Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imatinib mesylate (imatinib) is a new generation preparation that is now successfully used for treatment of cancer, particularly for chemotherapy of chronic myeloid leukemia (CML). Imatinib inhibits the activity of chimeric kinase BCR-ABL, which is responsible for the development of CML. The goal of this study was to investigate the role of a multidrug resistance protein, P-glycoprotein (Pgp), in the evolution of CML treated with imatinib. We demonstrate here that although imatinib is a substrate for Pgp, cultured CML cells (strain K562/i-S9), overexpressing active Pgp, do not exhibit imatinib resistance. Studies of CML patients in the accelerated phase have shown variations in the number of Pgp-positive cells (Pgp+) among individual patients treated with imatinib. During treatment of patients with imatinib for 6-12 months, the number of Pgp-positive cells significantly increased in most patients. The high number of Pgp+ cells remained in patients at least for 4.5 years and correlated with active Rhodamine 123 (Rh123) efflux. Such correlation was not found in the group of imatinib-resistant patients examined 35-60 months after onset of imatinib therapy: cells from the imatinib-resistant patients exhibited efficient Rh123 efflux irrespectively of Pgp expression. We also compared the mode of Rh123 efflux by cells from CML patients who underwent imatinib treatment for 6-24 months and the responsiveness of patients to this therapy. There were significant differences in survival of patients depending on the absence or the presence of Rh123 efflux. In addition to Pgp, patients' cells expressed other transport proteins of the ABC family. Our data suggest that treatment with imatinib causes selection of leukemic stem cells characterized by expression of Pgp and other ABC transporters.
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PMID:Role of P-glycoprotein in evolution of populations of chronic myeloid leukemia cells treated with imatinib. 1829 26

Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in chronic myeloid leukemia (CML) and in Bcr-Abl-positive acute lymphoblastic leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second-generation inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or imatinib-intolerant disease. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Overexpression of BCR-ABL and multidrug resistance gene (MDR-1) were found among the investigated mechanisms. We showed that nilotinib is a substrate of the multidrug resistance gene product, P-glycoprotein, using verapamil or PSC833 to block binding. Up-regulated expression of p53/56 Lyn kinase, both at the mRNA and protein level, was found in one of the resistant cell lines and Lyn silencing by small interfering RNA restored sensitivity to nilotinib. Moreover, failure of nilotinib treatment was accompanied by an increase of Lyn mRNA expression in patients with resistant CML. Two Src kinase inhibitors (PP1 and PP2) partially removed resistance but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn. Such mechanisms of resistance are close to those observed in imatinib-resistant cell lines and emphasize the critical role of Lyn in nilotinib resistance.
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PMID:Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. 1904 60

BCR-ABL tyrosine kinase, generated from the reciprocal chromosomal translocation t(9;22), causes chronic myeloid leukemia (CML). BCR-ABL is inhibited by imatinib; however, several mechanisms of imatinib resistance have been proposed that account for loss of imatinib efficacy in patients with CML. Previously, we showed that overexpression of the efflux drug transporter P-glycoprotein partially contributed to imatinib resistance in imatinib-resistant K562 CML cells having no BCR-ABL mutations. To explain an additional mechanism of drug resistance, we established a subclone (K562/R) of the cells and examined the BCR-ABL signaling pathway in these and wild-type K562 (K562/W) cells. We found the K562/R cells were 15 times more resistant to imatinib than their wild-type counterparts. In both cell lines, BCR-ABL and its downstream signaling molecules, such as ERK1/2, ERK5, STAT5, and AKT, were phosphorylated in the absence of imatinib. In both cell lines, imatinib effectively reduced the phosphorylation of all the above, except ERK1/2, whose phosphorylation was, interestingly, only inhibited in the wild-type cells. We then observed that phospho-ERK1/2 levels decreased in the presence of siRNA targeting BCR-ABL, again, only in the K562/W cells. However, using an ERK1/2 inhibitor, U0126, we found that we could reduce phospho-ERK1/2 levels in K562/R cells and restore their sensitivity to imatinib. Taken together, we conclude that the BCR-ABL-independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK1/2 could be a target for the treatment of CML patients whose imatinib resistance is due to this mechanism.
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PMID:Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells. 1984 70

