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1.
Cancer Lett ; 315(1): 1-11, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22033245

RESUMO

In this study, we investigated the anticancer effect of protopine on human hormone-refractory prostate cancer (HRPC) cells. Protopine exhibited an anti-proliferative effect by induction of tubulin polymerization and mitotic arrest, which ultimately led to apoptotic cell death. The data suggest that protopine increased the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex and that contributed to cell apoptosis by modulating mitochondria-mediated signaling pathways, such as Bcl-2 phosphorylation and Mcl-1 down-regulation. In conclusion, the data suggest that protopine is a novel microtubule stabilizer with anticancer activity in HRPC cells through apoptotic pathway by modulating Cdk1 activity and Bcl-2 family of proteins.


Assuntos
Apoptose/efeitos dos fármacos , Benzofenantridinas/farmacologia , Alcaloides de Berberina/farmacologia , Mitose/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Transfecção
2.
Proc Natl Acad Sci U S A ; 107(18): 8363-8, 2010 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-20404138

RESUMO

Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b(+) myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.


Assuntos
Antígeno CD11b/imunologia , Antígenos CD18/imunologia , Carcinoma de Células Escamosas/imunologia , Movimento Celular , Antígeno de Macrófago 1/imunologia , Células Mieloides/imunologia , Animais , Anticorpos/imunologia , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Camundongos Nus , Células Mieloides/citologia , Células Mieloides/efeitos da radiação , Recidiva , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Lett ; 292(2): 163-70, 2010 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-20056528

RESUMO

Attacking angiogenesis is considered an effective strategy for controls the expansion and metastasis of tumors and other related-diseases. The aim of this study was to assess the effects of moscatilin, a bibenzyl derivative, on VEGF and bFGF-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs. These results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy.


Assuntos
Compostos de Benzil/farmacologia , Divisão Celular/efeitos dos fármacos , Dendrobium/química , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Western Blotting , Linhagem Celular , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/fisiologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias/patologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/fisiologia
4.
Shock ; 32(3): 263-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19106818

RESUMO

Inflammation and low oxygen diffusion are recognized characteristics of cardiovascular diseases such as atherosclerosis. Evodiamine, extracted from the traditional Chinese herb, Evodia rutaecarpa, is a bioactive anti-inflammatory alkaloid. The objective of this study was to investigate whether evodiamine could repress hypoxia-induced inflammatory response. We showed that evodiamine repressed not only COX-2 and iNOS expression but also prostaglandin E2 release in a concentration-dependent manner under hypoxic conditions. Furthermore, our studies indicated that COX-2 mRNA was inhibited by evodiamine, implying that transcriptional activity is involved in the mechanistic pathway. It is striking that hypoxia-inducible factor 1alpha (HIF-1alpha) inhibitor, camptothecin, suppressed hypoxia-induced COX-2 expression rather than pyrrolidine dithiocarbamate, a nuclear factor kappaB inhibitor. In addition, our studies have confirmed that evodiamine inhibited HIF-1alpha, which accounted for the transcriptional activity of COX-2, rather than nuclear factor kappaB in RAW264.7 cells. Finally, evodiamine did not affect either the level of HIF-1alpha mRNA or the degradation rate of HIF-1alpha protein, but it regulated the translational process of HIF-1alpha. We found that hypoxia-evoked phosphorylation of Akt and p70S6K was blocked after evodiamine treatment, in addition to the inhibition of phosphorylation of 4E-BP. These results suggest that the mechanism of repression of hypoxia-induced COX-2 expression by evodiamine is through the inhibition of HIF-1alpha at the translational level and is primarily mediated via dephosphorylation of Akt and p70S6K. Therefore, evodiamine could be an effective therapeutic agent against inflammatory diseases involving hypoxia.


Assuntos
Anti-Inflamatórios/farmacologia , Hipóxia Celular/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Extratos Vegetais/farmacologia , Quinazolinas/farmacologia , Animais , Western Blotting , Camptotecina/farmacologia , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirrolidinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Tiocarbamatos/farmacologia
5.
Clin Cancer Res ; 14(13): 4250-8, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18594007

RESUMO

PURPOSE: To study the effect of moscatilin (purified from the stem of orchid Dendrobrium loddigesii) on the proliferation of human colorectal cancer HCT-116 cells in vitro and in vivo. EXPERIMENTAL DESIGN: The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on HCT-116 cells, c-Jun NH(2)-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Specific JNK inhibitor SP600125 was cotreated to reverse moscatilin-induced apoptosis. Tumor growth inhibition of moscatilin was done on HCT-116 xenograft models. RESULTS: Moscatilin induced a time-dependent arrest of the cell cycle at G(2)-M, with an increase of cells at sub-G(1). Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. Moscatilin also induced the phosphorylation of JNK1/2. SP600125 significantly inhibited the activation of caspase-9 and caspase-3 and the subsequent moscatilin-induced apoptosis. The data suggest that JNK activation may contribute to moscatilin-mediated apoptosis signaling. A parallel experiment showed that SP600125 significantly inhibits Taxol- and vincristine-induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents. Moreover, moscatilin induces DNA damage, phosphorylation of H2AX and p53, and up-regulation of p21. Our HCT-116 xenograft models show the in vivo efficacy of moscatilin. CONCLUSIONS: In summary, our results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage stress and that this leads to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway.


