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


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.

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
PLoS One ; 8(3): e57523, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23520471


Sarcomas are rare and heterogeneous mesenchymal tumors affecting both pediatric and adult populations with more than 70 recognized histologies. Doxorubicin and ifosfamide have been the main course of therapy for treatment of sarcomas; however, the response rate to these therapies is about 10-20% in metastatic setting. Toxicity with the drug combination is high, response rates remain low, and improvement in overall survival, especially in the metastatic disease, remains negligible and new agents are needed. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by MK1775 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas. In this study we investigated the therapeutic efficacy of MK1775 in various sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo both alone and in combination with gemcitabine, which is frequently used in the treatment of sarcomas. Our data demonstrate that MK1775 treatment as a single agent at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. Additionally, MK1775 significantly enhances the cytotoxic effect of gemcitabine in sarcoma cells lines with different p53 mutational status. In patient-derived bone and soft tissue sarcoma samples we showed that MK1775 alone and in combination with gemcitabine causes significant apoptotic cell death. Magnetic resonance imaging (MRI) and histopathologic studies showed that MK1775 induces significant cell death and terminal differentiation in a patient-derived xenograft mouse model of osteosarcoma in vivo. Our results together with the high safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent in the treatment of both adult as well as pediatric sarcoma patients.

Antimetabólitos Antineoplásicos , Proteínas de Ciclo Celular/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Neoplasias Femorais/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis , Pirimidinas , Adolescente , Adulto , Animais , Antimetabólitos Antineoplásicos/agonistas , Antimetabólitos Antineoplásicos/farmacologia , Morte Celular , Diferenciação Celular , Linhagem Celular Tumoral , Criança , Pré-Escolar , Desoxicitidina/agonistas , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Neoplasias Femorais/patologia , Humanos , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Transplante de Neoplasias , Osteossarcoma/patologia , Pirazóis/agonistas , Pirazóis/farmacologia , Pirimidinas/agonistas , Pirimidinas/farmacologia , Pirimidinonas , Transplante Heterólogo , Ensaios Antitumorais Modelo de Xenoenxerto
Exp Hematol ; 40(10): 800-10, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22687754


Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting. We used ~IC(10) drug concentrations (57 µM B, 1 µM M and 0.02 µM G), which individually did not have major effects on cell proliferation. Their combination resulted in 50% inhibition of proliferation. Reduction to almost half concentration (20 µM B, 0.7 µM M and 0.01 µM G) did not have significant effects, but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (0.6 µM) to this combination resulted in a marked (~65%) growth inhibition. The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway, phosphorylation of KRAB-associated protein-1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B. The addition of 5-aza-2'-deoxycytidine to (BMG+suberoylanilide hydroxamic acid) further enhances cell killing. Overall, BMG combinations are synergistically cytotoxic to lymphoma cells. Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity. This study provides a rationale for an ongoing clinical trial in our institution using (BMG+suberoylanilide hydroxamic acid) as pre-hematopoietic stem cell transplantation conditioning for lymphoma.

Antineoplásicos Alquilantes/farmacologia , Azacitidina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Epigênese Genética/efeitos dos fármacos , Linfoma/metabolismo , Linfoma/terapia , Antineoplásicos Alquilantes/agonistas , Proteínas Mutadas de Ataxia Telangiectasia , Azacitidina/agonistas , Azacitidina/farmacologia , Bussulfano/agonistas , Bussulfano/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2 , Citotoxinas , DNA (Citosina-5-)-Metiltransferases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Decitabina , Desoxicitidina/agonistas , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Ácidos Hidroxâmicos/agonistas , Ácidos Hidroxâmicos/farmacologia , Linfoma/patologia , Melfalan/agonistas , Melfalan/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Proteínas Supressoras de Tumor/metabolismo
Blood ; 118(15): 4140-9, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-21844567


Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G(1)/S and prompted us to examine combinations with the RNR inhibitor 2',2'-difluoro-2'-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNA-mediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCL murine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL.

Antimetabólitos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Indóis , Linfoma de Célula do Manto/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Ribonucleosídeo Difosfato Redutase/biossíntese , Compostos de Espiro , Animais , Antimetabólitos Antineoplásicos/agonistas , Antimetabólitos Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/agonistas , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Fase G1/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/agonistas , Indóis/farmacologia , Linfoma de Célula do Manto/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Fase S/efeitos dos fármacos , Compostos de Espiro/agonistas , Compostos de Espiro/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto