UNIPROT:P10415 - FACTA Search

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

Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although melphalan has been used as a therapeutic reagent for multiple myeloma, many patients become refractory. To elucidate the mechanism of resistance to melphalan, we generated a melphalan-resistant myeloma cell line, KHM-11(EMS), by treating a parental line, KHM-11, with a mutagen, ethylmethanesulfonate. KHM-11(EMS) is 55 times more resistant to melphalan. gamma-Glutamylcysteine synthetase, P-glycoprotein, multidrug-resistance-associated protein, lung-resistance-related protein and the Bcl-2 family of proteins were not responsible for the drug resistance in KHM-11(EMS). Intracellular incorporation of melphalan to myeloma cells was determined by using [(14)C]-labeled melphalan. Accumulation of melphalan in KHM-11(EMS) was 43% of KHM-11, while the efflux rates were comparable in both cell lines. The uptake of melphalan was inhibited by the addition of L-phenylalanine, indicating that melphalan is incorporated through the L-phenylalanine transporter as reported previously. Expression of CD98, which was recently cloned as an L-phenylalanine transporter, was 6-fold decreased in KHM-11(EMS), suggesting that CD98 may be correlated with the incorporation of melphalan. CD98 expression and incorporation of melphalan were analyzed in fresh purified myeloma cells from 5 patients. All myeloma cells from 4 cases expressed CD98 at a high level and incorporated melphalan. However, tumor cells from 1 case expressed CD98 at low levels and did not incorporate melphalan. Taken together, reduced melphalan uptake could be responsible for the drug resistance in KHM-11(EMS), and down-regulation of CD98 may be related to this phenomenon. Further investigation of the correlation between impaired drug uptake and down-regulation of CD98 in myeloma cells should be important to understand the mechanism of resistance to melphalan.
...
PMID:Down-regulation of CD98 in melphalan-resistant myeloma cells with reduced drug uptake. 1094 Jun 52

We have established a paclitaxel-resistant mutant cell line called H460/TAX which was derived from human non-small cell lung cancer (NSCLC) H460. A 64-fold greater resistant was shown in our assay as compared with the parental cells. High specificity of drug resistance was also observed since this mutant was not cross-resistant to several other anticancer drugs. Drug accumulation in H460/TAX was significantly less than that in H460. Many endogenous protein profiles were intact, including the expression level of P-glycoprotein, multidrug resistance-associated protein, the 70 kDa heat shock proteins as well as the phosphorylation of Bcl-2 in H460/TAX cells, except that the total amount of alpha- and beta- tubulins was higher in H460/TAX than in H460 cells. Higher drug concentration and longer treatment for paclitaxel were required in H460/TAX to exert the phosphorylation of keratin 19 which was then accompanied by reorganization of the intermediate filament and the microtubule networks. Since all of the aforementioned factors involved in paclitaxel-resistance in other systems were not found to be significantly altered in H460/TAX, there must be other paclitaxel-resistance mechanisms(s) which remains to be identified in human lung cancers.
...
PMID:Establishment and characterization of a paclitaxel-resistant human non-small cell lung cancer cell line. 1095 9

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells. Resting cells are also killed. This fact suggests that inhibition of cdks involved in the control of cell cycle is not the only mechanism of action. Inhibition of cdk's with additional functions (i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreover, direct and indirect inhibition of receptor activation (EGFR) and/or a direct inhibition of kinases (pp60 Src, PKC, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded that the inhibitory activity (IC50) of flavopiridol on these kinases is in the range of concentrations that might be achieved intracellularly after systemic application of non-toxic doses of flavopiridol. However, no in situ data from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 (in addition to inhibition of cdk's) flavopiridol is able to induce apoptosis. Thus many questions regarding the detailed mechanism of antitumoral action of flavopiridol are still open. For the design of protocols for future clinical studies this review covers the essential information available on the mechanism of antitumoral activity of flavopiridol. The characteristics of this antitumoral activity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its efficacy on pRb, p53 and Bcl-2 expression; lack of interference with the most frequent multidrug resistance proteins (P-glycoprotein and MRP-190); and a strong antiangiogenic activity. Based on these pharmacological data it can be concluded that flavopiridol could be therapeutically active in tumor patients: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2); in spite of drug resistance of their tumors induced by first line treatment (and caused by enhanced expression of multidrug resistance proteins); in combination with conventional chemotherapeutics preferentially given prior to flavopiridol; and due to a complex mechanism involving cytotoxicity on cycling and on resting tumor cells, apoptosis and antiangiogenic activity. In consequence, flavopiridol is a highly attractive, new antitumoral compound and deserves further elucidation of its clinical potency.
...
PMID:Mechanisms of action of flavopiridol. 1131 60

