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1.
FASEB J ; 35(10): e21885, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478585

RESUMO

In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacologia , Desoxicitidina/agonistas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Molecules ; 25(12)2020 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-32545807

RESUMO

Oral cancer-a type of head and neck cancer-is estimated to be the fifth most common cancer in Taiwan. However, efficacious therapies for oral cancer are still lacking due to drug resistance and recurrence. Consequently, the identification of new anticancer agents for clinical treatment is needed. Juniperus indica Bertol is a plant of the Juniperus genus often used as a treatment in traditional medicine due to its anti-inflammatory, antibacterial and diuretic functions. The biofunctions of Juniperus indica Bertol including its anticancer potential, have not been fully explored. As a result, the aim of this research was to investigate the anticancer activity of Juniperus indica Bertol extract (JIB extract) and determine whether JIB extract has synergistic effects with cisplatin in oral cancer. These results are the first to demonstrate that JIB extract exhibits anticancer capacity and synergizes with cisplatin to treat oral cancer. Our findings indicate that JIB extract has a potential to develop anticancer agent and chemo therapeutic adjuvant for oral cancer.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Cisplatino , Juniperus/química , Neoplasias Bucais , Proteínas de Neoplasias/metabolismo , Extratos Vegetais , Animais , Antineoplásicos Fitogênicos/agonistas , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacologia , Cães , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Madin Darby de Rim Canino , Camundongos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
3.
Basic Clin Pharmacol Toxicol ; 122(3): 346-354, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28889522

RESUMO

Natural products represent the source or the inspiration for the majority of the active ingredients of medicines because of their structural diversity and a wide range of biological effects. Our aims in this study were (i) to synthesize enzymatically salidroside (SAL), the most effective phenylethanoid glycoside in Rhodiola species; (ii) to examine its antioxidant capacity using cell-free assays (reducing power, DPPH radicals scavenging and Fe2+ -chelating assays); (iii) to assess its DNA-protective potential on plasmid DNA (DNA topology assay) and in HepG2 cells (comet assay) damaged by Fe2+ ions and hydrogen peroxide, respectively; and (iv) to investigate the effects of SAL, cisplatin (CDDP) and combined treatments of SAL + CDDP on cell viability (MTT test), level of DNA damage (comet assay), proliferation, cell cycle (flow cytometry) and the expression of signalling molecules associated with cell growth and apoptotic pathways (Western immunoblotting). We found out that SAL manifested low antioxidant and DNA-protective capacity in all assays used. In both parental A2780 and CDDP-resistant A2780/CP human ovarian carcinoma cells, SAL itself exerted in fact no impact on the viability, while in combination with CDDP it showed antagonistic effect supporting the chemopreventive activity on the CDDP-induced cell damage. These results were confirmed by the partial reversal of the cell cycle alterations and the DNA damage level, as well as with partial restoration of cell survival/signalling pathways, when the expression of these molecules partially returned to their proper levels.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Fenóis/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antioxidantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Cisplatino/agonistas , Cisplatino/antagonistas & inibidores , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Antagonismo de Drogas , Sinergismo Farmacológico , Feminino , Células Hep G2 , Hepatócitos/citologia , Humanos , Neoplasias Ovarianas/patologia , Substâncias Protetoras/farmacologia , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos
4.
J Cell Biochem ; 118(9): 2865-2876, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28214344

