RESUMO
In recent studies, we and others showed that autophagy is critical to estrogen receptor positive (ER+) breast cancer cell survival and the development of antiestrogen resistance. Consequently, new approaches are warranted for targeting autophagy in breast cancer cells undergoing antiestrogen therapy. Because crosstalk has been demonstrated between the autophagy- and proteasome-mediated pathways of protein degradation, this study investigated how the proteasome inhibitor bortezomib affects autophagy and cell survival in antiestrogen-treated ER+ breast cancer cells. Bortezomib, at clinically achievable doses, induced a robust death response in ER+, antiestrogen-sensitive and antiestrogen-resistant breast cancer cells undergoing hormonal therapy. Cleavage of PARP and lamin A was detectable as a read-out of cell death, following bortezomib-induced mitochondrial dysfunction. Prior to induction of cell death, bortezomib-treated cells showed high levels of light chain 3 (LC3) and p62, two protein markers for autophagy. The accumulation of these proteins was due to bortezomib-mediated blockade of long-lived protein turnover during macroautophagy. This novel action of bortezomib was linked to its blockade of cathepsin-L activity, which is required for autolysosomal-mediated protein turnover in ER+ breast cancer cells. Further, bortezomib-treated breast cancer cells showed induction of the unfolded protein response, with upregulation of CH OP and GRP78. Bortezomib also induced high levels of the pro-apoptotic protein BNIP3. Knockdown of CH OP and/or BNIP3 expression via RNAi targeting significantly attenuated the death-promoting effects of bortezomib. Thus, bortezomib inhibits prosurvival autophagy, in addition to its known function in blocking the proteasome, and is cytotoxic to hormonally treated ER+ breast cancer cells. These findings indicate that combining a proteasome inhibitor like bortezomib with antiestrogen therapy may have therapeutic advantage in the management of early-stage breast cancer.
Assuntos
Autofagia/efeitos dos fármacos , Ácidos Borônicos/farmacologia , Neoplasias da Mama/patologia , Caspases/fisiologia , Catepsinas/fisiologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Pirazinas/farmacologia , Antineoplásicos/farmacologia , Autofagia/genética , Autofagia/fisiologia , Bortezomib , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Metabolismo/efeitos dos fármacos , Metabolismo/genética , Receptores de Estrogênio/genética , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
FMS-like tyrosine kinase-3 (FLT3) is a member of the class III membrane receptor tyrosine kinase family and is important in survival, proliferation and differentiation of hematopoietic cells. FLT3 is mutated in approximately 30% of acute myelogenous leukemia patients. These mutations involve internal tandem duplications in the juxtamembrane domain of the receptor and tyrosine kinase point mutations in the activation loop. Over the past decade, due to the incidence and poor prognosis associated with FLT3, numerous agents have been developed to directly inhibit the activity of wild type and mutated FLT3. In this review, we focus on the preclinical data demonstrating in vitro activity, inhibition of downstream signaling pathways and potential synergy with traditional chemotherapeutic agents. Also, early clinical trial data specifically focusing on drug toxicity, clinical efficacy and future directions of FLT3-directed anticancer therapy are discussed.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatologia , Mutação , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primary AML cells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34(+) bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells.
Assuntos
Adenosina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação a DNA/antagonistas & inibidores , Epigênese Genética/efeitos dos fármacos , Ácidos Hidroxâmicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Adenosina/administração & dosagem , Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste , Inibidores Enzimáticos/administração & dosagem , Células HL-60 , Inibidores de Histona Desacetilases , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histonas/química , Histonas/metabolismo , Humanos , Indóis , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias , Proteínas Nucleares/metabolismo , Panobinostat , Complexo Repressor Polycomb 2 , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Células Tumorais CultivadasAssuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos/normas , Animais , Linhagem Celular Tumoral , Desoxicitidina/uso terapêutico , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
The authors developed a strategy that includes a novel approach of induction full-dose chemotherapy followed by traditional chemoradiation as a neoadjuvant therapy for pancreatic cancer. Here they report the results of a phase I/II trial of gemcitabine, cisplatin, and 5-FU for patients with advanced gastrointestinal malignancies.