against E7-expressing tumours. After experimental mice had been treated with low-dose/dense cisplatin therapy, flow cytometry was used to measure the expression of MHC class I surface antigens on cultured TC-1 cells. Splenocytes expressing both interferon (IFN)-γ and CD8 responsible for E7 antigens and the Treg population were also quantified using flow cytometry. The results indicate that in vivo treatment with metronomic cisplatin suppresses the growth of cultured TC-1 cells. An increase was also observed in the number of splenocytes expressing both IFN-γ and CD8 responsible for E7 antigens and the Treg population. These results support previous reports that metronomic low-dose/dense cisplatin chemotherapy is an effective treatment against ectopic cervical cancer with E7-expression.


Assuntos
Administração Metronômica , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Interferon gama/biossíntese , Camundongos , Neoplasias do Colo do Útero/patologia
16.
Carbohydr Polym ; 134: 438-47, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26428145

RESUMO

The antibacterial activity and biocompatibility of membranes of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and chitosan (CS) (PHBV)/CS) were evaluated in this study. Maleic anhydride (MA)-grafted polyhydroxyalkanoate (PHBV-g-MA) was evaluated as an alternative to PHBV. Mouse tail skin fibroblasts (FBs) were seeded on two series of these films to assess cytocompatibility. Collagen and cell proliferation analyses indicated that PHBV, PHBV-g-MA and their composite membranes were biocompatible with respect to FB proliferation. However, FB proliferation, collagen production and the percentage of normal cells growing on PHBV/CS membranes were greater than those for PHBV-g-MA/CS membranes. Cell-cycle and apoptosis assays by FBs on the PHBV-series membrane samples were not affected by DNA content related to damage; i.e. rapid apoptosis/necrosis was not observed, demonstrating the potential of PHBV/CS or PHBV-g-MA/CS membranes for biomedical material applications. Moreover, CS-based polysaccharide enhanced the Escherichia coli (BCRC 10239) antibacterial activity of the membranes. Membranes of PHBV-g-MA or PHBV containing CS-based polysaccharide had better antibacterial activity.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Quitosana/química , Teste de Materiais , Membranas Artificiais , Poliésteres/química , Polissacarídeos/química , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/biossíntese , Escherichia coli/efeitos dos fármacos , Anidridos Maleicos/química , Fenômenos Mecânicos , Camundongos
17.
FEBS Lett ; 589(16): 2058-65, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26140984

RESUMO

Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis. Suppression of ODC by its irreversible inhibitor, α-difluoromethylornithine (DFMO), or by RNA interference through siRNA, enhanced osteogenic gene expression and alkaline phosphatase activity, and accelerated matrix mineralization of human bone marrow-derived mesenchymal stem cells (hBMSCs). Besides, adipogenic gene expression and lipid accumulation was attenuated, indicating that the enhanced osteogenesis was accompanied by down-regulation of adipogenesis when ODC was suppressed. A decrease in the intracellular polyamine content of hBMSCs during osteogenic induction was observed, suggesting that the level of endogenous polyamines is regulated during differentiation of hBMSCs. This study elucidates the role of polyamine metabolism in the lineage commitment of stem cells and provides a potential new indication for DFMO as bone-stimulating drug.


Assuntos
Células-Tronco Mesenquimais/citologia , Ornitina Descarboxilase/metabolismo , Osteogênese , Adipogenia/efeitos dos fármacos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Matriz Óssea/química , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Eflornitina/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Cinética , Metabolismo dos Lipídeos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Ornitina Descarboxilase/química , Inibidores da Ornitina Descarboxilase/farmacologia , Osteogênese/efeitos dos fármacos , Putrescina/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Espermidina/metabolismo , Espermina/metabolismo
18.
Int J Mol Sci ; 16(6): 12424-35, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-26042464

