Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute promyelocytic leukemia (APL) is a unique disease that responds to differentiation-inducing effects of all-trans-retinoic acid (ATRA). ATRA induces complete clinical remissions (CRs) in most patients and now constitutes a standard therapy in patients with APL. However, CRs induced by ATRA are usually brief, and resistance to the therapy rapidly develops, leading to relapses in almost every patient; thus limiting the use of ATRA as a single agent. On the basis of clinical and in vitro studies, the following mechanisms have been proposed to explain ATRA resistance: 1) induction of accelerated metabolism of ATRA, 2) increased expression of cellular retinoic acid-binding proteins (CRABPs), 3) constitutive degradation of PML-RAR alpha, 4) point mutations in the ligand-binding domain of RAR alpha of PML-RAR alpha, 5) P-glycoprotein expression, 6) transcriptional repression by histone deacetylase activity, 7) isoforms of PML-RAR alpha, 8) persistent telomerase activity, and 9) expression of type II transglutaminase. In this review, we discuss the evidence provided in support of each mechanism, the mechanism's possible impact on the outcome of APL, and the newer approaches that are being employed to overcome ATRA resistance.
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PMID:ATRA(ouble) in the treatment of acute promyelocytic leukemia. 1150 68

Emergence of resistance to antineoplastic drugs poses a major impediment to the successful treatment of breast cancer. We previously reported that human breast carcinoma MCF-7 cells selected for resistance against doxorubicin (MCF-7/DOX cells) expressed high levels of tissue-type transglutaminase (tTGase), a calcium-dependent protein cross-linking enzyme that plays a role in apoptosis. The purpose of this study was to determine the mechanisms by which MCF-7/DOX cells survive and proliferate despite high levels of tTGase expression. Our results demonstrate that the MCF-7/DOX cells contain deficient intracellular calcium pools, which may explain their ability to survive and tolerate the high levels of tTGase expression. Treatment with thapsigargin failed to induce any significant killing of MCF-7/DOX cells. Similar treatment of the drug-sensitive MCF-7 wild-type (MCF-7/WT) cells, however, induced significant apoptosis. Treatment with the ionophore A23187, on the other hand, killed a large percentage of both the MCF-7/DOX and the MCF-7/WT cells. We also established a revertant cell line, MCF-7/RT, from MCF-7/DOX cells to rule out the involvement of P-glycoprotein (P-gp) in these phenomena. Unlike the MCF-7/DOX cells, the MCF-7/RT cells showed no detectable P-gp expression; the MCF-7/RT cells, however, continued to express high levels of tTGase. Moreover, like MCF-7/DOX cells, the MCF-7/RT cells were highly resistant to thapsigargin-induced apoptosis but were sensitive to the ionophore A23187-induced apoptosis. These results suggest that the resistance of MCF7/DOX cells to thapsigargin is linked to their defective intracellular Ca2+ stores, a notion that was directly confirmed by single-cell spectrofluorometric analysis.
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PMID:Multidrug-resistant MCF-7 breast cancer cells contain deficient intracellular calcium pools. 1200 42