RESUMO

Cisplatin is one of the most potent chemotherapeutic agents for the treatment of many types of solid tumors but its efficacy is often limited by the development of resistance and dose limiting toxicity. Neferine is an alkaloid isolated from seed embryo of Nelumbo nucifera, it has recently been shown to have anticancer effects in various human cancer cell lines. The present investigation is designed to study the chemosensitizing ability of neferine with cisplatin in A549 cells. Neferine potentiates the cisplatin induced apoptosis through the exploration of characteristic apoptotic morphological changes, induced sub-G1 cell cycle arrest, ROS hypergeneration, significant loss of cellular antioxidant enzymes, as well as loss of mitochondrial membrane potential (ΔΨM). Furthermore our results revealed that neferine combined with cisplatin down regulate the expression of Bcl-2 and up regulate the expression of Bax, Bad, Bak, release of cytochrome c, p53 levels, then activated cleavage forms of caspase-9, caspase-3, and PARP. Moreover neferine and cisplatin combination significantly down regulated the protein levels of FAK and VEGF. In addition, we observed the activity of MMP-2 and MMP-9. Thus this study provides molecular evidence for the ROS mediated apoptosis of the combinatorial regimen of cisplatin and neferine in lung cancer cells. Thus these results suggest that using neferine with cisplatin combinatorial regimen could be potentiating the effect of cisplatin and neferine reduces the cisplatin dose requirement in cancer chemotherapy. J. Cell. Biochem. 118: 2865-2876, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/metabolismo , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Benzilisoquinolinas/agonistas , Linhagem Celular Tumoral , Cisplatino/agonistas , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mitocôndrias/patologia , Proteínas de Neoplasias/metabolismo
5.
Mol Cell Biochem ; 427(1-2): 13-22, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27995416

RESUMO

The aim of our study was to determine whether the use of cisplatin in the presence echistatin in MDA-MB-231 breast cancer cells leads to a reduction of toxic effects associated with the use of cisplatin. The expression of ß1-integrin and insulin-like growth factor 1 receptor (IGF-IR), signaling pathway protein expression: protein kinase B (AKT), mitogen-activated protein kinases (ERK1/ERK2), nuclear factor kappa B (NFκB), and caspase-3 and -9 activity was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The viability of MDA-MB-231 breast cancer cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Annexin V-FITC/propidium iodide staining assay was performed to detect the induction of apoptosis. Inhibition DNA biosynthesis was determined by [3H]thymidine incorporation into DNA. The expression of of ß1-integrin, IGF-IR, AKT, ERK1/ERK2, NFκB, caspase-3 and -9 was evaluated using Western blot. The results suggest that treatment of MDA-MB-231 breast cancer cells for 24 h cisplatin plus echistatin severely inhibits cell growth and activates apoptosis by upregulation of caspase-3 and -9 expressions. The effect was stronger than treatment cisplatin and echistatin alone. In this study, we have found that cisplatin plus echistatin treatment decreases collagen biosynthesis in MDA-MB-231 breast cancer cells stronger than the individual compounds. The inhibition was found to be dependent on the ß1-integrin and IGF receptor activation. A significant reduction of ERK1/ERK2, AKT expression in cancer cells after cisplatin plus echistatin treatment was also found. The cancer cells treated by echistatin, cisplatin, and in particular the combination of both compounds drastically increased expression of NFκB transcription factor. Our results suggest that combined therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin. This mechanism probably is due to downregulation of expression of ß1-integrin and IGF-IR receptors, and the signaling pathway proteins induced by these receptors. Our results suggest that therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Peptídeos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cisplatino/agonistas , Sinergismo Farmacológico , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Neoplasias/metabolismo , Peptídeos/agonistas
6.
J Pineal Res ; 60(1): 55-64, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26462739

RESUMO

Melatonin has antitumor activity via several mechanisms including its antiproliferative and pro-apoptotic effects as well as its potent antioxidant actions, although recent evidence has indicated that melatonin may perform pro-oxidant actions in tumor cells. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was intended to evaluate the in vitro effect of melatonin on the cytotoxic and pro-apoptotic actions of various chemotherapeutic agents in cervical cancer HeLa cells. Herein, we found that both melatonin and three of the chemotherapeutic drugs tested, namely cisplatin (CIS), 5-fluorouracil (5-FU), and doxorubicin, induced a decrease in HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of such chemotherapeutic agents. Consistently, costimulation of HeLa cells with any chemotherapeutic agent in the presence of melatonin further increased caspase-3 activation, particularly in CIS- and 5-FU-challenged cells. Likewise, concomitant treatments with melatonin and CIS significantly enhanced the ratio of cells entering mitochondrial apoptosis due to reactive oxygen species (ROS) overproduction, substantially augmented the population of apoptotic cells, and markedly enlarged DNA fragmentation compared to the treatments with CIS alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in 5-FU-stimulated HeLa cells, as suggested by slight increments in the percentage of cells stimulated for ROS production and in the proportion of early apoptotic cells compared to the treatments with 5-FU alone. In summary, our findings provided evidence that in vitro melatonin strongly enhances CIS-induced cytotoxicity and apoptosis in HeLa cells and, hence, the indoleamine could be potentially applied to cervical cancer treatment as a powerful synergistic agent.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Cisplatino/agonistas , Citotoxinas/agonistas , Feminino , Células HeLa , Humanos , Melatonina/agonistas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
7.
Biomed Res Int ; 2015: 397563, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26491668