Assuntos
Apoptose , Compostos de Benzil/farmacologia , Neoplasias Colorretais/patologia , Dano ao DNA , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Tubulina (Proteína)/química , Animais , Linhagem Celular Tumoral , Separação Celular , Neoplasias Colorretais/metabolismo , Ensaio Cometa , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Camundongos , Transplante de Neoplasias
6.
Biochem Pharmacol ; 75(4): 847-56, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18035333

RESUMO

Anthracyclines and anthracenediones are well-known cancer chemotherapeutic agents but their uses are limited with cardiotoxicity and drug resistance. Several l- and d-form amino acids were introduced into the anthraquinone skeleton and numerous derivatives were synthesized for the evaluation of anticancer activity. The screening tests showed that WRC-213, an l-methionine conjugation, was the most effective derivative to inhibit proliferative effect of human androgen-independent prostate cancer PC-3 cells (IC50=50 nM). In an extension evaluation, WRC-213 displayed a potent anti-proliferative activity in various cancer cell lines, including non-small cell lung cancer A549, androgen-independent prostate cancer DU145, colorectal cancer HT-29, breast cancer MCF-7 and hepatocellular carcinoma Hep3B and HepG2. It induced cell-cycle arrest at S and G2, but not mitotic phase, in PC-3 cells. The comet assay revealed that induction of DNA damage and inhibition of topoisomerase II were the primary insults. After the checkpoint arrest of the cell-cycle, WRC-213 induced the mitochondria-mediated intrinsic apoptotic pathway, including Mcl-1 cleavage, Bcl-2 down-regulation and activation of caspase-9/caspase-3 cascades. Survivin degradation and caspase-2 activation also contributed to WRC-213-induced apoptosis. Moreover, the assessment of cytotoxicity in H9c2 cardiomyocytes and drug resistance in NCI/ADR-RES cells demonstrated that WRC-213 showed much lower cardiotoxicity and P-glycoprotein-related resistance than those of mitoxantrone, etoposide and doxorubicin. In conclusion, it is suggested that WRC-213 is a potential topoisomerase II inhibitor with reduced cardiotoxicity and drug resistance. It inhibits topoisomerase II activity and induces chromosomal DNA strand breaks, leading to S and G2 arrest of the cell-cycle and activation of mitochondria-mediated apoptotic pathways.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metionina/análogos & derivados , Metionina/química , Mitoxantrona/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Neoplasias da Próstata , Inibidores da Topoisomerase II , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Masculino , Metionina/efeitos adversos , Metionina/farmacologia , Mitoxantrona/efeitos adversos , Mitoxantrona/química , Mitoxantrona/farmacologia , Estrutura Molecular , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
7.
Neoplasia ; 9(10): 830-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17971903

RESUMO

Quinazoline-based alpha1-adrenoceptor antagonists, in particular doxazosin and terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other alpha1-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G2 checkpoint arrest and subsequent apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA strand breaks and ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdk1 activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated and caspase-executed apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdk1 inactivation and G2 checkpoint arrest. Subsequently, mitochondria-mediated caspase cascades are triggered to induce apoptosis in PC-3 cells.


Assuntos
Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Prazosina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaio Cometa , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Carcinogenesis ; 26(5): 968-75, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15705600