Apoptosis is cellular suicide, the functional opposite of mitosis. It may play an important role in tissue growth control and removal of damaged and premalignant cells. The fact that diverse chemotherapeutic agents induce apoptosis, while they engage different intracellular targets and cause DNA damage, raises a concern that tumors resistant to chemotherapy are unable to initiate the apoptotic process. The anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-X(L), play an important role in the regulation of apoptotic cell death. Bcl-2 and Bcl-X(L)have been reported to confer chemotherapy resistance in short-term survival assays in vitro. However, they failed to provide a long-term clonogenic survival advantage. Thus, the role of anti-apoptotic Bcl-2 and Bcl-X(L)on chemotherapy resistance in vivo remains unclear. In vivo, tumor cells receive survival signals from the extracellular microenvironment. Since the microenvironmental factors have been reported to modulate the expression and function of Bcl-2 family proteins, Bcl-2 and Bcl-X(L)might be associated with the chemotherapy resistance in vivo through the influence of these factors. Consistent with this hypothesis, several investigators have recently reported that the sensitivity to chemotherapy in in vitro clonogenic assays did not correlate with that in in vivo tumor models. The lack of microenvironmental factors might cause the discrepancy between in vitro clonogenic growth and in vivo tumor growth. These results suggest that Bcl-2 and Bcl-X(L)could contribute to chemotherapy resistance in vivo, along with already defined drug resistance mechanisms (i.e. P-glycoprotein, MRP). Therapies aimed at suppressing the expression and function of Bcl-2 and Bcl-X(L)or at intercepting microenvironmental factors might successfully overcome chemotherapy resistance. Copyright 2000 Harcourt Publishers Ltd.
...
PMID:In vivo veritas: Bcl-2 and Bcl-X(L)mediate tumor cell resistance to chemotherapy. 1149 79

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.
...
PMID:Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein. 1151 98

The expression of multidrug resistant proteins in bladder cancer and clinical implication was studied. Expression of multidrug-associated protein (MRP), P-glycoprotein (P-gp), P53 and Bcl-2 proteins were detected by using immunohistochemical method in 40 specimens of bladder transitional cell carcinoma. The results showed that the positive rate of MRP, P-gp, P53 and Bcl-2 was 52.5%, 57.5%, 47.5% and 62.5% respectively. The positive rate of MRP, P-gp, P53 and Bcl-2 in the grade I, II and III of tumors was 46.3%, 38.5%, 38.5%, 23.1%; 52.9%, 39.8%, 47.1%, 76.4%; 60.0%, 80.0%, 60.0%, 90.0% respectively. The positive rate of MRP, P-gp, P53 and Bcl-2 in 24 primary tumor specimens was 37.5%, 41.7%, 33.3%, 45.8% and that in 16 cases in recurrent specimens receiving chemotherapy 75.0%, 81.3%, 68.8%, 87.5% respectively. It was suggested the positive rate of MRP, P-gp, P53 and Bcl-2 was increased with the advance of tumor grade. The positive rate of four proteins in all recurrent cases was significantly increased (P < 0.05). The expression of MRP, P-gp, P53 and Bcl-2 proteins might be the important factors for chemotherapy failure.
...
PMID:Expression of multidrug-associated protein, P-glycoprotein, P53 and Bcl-2 proteins in bladder cancer and clinical implication. 1152 49

We evaluated the effect of interferon-alpha2b as a chemosensitiser on HCT-15 cell line in treatment with doxorubicin. Chemosensitivity was determined by [3H]-thymidine incorporation and tetrazolium assays. The levels of expression of P-glycoprotein, Bcl-2 oncoprotein and HLA-ABC complex, and cell cycle/apoptosis analysis were determined by flow cytometry. Dox 50 ng/ml - IFN alpha 2b 500 IU/ml treatment inhibited cell proliferation (47.2 +/- 1.4%, p < 0.0001; MTT assay: 40.6 +/- 1.2%, p < 0.0001) and augmented the expression of P-170, Bcl-2 and HLA-ABC, while it didn't exert apoptosis, producing a slight G2/M arrest. A concentration of IFN-alpha2b, that by itself is not cytotoxic, can potentiate the efficacy of the anticancer drug. This effect is not due to a down-modulation of P-170. The absence of apoptosis and augmented levels of Bcl-2 expression suggests that this could be one of the mechanisms of drug resistance exerted by these cells.
...
PMID:Interferon-alpha 2b modulation of doxorubicin sensitivity in a multidrug resistant cell line. 1171 20