Although the development of tyrosine kinase inhibitors (TKIs) to control the unregulated activity of BCR-ABL revolutionized the therapy of chronic myeloid leukemia, resistance to TKIs is a clinical reality. Among the postulated mechanisms of resistance is the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which mediate reduced intracellular drug accumulation. We compared the interactions of the TKIs imatinib, nilotinib, and dasatinib with ABCB1 and ABCG2 in ex vivo and in vitro systems. The TKIs inhibited rhodamine 123 and Hoechst 33342 efflux mediated by endogenous expression of the transporters in murine and human hematopoietic stem cells with potency order nilotinib >> imatinib >> dasatinib. Studies with ABCB1-, ABCG2-, and ABCC1-transfected human embryonic kidney 293 cells verified that nilotinib was the most potent inhibitor of ABCB1 and ABCG2. Cytotoxicity assays in stably transduced K562-ABCG2 and K562-ABCB1 cells confirmed that the TKIs were also substrates for the two transporters. Like imatinib, both nilotinib and dasatinib decreased ABCG2 surface expression in K562-ABCG2 cells. Finally, we found that all TKIs were able to compete labeling of ABCB1 and ABCG2 by the photo-cross-linkable prazosin analog [(125)I]iodoarylazidoprazosin, suggesting interaction at the prazosin-binding site of both proteins. Our experiments support the hypothesis that all three TKIs are substrates of ABC transporters and that, at higher concentrations, TKIs overcome transporter function. Taken together, the results suggest that therapeutic doses of imatinib and nilotinib may diminish the potential of ABCB1 and ABCG2 to limit oral absorption or confer resistance. Clinical data are required to definitively answer the latter question.
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PMID:Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. 2042 56

We used two imatinib resistant cell lines, K562-ADM cells, which over-express P-glycoprotein (a product of the ABCB1 gene, more commonly known as MDR1), and K562-hTERT cells, which over-express the telomerase reverse transcriptase (TERT), as models to show that the acquisition of multidrug resistance in CML is associated with the enhanced phosphorylation of signal transducer and activator of transcription 5 (STAT5). The induction of P-glycoprotein expression that occurred in response to adriamycin treatment was accompanied by increased phosphorylation of BCR-ABL and STAT5, as well as increased telomerase protein expression. Intriguingly, a ChIP assay using an anti-STAT5 antibody revealed direct binding of STAT5 to the promoter regions of both the human TERT gene and the MDR1 gene in K562-ADM cells. Conversely, silencing of endogenous STAT5 expression by siRNA significantly reduced both the expression of P-glycoprotein and telomerase activity and resulted in the recovery of the imatinib sensitivity of K562-ADM cells. These findings indicate a critical role for STAT5 in the induction of P-glycoprotein and in the modulation of telomerase activity in drug-resistant CML cells. Furthermore, primary leukemic cells obtained from patients in blast crisis showed increased levels of phospho-STAT5, P-glycoprotein and telomerase. In contrast, none of these proteins were detectable in the cells obtained from patients in the chronic phase. Together, these findings indicate a novel mechanism that contributes toward multidrug resistance involving STAT5 as a sensor for cytotoxic drugs in CML patients.
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PMID:Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1. 2135 8

Tasigna (Nilotinib) is a BCR-ABL kinase inhibitor recently approved by the Food and Drug Administration, which is indicated for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively pump these drugs out of cells utilizing ATP as an energy source, has been linked to the development of drug resistance in CML patients. We report here the synthesis and characterization of a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. A fluorescent derivative of Tasigna, BODIPY FL Tasigna, inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp- and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. In addition, [(3)H]-Tasigna was found to be transported by Pgp-expressing polarized LLC-PK1 cells in a transepithelial transport assay. Consistent with these results, both Tasigna and BODIPY FL Tasigna were less effective at inhibiting the phosphorylation of Crkl (a substrate of BCR-ABL kinase) in Pgp- and ABCG2-expressing K562 cells due to their reduced intracellular concentration. Taken together, these data provide evidence that BODIPY FL Tasigna is transported by Pgp and ABCG2, and Tasigna is transported by Pgp. Further, we propose that BODIPY FL Tasigna can potentially be used as a probe for functional analysis of Pgp and ABCG2 in cancer cells and in other preclinical studies.
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PMID:Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. 2163 Jun 81