RESUMO

Drug resistance is one of the main obstacles to the successful treatment of cancer. The availability of agents that are highly effective against drug-resistant cancer cells is therefore essential. The present study was performed to examine the anticancer effects of evodiamine, a major constituent of the Chinese herb Evodiae fructus, in adriamycin-resistant human breast cancer NCI/ADR-RES cells. Evodiamine inhibited the proliferation of NCI/ADR-RES cells in a concentration-dependent manner with a GI50 of 0.59 +/- 0.11 microM. This agent also caused a substantial apoptosis at 1 microM. FACScan flow cytometric analysis of cell cycle progression revealed that a G2/M arrest was initiated after a 12-h exposure to the drug. Evodiamine increased tubulin polymerization as determined by the immunocytochemical and in vivo tubulin polymerization analyses. In a time- and concentration-dependent manner, evodiamine also promoted the phosphorylations of Raf-1 kinase and Bcl-2. The phosphorylation site of Raf-1 kinase was identified to be serine338. The in vivo anticancer effects of evodiamine were evaluated in Balb-c/nude mice following a tumor xenograft implantation of NCI/ADR-RES cells. The antitumor activity of evodiamine against the human multiple-drug resistant tumor xenograft was found to be superior to that of paclitaxel. Evodiamine therefore represents a highly promising chemotherapeutic agent in the treatment of human multiple-drug resistant cancer cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Evodia/metabolismo , Extratos Vegetais/farmacologia , Quinazolinas/farmacologia , Alcaloides/farmacologia , Animais , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Nus , Microtúbulos/efeitos dos fármacos , Paclitaxel/farmacocinética , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinolinas/farmacologia
9.
Biochem Pharmacol ; 67(11): 2031-8, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15135300

RESUMO

Genistein, a natural isoflavone phytoestrogen present in soybeans, has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The traditional Asian diet is rich in soy products may explain in part why the incidence of breast cancer in Asian women is relatively low. To improve therapeutic benefits, we investigated the combination of genistein with chemotherapeutic agents in phenotypically dissimilar human breast cancer cells, MCF-7 and MDA-MB-231, in which estrogen receptor expression is positive and negative, respectively. In the present study, genistein significantly decreased cell apoptosis induced by tubulin-binding agents, paclitaxel and vincristine. FACScan analysis revealed that genistein also diminished the accumulation of the G2/M phase in the cell cycle caused by tubulin-binding agents. In situ staining of microtubules revealed that genistein could decrease paclitaxel-induced tubulin polymerization. However, in vivo tubulin polymerization assay revealed that simultaneous treatment of genistein did not change the tubulin/microtubule dynamic. Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression. p53 and p21 expression, monitored by Western blotting, was not altered by genistein. However, the expression of cyclin B1 and CDC2 kinase was markedly decreased in combination with genistein. In conclusion, genistein inversely affected tubulin-binding agent-induced apoptosis via down-regulation of cyclin B1/CDC2 kinase expression resulting in reduced Bcl-2 phosphorylation.


Assuntos
Apoptose , Genisteína/farmacologia , Paclitaxel/farmacologia , Neoplasias da Mama , Proteína Quinase CDC2/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ciclina B/metabolismo , Ciclina B1 , Antagonismo de Drogas , Feminino , Fase G2/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Paclitaxel/antagonistas & inibidores , Fosforilação , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas , Vincristina/antagonistas & inibidores , Vincristina/farmacologia
10.
J Pharm Pharmacol ; 54(7): 967-74, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12162716

RESUMO

Because the metabolites of arachidonic acid participate in many physiopathological responses, including inflammation and platelet aggregation, cyclooxygenase inhibitors are important in the treatment of associated diseases. A biologically active compound, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), selectively and concentration dependently inhibited aggregation of platelets from man and ATP release caused by arachidonic acid (200 microM) and collagen (10 microg mL(-1)) without affecting the aggregation caused by thrombin (0.1 U mL(-1)) and U46619 (2 microM). The IC50 value (drug concentration inhibiting maximum response by 50%) of KTC-5 for aggregation induced by arachidonic acid and collagen was 0.11+/-0.04 microM and 0.20+/-0.03 microM, respectively. This inhibitory effect of KTC-5 was reversible and time dependent. KTC-5 specifically inhibited intracellular calcium mobilization initiated by arachidonic acid or collagen without affecting that caused by thrombin or U46619 in human platelets. Furthermore, KTC-5 inhibited thromboxane B2 and prostaglandin D2 formation provoked by arachidonic acid. The IC50 value of KTC-5 for arachidonic-acid-induced thromboxane B2 formation was 0.07+/-0.02 microM. Based on these observations, the data indicated that KTC-5 potently inhibited human platelet aggregation and ATP release mainly via the inhibition of the cyclooxygenase-1 activity. Moreover, KTC-5 inhibited lipopolysaccharide-induced prostaglandin E2 formation in RAW264.7 cells in the presence of external arachidonic acid with an IC50 value of 0.17+/-0.06 microM. Immunoblot analysis showed that KTC-5 did not affect the cyclooxygenase-2 expression in the presence of lipopolysaccharide on RAW264.7 cells. This result indicated that KTC-5 affects the activity of cyclooxygenase-2. According to these data, we concluded that KTC-5 is a cyclooxygenase inhibitor for both subtypes.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Inibidores de Ciclo-Oxigenase/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Quinolinas/farmacologia , Trifosfato de Adenosina/metabolismo , Ácido Araquidônico/farmacologia , Técnicas de Cultura de Células , Colágeno/farmacologia , Humanos , Cinética
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