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1.
Leukemia ; 31(3): 645-653, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27677741

RESUMO

While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCFSkp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCFSkp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138+ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138+ cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCFSkp2 complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCFSkp2 inhibitors to treat BTZ resistant disease.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Farmacogenética , Proteínas Quinases Associadas a Fase S/metabolismo , Bibliotecas de Moléculas Pequenas , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas Culina/genética , Modelos Animais de Doenças , Descoberta de Drogas , Sinergismo Farmacológico , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Farmacogenética/métodos , Prognóstico , Inibidores de Proteassoma/farmacologia , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Leukemia ; 29(11): 2184-91, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26108695

RESUMO

Although the therapeutic benefit of proteasome inhibition in multiple myeloma remains unchallenged, drug resistance inevitably emerges through mechanisms that remain elusive. Bortezomib provokes unwanted protein accumulation and the endoplasmic reticulum stress to activate the unfolded protein response (UPR) and autophagy as compensatory mechanisms that restore protein homeostasis. High-throughput screens to detect pharmacologics that modulated autophagy to enhance the anti-myeloma effect of bortezomib revealed metformin, a widely used antidiabetic agent with proven efficacy and limited adverse effects. Metformin co-treatment with bortezomib suppressed induction of the critical UPR effector glucose-regulated protein 78 (GRP78) to impair autophagosome formation and enhance apoptosis. Gene expression profiling of newly diagnosed myeloma patient tumors further correlated the hyperexpression of GRP78-encoding HSPA5 with reduced clinical response to bortezomib. The effect of bortezomib was enhanced with metformin co-treatment using myeloma patient tumor cells and the chemoresistant, stem cell-like side population that may contribute to disease recurrence. The relevance of the findings was confirmed in vivo as shown by metformin co-treatment with bortezomib that delayed the growth of myeloma xenotransplants. Taken together, our results suggest that metformin suppresses GRP78, a key driver of bortezomib-induced autophagy, and support the pharmacologic repositioning of metformin to enhance the anti-myeloma benefit of bortezomib.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Bortezomib/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Metformina/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/fisiologia , Humanos , Camundongos , Fosfatidilinositol 3-Quinases/fisiologia
3.
Leukemia ; 29(3): 727-38, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25234165

RESUMO

Evading apoptosis is a cancer hallmark that remains a serious obstacle in current treatment approaches. Although proteasome inhibitors (PIs) have transformed management of multiple myeloma (MM), drug resistance emerges through induction of the aggresome+autophagy pathway as a compensatory protein clearance mechanism. Genome-wide profiling identified microRNAs (miRs) differentially expressed in bortezomib-resistant myeloma cells compared with drug-naive cells. The effect of individual miRs on proteasomal degradation of short-lived fluorescent reporter proteins was then determined in live cells. MiR-29b was significantly reduced in bortezomib-resistant cells as well as in cells resistant to second-generation PIs carfilzomib and ixazomib. Luciferase reporter assays demonstrated that miR-29b targeted PSME4 that encodes the proteasome activator PA200. Synthetically engineered miR-29b replacements impaired the growth of myeloma cells, patient tumor cells and xenotransplants. MiR-29b replacements also decreased PA200 association with proteasomes, reduced the proteasome's peptidase activity and inhibited ornithine decarboxylase turnover, a proteasome substrate degraded through ubiquitin-independent mechanisms. Immunofluorescence studies revealed that miR-29b replacements enhanced the bortezomib-induced accumulation of ubiquitinated proteins but did not reveal aggresome or autophagosome formation. Taken together, our study identifies miR-29b replacements as the first-in-class miR-based PIs that also disrupt the autophagy pathway and highlight their potential to synergistically enhance the antimyeloma effect of bortezomib.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Pirazinas/farmacologia , RNA Interferente Pequeno/genética , Animais , Apoptose/efeitos dos fármacos , Bortezomib , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Vetores Genéticos , Humanos , Lentivirus/genética , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Transplante de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ornitina Descarboxilase/genética , Ornitina Descarboxilase/metabolismo , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida
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