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1.
Oncogenesis ; 3: e90, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24590311

ABSTRACT

The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.

2.
Leukemia ; 26(4): 757-68, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21941364

ABSTRACT

Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the ß5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZ-resistant cells revealed upregulation of mutant ß5 subunit of the proteasome. These newly identified ß5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the ß5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant ß5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the α7 subunit of the proteasome can overcome this drug resistance modality.


Subject(s)
Antineoplastic Agents/metabolism , Boronic Acids/metabolism , Multiple Myeloma/drug therapy , Mutation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Proteasome Endopeptidase Complex/genetics , Pyrazines/metabolism , Amino Acid Substitution , Boronic Acids/therapeutic use , Bortezomib , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors , Pyrazines/therapeutic use
3.
J Biol Chem ; 267(1): 192-6, 1992 Jan 05.
Article in English | MEDLINE | ID: mdl-1730587

ABSTRACT

When in situ perfused rat livers were administered tracer or physiologic concentrations of [35S]cysteine, a zone III (perivenous) predominance of uptake was observed in either antegrade or retrograde single-pass perfusion, as determined by quantitative densitometry of autoradiographs of liver section. This pattern remained unchanged from 30 s to 5 min observed. At higher supraphysiologic doses a more uniform acinar distribution of cysteine uptake was observed. Uptake rates of cysteine in antegrade perfusion indicated an apparent saturable component at low but physiologic cysteine concentrations. That uptake rather than metabolic trapping accounts for this perivenular pattern was supported by finding identical zonal distribution under conditions in which GSH and protein synthesis were markedly inhibited. Furthermore, increasing or decreasing hepatic cysteine pool sizes did not affect the extraction or zonation. These results suggest that a low Km transport system for cysteine is localized in zone III of the hepatic acinus.


Subject(s)
Cysteine/metabolism , Liver/metabolism , Animals , Autoradiography , Glutathione/metabolism , Glycocholic Acid/metabolism , In Vitro Techniques , Male , Perfusion , Proteins/metabolism , Rats , Rats, Inbred Strains
4.
Pharmacology ; 44(6): 334-43, 1992.
Article in English | MEDLINE | ID: mdl-1508963

ABSTRACT

We studied the effect of inhibition of oxyradical formation and of endogenous glutathione (GSH) depletion on lesion formation in the gastrointestinal tract in a modified rat hemorrhagic shock model (1 h hypotension and 1 h reperfusion). Allopurinol, an inhibitor of xanthine oxidase, did not protect against lesion formation. This suggests that oxygen radicals generated from xanthine oxidase may not be the major cause of injury under these conditions of prolonged 'ischemia'-reperfusion. Phorone (diisopropylideneacetone), a GSH depletor, decreased mucosal GSH levels in the corpus, duodenum and small intestine, and also significantly reduced lesion formation histologically in the corpus, antrum, duodenum and small intestine. However, there was no significant differences in mucosal blood flow (as estimated by changes in mucosal hemoglobin concentrations and oxygen saturation of mucosal hemoglobin) in the corpus, antrum, duodenum and small intestine between phorone-pretreated and control rats. We conclude that phorone decreased mucosal GSH concentrations and exerted a protective effect against hemorrhagic shock-induced gastrointestinal mucosal lesions. The protective effect appears to be independent of mucosal blood flow.


Subject(s)
Allopurinol/pharmacology , Gastric Mucosa/drug effects , Intestinal Mucosa/drug effects , Ketones/pharmacology , Reperfusion Injury/drug therapy , Animals , Duodenum/drug effects , Free Radicals , Gastric Mucosa/blood supply , Gastric Mucosa/metabolism , Glutathione/metabolism , Intestinal Mucosa/blood supply , Intestinal Mucosa/metabolism , Intestine, Small/drug effects , Male , Oxygen Consumption/drug effects , Rats , Rats, Inbred Strains , Regional Blood Flow/drug effects , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathology , Shock, Hemorrhagic/complications
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