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)

Recent studies have shown that high levels of the apoptosis-related proteins bcl-2 and bcl-xL increase, while over-expression of bcl-xs or bax decreases, resistance to drugs that induce apoptosis in some human cancer cells. In the present report, we investigated whether expression of these apoptosis-related proteins correlates with changes in the degree of resistance to apoptosis induced by doxorubucin, taxol, vincristine and VP-16 and contributes to the development of acquired resistance in multidrug-resistant MCF-7/Adr breast cancer cells. In this study, high levels of bcl-xL and bax proteins are detected in both MCF-7 and MCF-7/Adr cells. In contrast, bcl-2 protein is down-regulated about 10-fold in MCF-7/Adr cells compared with MCF-7 cells. RT-PCR analysis showed that MCF-7/Adr cells express approximately 2-fold less bcl-2 mRNA than MCF-7 cells. Moreover, 4-24 hr cycloheximide treatment of MCF-7 and MCF-7/Adr cells did not affect the expression of bcl-2 protein, indicating that this protein is very stable in both cell lines. Our results suggest that bcl-2 expression is modulated partly by transcriptional, but mainly by post-transcriptional, mechanisms. Despite the down-regulation of bcl-2 in MCF-7/Adr cells and equal levels of bcl-x, and bax proteins in both cell lines, cytoplasmic DNA-histone complexes induced by doxorubucin, taxol, vincristine and VP-16 indicate that MCF-7/Adr cells are highly resistant to apoptosis. Moreover, treatments of MCF-7/Adr cells with P-glycoprotein (P-gp) modulators, cyclosporin A and verapamil increased doxorubicin and vincristine-induced DNA fragmentation about 1.4- and 2.5-fold, indicating that P-gp is involved in the development of resistance to chemotherapy-induced apoptosis in this cell line.
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PMID:Down-regulation of apoptosis-related bcl-2 but not bcl-xL or bax proteins in multidrug-resistant MCF-7/Adr human breast cancer cells. 878 46

The cells from approximately 70% patients with acute myeloblastic leukaemia exhibit autonomous growth characteristics in vitro, which have been associated with a poor response to therapy. We have previously shown that leukaemic cells with autonomous growth characteristics express high levels of bcl-2 and are relatively resistant to apoptosis. As bcl-x(L) is a bcl-2-related gene with anti-apoptotic activity which also confers resistance to cytotoxic drugs we have studied its expression in AML in relation to cellular growth characteristics and to the expression of P-glycoprotein. Cells from 15 patients were studied. Immunoblotting demonstrated bands at 31 kDa corresponding to bcl-x(L) from the cells of all patients. Bcl-x(S) was not detected in any sample. Using standardised, quantitative flow cytometry, bcl-x(L) expression ranged from 0.25 x 10(5) to 4.24 x 10(5) bound FITC molecules, (median 1.35 x 10[5]). AML blasts with autonomous growth in vitro expressed more bcl-x(L) (median 1.76 x 10[5]) than those which did not (median 0.86 x 10(5), P=0.01). Quantitative bcl-x(L) expression strongly correlated with that of P-glycoprotein, also measured by quantitative flow cytometry using the MRK16 antibody (r=0.95, P < 0.001), but not with MRPr1. These results provide a further explanation for the poor prognosis associated with autonomous in vitro growth of AML blasts and illustrate that these cells may coexpress different modalities of resistance to cytotoxic drug therapy involving both anti-apoptotic pathways (bcl-x(L), bcl-2) and classic multidrug resistance (MDR1). The implication of these findings is that the use of agents to reverse MDR1 function in AML may be unsuccessful in the absence of strategies to reduce resistance to apoptosis.
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PMID:Bcl-x(L) is heterogenously expressed by acute myeloblastic leukaemia cells and is associated with autonomous growth in vitro and with P-glycoprotein expression. 920 73

Pluronic block copolymer P85 (P85) sensitizes multidrug resistant (MDR) cancer cells resulting in the increase of cytotoxic activity of antineoplastic agents. This effect is attributed to the inhibition of the most clinically relevant drug efflux transporter, P-glycoprotein (Pgp), through the combined ATP depletion and inhibition of Pgp ATPase activity. The present study elucidates effects of an anticancer agent, doxorubicin (Dox), formulated with P85 on drug-induced apoptosis in MDR cancer cells. Early and late stages of apoptosis were detected by Annexin V and TUNEL methods, respectively. In parallel experiments, the expression of genes related to apoptosis, BCL2, BCLXL, BAX, P53, APAF1, Caspase 3, and Caspase 9, was determined by RT-PCR. The obtained data suggest that Dox/P85 formulation induces apoptosis in the resistant cancer cells more efficiently than free Dox. The treatment of the cells with Dox alone simultaneously activated a proapoptotic signal and an antiapoptotic cellular defense. Therefore, the apoptosis induction by Dox was substantially limited. In contrast, the treatment of the cells with Dox/P85 formulation significantly enhanced the proapoptotic activity of the drug and prevented the activation of the antiapoptotic cellular defense. This is likely to result in the stronger cytotoxic response of the resistant cells to the Dox/P85 formulation compared to the free drug.
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PMID:Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells. 1593