RESUMO

The purpose of this study was to evaluate the anticancer efficacy of cetuximab combined with cisplatin (combination treatment) on colon cancer growth, as well as its underlying action mechanism. Combination treatment synergistically potentiated the effect of cetuximab on cell growth inhibition and apoptosis induction in HCT116 and SW480 cells. Combination treatment further suppressed the expression of the activated form of epidermal growth factor receptor (EGFR) and MAP kinase (p-ERK and p-p38) and also significantly inhibited the activity of activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). Additionally, the expression of cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA was significantly reduced by the combination treatment as compared to the expression seen for treatment with cetuximab or cisplatin alone. We found that the synergistic inhibitory effects of cetuximab and cisplatin on AP-1 and NF-κB activation, as well as on cell viability, were reversed by pretreatment with an ERK inhibitor. Results demonstrate that combined treatment with cetuximab and cisplatin exerts synergistic anticancer effects on colon cancer cells and also suggest that the ERK pathway plays a critical role in these effects via the suppression of the EGFR signaling pathway, along with the inhibition of COX-2, IL-8, and AP-1 and NF-κB.


Assuntos
Cetuximab/farmacologia , Cisplatino/farmacologia , Neoplasias do Colo , Receptores ErbB/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/agonistas , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Humanos
8.
Int J Mol Med ; 36(4): 957-66, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26310353

RESUMO

Drug resistance remains a major challenge in cancer therapy. Butein, a polyphenolic compound, has been shown to exhibit anticancer activity through the inhibition of the activation of the protein kinase B (PKB/AKT) and mitogen-activated protein kinase (MAPK) pathways, which are two pathways known to be involved in resistance to cisplatin. Hence, we hypotheiszed that butein may be a chemosensitizer to cisplatin. In the present study, we demonstrated that butein synergistically enhanced the growth inhibitory and apoptosis-inducing effects of cisplatin on HeLa cells. Moreover, the combination of butein and cisplatin led to G1 phase arrest. We then aimed to explore the underlying mechanisms. We found that butein inhibited the activation of AKT, extracellular signal-regulated kinase (ERKs) and p38 kinases in the presence of cisplatin. The use of the AKT inhibitor, LY294002, in combination with cisplatin, induced an increase in apoptosis compared to treatment with cisplatin alone, although this effect was not as prominent as that exerted by butein in combination with cisplatin. Of note, the inhibition of ERK or p38 MAPK by U0126 or SB203580, respectively, decreased the apoptosis induced by cisplatin; however, enhanced apoptotic effects were observed with the use of ERK/p38 MAPK inhibitor in combination with butein. These data suggest that the AKT and ERK/p38 MAPK pathways are involved in the synergistic effects of butein and cisplatin. Furthermore, co-treatment with butein and cisplatin promoted the nuclear translocation and expression of forkhead box O3a (FoxO3 or FoxO3a). FoxO3a may be the key molecule on which these pathways converge and is thus implicated in the synergistic effects of butein and cisplatin. This was further confirmed by the RNAi-mediated suppression of FoxO3a. FoxO3a target genes involved in cell cycle progression and apoptosis were also investigated, and combined treatment with butein and cisplatin resulted in the downregulation of cyclin D1 and Bcl-2 and the upregulation of p27 and Bax. In addition, the combination of both agents markedly inhibited tumor growth and increased the expression of FoxO3a in mouse tumor xenograft models of cervical cancer. Taken together, to the best of our knowledge, our results reveal for the first time that butein sensitizes cervical cancer cells to cisplatin in vitro and in vivo, and these effects of butien may be related to the inhibition of the activation of the AKT and ERK/p38 MAPK pathways by targeting FoxO3a.