The blood-testis barrier (BTB), one of the tightest blood-tissue barriers in the mammalian body, creates an immune-privileged site for postmeiotic spermatid development to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. However, the BTB undergoes extensive restructuring at stage VIII of the epithelial cycle to facilitate the transit of preleptotene spermatocytes and to prepare for meiosis. This action thus prompted us to investigate whether this stage can be a physiological window for the delivery of therapeutic and/or contraceptive drugs across the BTB to exert their effects at the immune-privileged site. Herein, we report findings that P-glycoprotein, an ATP-dependent efflux drug transporter and an integrated component of the occludin/zonula occludens 1 (ZO-1) adhesion complex at the BTB, structurally interacted with focal adhesion kinase (FAK), creating the occludin/ZO-1/FAK/P-glycoprotein regulatory complex. Interestingly, a knockdown of P-glycoprotein by RNAi was found to impede Sertoli cell BTB function, making the tight junction (TJ) barrier "leaky." This effect was mediated by changes in the protein phosphorylation status of occludin via the action of FAK, thereby affecting the endocytic vesicle-mediated protein trafficking events that destabilized the TJ barrier. However, the silencing of P-glycoprotein, although capable of impeding drug transport across the BTB and TJ permeability barrier function, was not able to induce the BTB to be "freely" permeable to adjudin. These findings indicate that P-glycoprotein is involved in BTB restructuring during spermatogenesis but that P-glycoprotein-mediated restructuring does not "open up" the BTB to make it freely permeable to drugs.
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PMID:P-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK). 2210 13

Multidrug resistance observed in cancer chemotherapy is commonly attributed to overexpression of efflux transporter proteins. These proteins act as ATP-dependent drug efflux pumps, actively extruding chemotherapeutic agents from cells and causing a decrease in intracellular drug accumulation. Besides the well-recognized role of P-glycoprotein (P-gp, ABCB1), the breast cancer resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an important role in multidrug resistance. In contrast to P-glycoprotein, only a few inhibitors of ABCG2 are known. According to the literature, tyrosine kinase inhibitors (TKIs) can be considered to be broad-spectrum inhibitors, interacting with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs, gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR inhibitors such as gefitinib and PD158780 reduced both total and surface expression of ABCG2 in EGRF-positive MDCK BCRP cells by interaction with the PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect of XR9577, a well-known ABCG2 modulator, lowering the concentration required for half maximal inhibition. On the other hand, BCR-ABL inhibitors had no influence on ABCG2 expression and modulator activity. Interestingly, a combination of an EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant reduction of ABCG2 expression at low concentrations of the drugs. Based on our results, we assume that EGFR exerts a post-transcriptional enhancing effect on ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression with EGFR inhibitors, combined with the inhibition of ABCG2 with potent modulators might be a promising approach to circumvent MDR in cancer cells.
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PMID:Tyrosine kinase inhibitors influence ABCG2 expression in EGFR-positive MDCK BCRP cells via the PI3K/Akt signaling pathway. 2235 38

Promoter CpG hypermethylation of tumor suppressor genes is an essential step in cancer progression but little is known about its effect on cancer multidrug resistance. In this study, we showed that CDH1 promoter was hypermethylated in drug resistance of a doxorubicin-induced multidrug resistant hepatocellular carcinoma cell line R-HepG2. Transfection of CDH1 cDNA into R-HepG2 cells led to increased amount of doxorubicin uptake, decreased cell viability, decreased P-glycoprotein expression and increased apoptotic population of cells exposed to doxorubicin. Proto-oncogene tyrosine-protein kinase FYN was over-expressed in R-HepG2 cells which displayed a negative correlation with the expression of CDH1. FYN was knocked down in R-HepG2 cells, leading to less drug resistance by increased cell viability, increased doxorubicin uptake and attenuated P-glycoprotein expression. Our findings identified epigenetic silencing of CDH1 in cancer cells might be a new molecular event of multidrug resistance.
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PMID:Epigenetic loss of CDH1 correlates with multidrug resistance in human hepatocellular carcinoma cells. 2263 15

Erlotinib was originally developed as an epidermal growth factor receptor (EGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated. Conversely, in preclinical settings, erlotinib has been shown to inhibit the constitutive activation of SRC kinases and mTOR, as well as to synergize with the DNA methyltransferase inhibitor azacytidine (a reference therapeutic for a subset of leukemia patients) by promoting its intracellular accumulation. Here, we show that both erlotinib and gefitinib (another EGFR inhibitor) inhibit transmembrane transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), also in acute myeloid leukemia (AML) cells that do not overexpress these pumps. Thus, inhibition of drug efflux by erlotinib and gefitinib selectively exacerbated (in a synergistic or additive fashion) the cytotoxic response of KG-1 cells to chemotherapeutic agents that are normally extruded by ABC transporters (e.g., doxorubicin and etoposide). Erlotinib limited drug export via ABC transporters by multiple mechanisms, including the downregulation of surface-exposed pumps and the modulation of their ATPase activity. The effects of erlotinib on drug efflux and its chemosensitization profile persisted in patient-derived CD34+ cells, suggesting that erlotinib might be particularly efficient in antagonizing leukemic (stem cell) subpopulations, irrespective of whether they exhibit or not increased drug efflux via ABC transporters.
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PMID:Erlotinib antagonizes ABC transporters in acute myeloid leukemia. 2309 22


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