RESUMO

Pogostemon cablin (PC) is a traditional herbal medicine used in the treatment of the common cold, nausea, diarrhea, and even for headaches and fever. However, the mechanisms underlying the anti-proliferative activity of PC in endometrial cancer (EC) cells have yet to be fully elucidated. This study investigated the anticancer effects of an aqueous extract of Pogostemon cablin (PCAE), specifically induced apoptosis in EC (Ishikawa) cells. Proliferation of EC cells following exposure to PCAE was assessed by an MTT assay. DNA content and the induction of cell cycle apoptosis were analyzed by flow cytometry (FACS Calibur). Protein caspase-3 and, -9 as well as AIF were investigated using Western blot. Our results demonstrate growth inhibition of Ishikawa cells by PCAE. Furthermore, caspase-3 activity caused PCAE-treated cell lines to accumulate in apoptosis. Gene expression profiling (GEP) results further suggest that, in addition to its known effects with regard to EC prevention, PCAE may also exert antitumor activity on established EC cells. Many previous studies have identified the chemo-preventive effects of natural plant materials and the potential role of these materials in chemotherapy. This current study used human EC Ishikawa cells to investigate the anti-tumor effects of PCAE in EC cells. Our results demonstrate that PCAE inhibits the growth of cancer cells and induces apoptosis, which suggests the potential applicability of PCAE as an antitumor agent.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Endométrio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lamiaceae/química , Extratos Vegetais/farmacologia , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos
19.
Mater Sci Eng C Mater Biol Appl ; 50: 309-16, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25746275

RESUMO

This work evaluated the cytocompatibility, thermal and mechanical properties of composites of polylactide (PLA) and marine algae powder (MAP). To improve the thermal and mechanical properties of PLA-MAP composites, glycidyl methacrylate (GMA) was used as the compatibilizer for the blending of PLA and MAP. The PLA-g-GMA/MAP composites exhibited superior mechanical properties, attributing to higher compatibility between the polymer and MAP, comparing to PLA/MAP composites. The dispersion of MAP in the PLA-g-GMA matrix was highly homogeneous as a result of etherification. The lower melt torque of the PLA-g-GMA/MAP composites also made them more processable than PLA/MAP. To assess the cytocompatibility, normal human foreskin fibroblasts (FBs) were seeded onto each type of the composites. Results of FB proliferation, collagen production, and cytotoxicity assays indicated greater cytocompatibility for the PLA/MAP composites than for the PLA-g-GMA/MAP composites. Furthermore, both PLA/MAP and PLA-g-GMA/MAP composites were more cytocompatible than pure PLA.


Assuntos
Organismos Aquáticos/química , Materiais Biocompatíveis/farmacologia , Clorófitas/química , Fibroblastos/citologia , Teste de Materiais/métodos , Poliésteres/farmacologia , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Proliferação de Células/efeitos dos fármacos , Colágeno/biossíntese , Elasticidade/efeitos dos fármacos , Compostos de Epóxi/química , Fibroblastos/efeitos dos fármacos , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Masculino , Metacrilatos/química , Poliésteres/química , Pós , Temperatura , Torque , Viscosidade/efeitos dos fármacos
20.
Biomed Res Int ; 2015: 372819, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25695065

RESUMO

BACKGROUND: Severe burns result in hypercatabolic state and concomitant muscle atrophy that persists for several months, thereby limiting patient recovery. However, the effects of burns on the corresponding spinal dermatome remain unknown. This study aimed to investigate whether burns induce apoptosis of spinal cord ventral horn motor neurons (VHMNs) and consequently cause skeletal muscle wasting. METHODS: Third-degree hindpaw burn injury with 1% total body surface area (TBSA) rats were euthanized 4 and 8 weeks after burn injury. The apoptosis profiles in the ventral horns of the lumbar spinal cords, sciatic nerves, and gastrocnemius muscles were examined. The Schwann cells in the sciatic nerve were marked with S100. The gastrocnemius muscles were harvested to measure the denervation atrophy. RESULT: The VHMNs apoptosis in the spinal cord was observed after inducing third-degree burns in the hindpaw. The S100 and TUNEL double-positive cells in the sciatic nerve increased significantly after the burn injury. Gastrocnemius muscle apoptosis and denervation atrophy area increased significantly after the burn injury. CONCLUSION: Local hindpaw burn induces apoptosis in VHMNs and Schwann cells in sciatic nerve, which causes corresponding gastrocnemius muscle denervation atrophy. Our results provided an animal model to evaluate burn-induced muscle wasting, and elucidate the underlying mechanisms.


Assuntos
Células do Corno Anterior/patologia , Apoptose/fisiologia , Queimaduras/patologia , Membro Posterior/patologia , Atrofia Muscular/patologia , Nervo Isquiático/patologia , Corno Ventral da Medula Espinal/patologia , Animais , Marcação In Situ das Extremidades Cortadas/métodos , Masculino , Músculo Esquelético/patologia , Ratos , Ratos Sprague-Dawley , Células de Schwann/patologia
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