RESUMEN
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.
Asunto(s)
Autofagia/efectos de los fármacos , Ácidos Borónicos/farmacología , Neoplasias de la Mama/patología , Caspasas/fisiología , Catepsinas/fisiología , Resistencia a Antineoplásicos/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Pirazinas/farmacología , Antineoplásicos/farmacología , Autofagia/genética , Autofagia/fisiología , Bortezomib , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Evaluación Preclínica de Medicamentos , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Humanos , Metabolismo/efectos de los fármacos , Metabolismo/genética , Receptores de Estrógenos/genética , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Drogas en Investigación/farmacología , Drogas en Investigación/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatología , Mutación , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
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.
Asunto(s)
Adenosina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Unión al ADN/antagonistas & inhibidores , Epigénesis Genética/efectos de los fármacos , Ácidos Hidroxámicos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Adenosina/administración & dosificación , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Ciclo Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Evaluación Preclínica de Medicamentos , Proteína Potenciadora del Homólogo Zeste 2 , Inhibidores Enzimáticos/administración & dosificación , Células HL-60 , Inhibidores de Histona Desacetilasas , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Histonas/química , Histonas/metabolismo , Humanos , Indoles , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias , Proteínas Nucleares/metabolismo , Panobinostat , Complejo Represivo Polycomb 2 , Factores de Transcripción/metabolismo , Resultado del Tratamiento , Células Tumorales CultivadasAsunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Evaluación Preclínica de Medicamentos/normas , Animales , Línea Celular Tumoral , Desoxicitidina/uso terapéutico , Femenino , Humanos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
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.