ABSTRACT
Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) ß. ERß expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERß were sensitive, whereas cells with low ERß were insensitive to diosmetin. Knockdown of ERß confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERß with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618-26. ©2017 AACR.
Subject(s)
Estrogen Receptor beta/genetics , Flavonoids/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Neoplastic Stem Cells/drug effects , Animals , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Hematopoietic Stem Cells/drug effects , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice , Molecular Targeted Therapy , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Current practice guidelines are unclear regarding the role of secondary prophylaxis of febrile neutropenia in advanced-stage Hodgkin lymphoma despite several small retrospective studies that demonstrate the omission of growth factors to be a safe and economic practice. We used a decision-analytic model to compare secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF) to no G-CSF with the onset of severe neutropenia for a hypothetical cohort of patients with advanced-stage Hodgkin lymphoma treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). There was a net benefit of 0.017 years and 0.037 quality-adjusted life years for no G-CSF use in severe neutropenia. On microsimulation (10 000 trials), 96% of the simulations showed that the no G-CSF strategy is preferred to the use of G-CSF. This finding was robust across a wide range of sensitivity analyses. Our analysis suggests that G-CSF not be used as secondary prophylaxis of febrile neutropenia in advanced-stage Hodgkin lymphoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Decision Support Techniques , Febrile Neutropenia/chemically induced , Febrile Neutropenia/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Hodgkin Disease/complications , Hodgkin Disease/drug therapy , Premedication , Bleomycin/adverse effects , Bleomycin/therapeutic use , Dacarbazine/adverse effects , Dacarbazine/therapeutic use , Decision Trees , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Hodgkin Disease/mortality , Hodgkin Disease/pathology , Humans , Markov Chains , Neoplasm Staging , Quality-Adjusted Life Years , Treatment Outcome , Vinblastine/adverse effects , Vinblastine/therapeutic useABSTRACT
Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wild-type ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of full-length ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm.
Subject(s)
Active Transport, Cell Nucleus , Karyopherins/chemistry , Nerve Tissue Proteins/metabolism , Nuclear Export Signals , Receptors, Cytoplasmic and Nuclear/chemistry , 3T3 Cells , Animals , Ataxin-7 , Cerebellar Diseases/metabolism , Cerebellum/cytology , Conserved Sequence , Humans , Mice , Neurons/metabolism , Nuclear Export Signals/genetics , Peptides/pharmacology , Point Mutation , Transcription Factors , Transfection , Exportin 1 ProteinABSTRACT
Spinocerebellar ataxia type 1 (SCA1) is a dominant neurodegenerative disease caused by the expression of mutant ataxin-1 containing an expanded polyglutamine tract. Ataxin-1 is a nuclear protein that localizes to punctate inclusions similar to neuronal nuclear inclusions seen in many polyglutamine expansion disease proteins. We demonstrate that ataxin-1 localization to inclusions and inclusion dynamics within the nucleus are RNA and transcription dependent, but not dependent on the polyglutamine tract. Ataxin-1 nuclear inclusions are distinct from other described nuclear bodies but recruit the mRNA export factor, TAP/NXF1, in a manner that is enhanced by cell heat shock. By FRAP protein dynamic studies in live cells, we found that wild-type, but not mutant, ataxin-1 was capable of nuclear export. These results suggest that the normal role of ataxin-1 may be in RNA processing, perhaps nuclear RNA export. Thus, nuclear retention of mutant ataxin-1 may be an important toxic gain of function in SCA1 disease.