Assuntos
Chalconas/farmacologia , Cisplatino/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Chalconas/agonistas , Cisplatino/agonistas , Feminino , Proteína Forkhead Box O3 , Células HeLa , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
9.
PLoS One ; 10(4): e0126147, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25923669

RESUMO

Hypopharyngeal squamous cell carcinoma (HSCC) has the worst prognosis among head and neck cancers. Cisplatin (DDP)-based chemotherapy is an important part of multimodal treatments. However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC. Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC. We inoculated BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells to generate our animal model. Mice were randomly divided into 4 groups and treated with vehicle control, CQ (60 mg/kg/day), DDP (5 mg/kg/6 days), or a combination of DDP and CQ. Tumor growth and survival of the mice were monitored. We found that CQ inhibited autophagy and increased DDP-induced apoptosis in the xenograft mouse model. CQ enhanced the efficacy of DDP, resulting in decreased tumor growth and prolonged survival of the mice. To test whether blocking autophagy enhanced the efficacy of DDP, FaDu cells were infected with lentiviral shRNA to Beclin-1 and inoculated into the flanks of nude mice. Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect. Our study suggests that the addition of CQ to DDP-based chemotherapy could be a potential therapeutic strategy for treating HSCC, and the inhibition of autophagy may contribute to chemotherapy sensitization in HSCC.


Assuntos
Apoptose/efeitos dos fármacos , Cloroquina/farmacologia , Cisplatino/farmacologia , Neoplasias Hipofaríngeas/tratamento farmacológico , Animais , Apoptose/genética , Linhagem Celular Tumoral , Cloroquina/agonistas , Cisplatino/agonistas , Agonismo de Drogas , Feminino , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/metabolismo , Neoplasias Hipofaríngeas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Am J Respir Cell Mol Biol ; 49(2): 241-50, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23526220

RESUMO

Metformin has been used as first-line treatment in patients with type 2 diabetes, and is reported to reduce cancer risk and progression by activating the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Cisplatin remains the main drug for treating advanced non-small-cell lung cancer. However, drug resistance often develops through several mechanisms during the treatment course, including one mechanism mediated by the activation of the IL-6/signal transducer and activator of transcription (STAT)-3 pathway, related to the generation of reactive oxygen species (ROS). This study demonstrated a correlation between STAT3 phosphorylation and cisplatin cytotoxicity, using AS2 (PC14PE6/AS2)-derived cell lines (AS2/S3C) that contained constitutively active STAT3 plasmids as a model. A STAT3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 cells, whereas metformin inhibited STAT3 phosphorylation and enhanced cisplatin cytotoxicity. By contrast, another AMPK activator (5-aminoimidazole-4-carboxamide-riboside) failed to produce these effects. LKB1-AMPK silencing by small, interfering RNA or mammalian target of rapamycin (mTOR) inhibition by rapamycin or pp242 did not alter the effect of metformin on STAT3 activity suppression, suggesting that metformin can modulate the STAT3 pathway through an LKB1-AMPK-independent and probably mTOR-independent mechanism. Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 secretion in AS2 cells. Both mechanisms contributed to the ability of metformin to suppress STAT3 activation in cancer cells, which resulted in the decreased secretion of vascular endothelial growth factor by cancer cells. The growth of subcutaneous tumor xenografts was significantly delayed by a combination of cisplatin and metformin. This is the first study to demonstrate that metformin suppresses STAT3 activation via LKB1-AMPK-mTOR-independent but ROS-related and autocrine IL-6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting STAT3.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Metformina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Antineoplásicos/agonistas , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cisplatino/agonistas , Sinergismo Farmacológico , Inativação Gênica , Humanos , Hipoglicemiantes/agonistas , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metformina/agonistas , Camundongos , Camundongos SCID , Proteínas Serina-Treonina Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncogene ; 27(33): 4603-14, 2008 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-18391982

RESUMO

To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3beta (GSK3beta), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3beta axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Cisplatino/farmacologia , Diterpenos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Fenantrenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos Alquilantes/agonistas , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/agonistas , Diterpenos/agonistas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Compostos de Epóxi/agonistas , Compostos de Epóxi/farmacologia , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Fenantrenos/agonistas , Ligação Proteica/efeitos dos fármacos , Proteína Quinase C/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
Cancer Gene Ther ; 15(1): 40-50, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18034197

