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)

The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Bcl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway.
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PMID:Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein. 1151 98

We studied the human HL60 leukemia cell line and its multidrug resistant (MDR) variant HL60R. In contrast to the HL60, HL60R showed an inability to undergo apoptosis from doxorubicin (Dox) or other different stimuli, including cisplatin, Fas ligation and serum withdrawal. HL60R cells lost surface Fas expression, but we found no evidence that Fas/FasL mediates the apoptotic effects of Dox in HL60. P-glycoprotein (P-gp) did not seem to play a major role as a specific inhibitor of apoptosis. In fact, the P-gp inhibitor verapamil reversed only partially the resistance to Dox-induced apoptosis of the MDR cells. In addition, it did not modify the rate of apoptosis induced from the other stimuli in the same cells. The expression of p53 or Bcl-2 was not different between HL60 and HL60R. However, in HL60R there was an increase in the mRNAs of inhibitory of apoptosis proteins (IAPs) like neuronal apoptosis inhibitory protein (NAIP), c-IAP-2 and survivin. Treatment with Dox or serum starvation strongly down-regulated X-linked IAP and survivin mRNAs in HL60. Cisplatin decreased NAIP and survivin mRNAs in the same cells. However, in HL60R the levels of these IAP mRNAs were much less affected by the treatments. These results support that IAPs may be involved in tumor resistance to chemotherapeutic drugs or other apoptotic agents.
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PMID:Resistance to diverse apoptotic triggers in multidrug resistant HL60 cells and its possible relationship to the expression of P-glycoprotein, Fas and of the novel anti-apoptosis factors IAP (inhibitory of apoptosis proteins). 1191 75

Cancer cells developing multidrug resistance (MDR) is one of the most serious clinical problems responsible for the failure of cancer chemotherapy. P-glycoprotein (P-gp) overexpression and inhibitor of apoptosis proteins (IAPs) overexpression in cancer cells are the two common mechanisms of MDR. However, the relationship between IAPs and P-gp in MDR cancer cells is unknown. We investigated the expression levels of two IAPs, Survivin and XIAP, and their interaction with P-gp in MDR cancer cells. We have found that the human epidermoid carcinoma cells KBv200 and breast cancer cells MCF-7/Adr overexpress not only P-gp but also XIAP and Survivin, and showed high resistance to chemotherapeutic drugs doxorubicin, docetaxel and vincristine, in contrast to their parental cells KB and MCF-7. Furthermore, upregulation of Survivin or XIAP through transfection with the plasmid pECFPN1-Survivin or pcDNA3-6myc-XIAP in these four cell sublines did not affect the P-gp expression. Downregulation of Survivin or XIAP through transfection with the Survivin or XIAP siRNA did not have an effect on the P-gp expression in these resistant cells. Additionally, our immunoprecipitation results showed that Survivin or XIAP did not directly bind to P-gp. In summary, our study suggested that the overexpression of Survivin and XIAP in MDR cancer cells does not directly interact with P-gp.
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PMID:Overexpression of Survivin and XIAP in MDR cancer cells unrelated to P-glycoprotein. 1734 44

Overexpression of P-glycoprotein (Pgp/ABCB1) in tumor cells is associated with a classic phenotype of multidrug resistance (MDR). Moreover, some members of the inhibitor of apoptosis protein (IAP) family, such as survivin, contribute to an apoptosis-resistant phenotype, by inhibiting chemotherapy-induced cell death and promoting MDR. By using Western blotting, qRT-PCR, Annexin V and immunofluorescence assays we have demonstrated a relationship between Pgp and survivin in a prior sensitive chronic myeloid leukemia (CML) cell line (K562). A high dose of vincristine induced a concomitant overexpression of Pgp and survivin, which was associated with a low apoptotic index in the K562 cell line. In addition, we observed a cytoplasmic co-localization of Pgp and survivin, suggesting a functional association between these two proteins in apoptosis control by a common mechanism. In summary, our data suggest that Pgp and survivin should be analyzed in aggregate because they may have significant impact on drug resistance in CML cells.
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PMID:P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells. 2172 Jul 8

Multidrug resistance (MDR) is considered a multifactorial phenotype which prevents a successful clinical cancer treatment. This phenomenon is mainly associated with mechanisms that include drug extrusion by P-glycoprotein (Pgp) overexpression and resistance to apoptosis derived by members of the inhibitor of apoptosis proteins (IAPs), such as XIAP. Studies have proposed the use of compounds that are able to inhibit or modulate Pgp function, with no changes in the physiological expression of this protein. Based on that, the present study aimed to evaluate the reversal of MDR phenotype through modulation of Pgp efflux pump activity in leukemia multidrug-resistant cells, using a low dose of cyclosporine A (CsA). We showed that modulation of Pgp activity by using CsA did not induce cytotoxic effects in leukemia cells, independently of Pgp expression. However, during the modulation condition, we could observe that vincristine-induced apoptosis was significant in resistant cells, which was also coupled with decreasing expression of the inhibitor of apoptosis protein XIAP. In summary, our data suggest that CsA is able to reversing MDR phenotype in vitro, inducing sensibility in multidrug-resistant cells with no alterations in Pgp expression. These findings contribute to our knowledge for the circumvention of MDR in cancer cells and could be helpful for new treatment approaches.
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PMID:Cyclosporine A enables vincristine-induced apoptosis during reversal of multidrug resistance phenotype in chronic myeloid leukemia cells. 2229 Apr 25

Chemokine ligand 25 (CCL25) and chemokine receptor 9 (CCR9) are important regulators of migration, proliferation and apoptosis in leukocytes and cancer cells. Blocking of the CCR9/CCL25 signal has been demonstrated to be a potential novel cancer therapy. Research into CCR9 and CCL25 has revealed their associated upstream and downstream signaling pathways; CCR9 is regulated by several immunological factors, including NOTCH, interleukin 2, interleukin 4 and retinoic acid. NOTCH in particular, has been revealed to be a crucial upstream regulator of CCR9. Furthermore, proteins including matrix metalloproteinases, P-glycoprotein, Ezrin/Radixin/Moesin and Livin are regulated via phosphatidylinositol-3 kinase/protein kinase B, which are in turn stimulated by CCR9/CCL25. This is a review of the current literature on the functions and signaling pathways of CCR9/CCL25.
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PMID:The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells. 3000 2