RESUMO

The majority of clinical trials evaluating replication-selective oncolytic adenoviruses utilized mutants with immunomodulatory E3B genes deleted, likely contributing to the attenuated efficacy. We investigated whether an intact immune response could contribute to the observed improved efficacy in response to combinations with chemotherapeutics. Seven carcinoma cell lines were evaluated by combining viral mutants; dl309 (DeltaE3B), dl704 (DeltaE3gp19K), dl312 (DeltaE1A) or wild-type Ad5 with the commonly used clinical drugs cisplatin and paclitaxel. Synergistic effects on cell death were determined by generation of combination indexes in cultured cells. In vivo tumor growth inhibition was achieved by virotherapy alone and was most efficacious with wild-type virus and least with the DeltaE3B mutant. Significantly higher efficacy was observed when the viruses were combined with drugs. The greatest enhancement of tumor inhibition was in combination with the DeltaE3B mutant restoring potency to that of Ad5 wild-type levels, observed only in animals with intact immune response. Increases in infectivity, viral gene expression and replication were identified as potential mechanisms contributing to the synergistic effects. Our results suggest that the attenuation of DeltaE3B mutants can be overcome by low doses of chemotherapeutics only in the presence of an intact immune response indicating a role for T-cell-mediated functions.


Assuntos
Adenoviridae/metabolismo , Proteínas E1A de Adenovirus/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Cisplatino/farmacologia , Neoplasias Experimentais/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/metabolismo , Paclitaxel/farmacologia , Adenoviridae/genética , Adenoviridae/imunologia , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/imunologia , Proteínas E3 de Adenovirus/genética , Animais , Antineoplásicos Fitogênicos/agonistas , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Morte Celular/imunologia , Linhagem Celular Tumoral , Cisplatino/agonistas , Deleção de Genes , Humanos , Imunidade Celular , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Paclitaxel/agonistas , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Cancer Ther ; 3(6): 699-707, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15210856

RESUMO

Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (>96 hours) with cisplatin (IC(50) = 27.5 to 35.5 micromol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC(50) = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC(50) from >200 micromol/L with cisplatin alone to 9 to 20 micromol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Apoptose/genética , Proteínas Reguladoras de Apoptose , Caspase 3 , Caspases/metabolismo , Linhagem Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Masculino , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Morfolinas/farmacologia , Morfolinos , Oligodesoxirribonucleotídeos Antissenso/genética , Oligodesoxirribonucleotídeos Antissenso/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas/genética , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/agonistas , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X
14.
Res Commun Mol Pathol Pharmacol ; 110(1-2): 59-72, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-12090357

RESUMO

Stimulation of alpha-adrenergic receptors by cold stress or adrenergic agents has been shown to potentiate the toxicity of numerous toxicants. Several lines of evidence indicate that this interaction is dependent on glutathione depression and increased cytosolic Ca2+ concentrations produced by alpha1-adrenergic compounds. In this report, evidence is provided in support of the mechanism of adrenoreceptor-mediated potentiation of nephrotoxicity. Alpha1-adrenergic agonists are shown to potentiate the toxicity of nephrotoxicants that exert their toxic effects via glutathione conjugation or Ca2+ deregulation. This review summarizes the effects of the alpha1-adrenergic agonist, phenylephrine, at enhancing the toxicity of 2-bromohydroquinone, 1,2-dibromoethane, and cis-diammineplatinum(II) dichloride.


Assuntos
Benzoquinonas/toxicidade , Cisplatino/toxicidade , Dibrometo de Etileno/toxicidade , Nefropatias/induzido quimicamente , Fenilefrina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Animais , Benzoquinonas/agonistas , Benzoquinonas/metabolismo , Cisplatino/agonistas , Cisplatino/metabolismo , Interações Medicamentosas , Dibrometo de Etileno/agonistas , Dibrometo de Etileno/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Receptores Adrenérgicos alfa/metabolismo
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