P-glycoprotein (P-gp) is a 170-kDa glycoprotein encoded by the MDR-1 gene. In tumor cells overexpression of P-gp is associated with resistance to chemotherapy-induced apoptosis. P-gp is also expressed on cells of the immune system; however, its role in lymphocyte physiology remains unclear. Therefore, in this investigation, we examined a possible role of P-gp in the survival of in vitro activated peripheral blood mononuclear cells (MNCs). MNCs were activated with anti-CD3 monoclonal antibody (mAb) for 96 hr in the presence or absence of anti-P-gp mAb or isotype control and examined for apoptosis by TUNEL assay. Activation of caspase was determined by colorimetric assay. Activated lymphocytes (96 hr) are resistant to apoptosis. However, anti-P-gp mAb-induced apoptosis in anti-CD3 activated MNC. Induction of apoptosis was associated with increased expression of CD95L; activation of caspase 3, however, did not affect the expression of Bcl-2 and Bcl-xL. Furthermore, both recombinant Fas-Fc fusion protein, a blocker of CD95-CD95L interactions, and Z-DEVD-FMK, a cell-permeable caspase 3 inhibitor, reversed anti-P-gp-induced apoptosis. These data demonstrate that anti-P-gp mAb promotes apoptosis in activated T lymphocytes by up-regulating CD95L expression and via CD95-CD95L interactions and suggest a possible role of P-gp in lymphocyte survival.
...
PMID:Anti-P-glycoprotein antibody-induced apoptosis of activated peripheral blood lymphocytes: a possible role of P-glycoprotein in lymphocyte survival. 1181 87

When P-glycoprotein (PGP) was first identified as a direct mediator of multidrug resistance (MDR) a great deal of excitement was generated as scientists and clinicians anticipated the ability to successfully treat previously refractory cancers by blocking this drug efflux pump. More than twenty years later there is still minimal evidence that inhibiting PGP will have widespread impact on the chemosensitivity of human tumors. Yet, we know that PGP is over-expressed in many cancers, is associated with poor prognosis in certain tumor types and, if functional, will certainly reduce the accumulation of many common anticancer drugs inside tumor cells exhibiting elevated PGP levels. Similar situations have arisen more recently for other potential mediators of chemosensitivity such as the apoptosis antagonist protein Bcl-2. Bcl-2 has been linked to drug resistance and poor patient prognosis in numerous studies. There has been a great deal of interest in blocking expression or function of this protein to increase the susceptibility of tumor cells to apoptotic stimuli such as chemotherapy. However, preclinical and clinical evidence supporting this approach as a unilateral means of significantly enhancing the response of tumors to chemotherapy is limited. In view of these examples, it would appear likely that similar caveats will be experienced in the future as new molecular targets are identified for potential MDR reversal. Given the ever increasing evidence of genetic diversity in cancer development and progression, it should not be surprising that the development of MDR is also complex and heterogeneous. Consequently, it should also not be surprising that solutions to this problem are unlikely to arise from interventions aimed at any single resistance mechanism. These concepts suggest that new approaches to addressing the various molecular and pharmacological features associated with MDR will be necessary in order to make significant in-roads into improving the clinical activity of current and future anticancer agents. This review summarizes many of the current directions being taken to overcome MDR and how liposomal drug delivery systems may play an important role in achieving this aim.
...
PMID:The role for liposomal drug delivery in molecular and pharmacological strategies to overcome multidrug resistance. 1183 52

Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most chemotherapeutic treatments probably due to the expression of various multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp) is established as one such factor, but other mechanisms such as at-MDR, characterized by attenuated DNA-topoisomerase II (topoII) activity, may be functional as well. In addition, regulating proteins involved in apoptosis can exhibit multidrug resistant features. However, prevention of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor has the cytotoxicity of a variety of chemotherapeutic agents known to trigger apoptotic or necrotic cell death been tested in RCC in a systematic fashion. Using immunohistochemistry and Western blotting, Bcl-2 and Bax expression was determined in a panel of multidrug resistant RCC lines featuring Pgp and/or at-MDR. The results were related to apoptotic activity and kind of cell death in these cell lines, demonstrated by incubation with Hoechst 33342 and propidium iodide after treatment with various cytotoxic agents and quantitated by MTT. In the drug resistant sublines, some decreased Bax and strongly increased Bcl-2 expression was seen by immunohistochemistry indicating prevention of apoptosis as a distinct feature of MDR in RCC. This was confirmed by Western blotting. Sublines revealed significant resistance for all drugs, except for CC-313 and DiMIQ. However, these drugs induced necrotic cell death, in contrast to all other drugs tested, which induced apoptotic cell death. We conclude that, in chemoselected RCC sublines, multidrug resistance appears to be functional due to inhibition of apoptosis, apart from the MDR1 and at-MDR resistance mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC, probably because they do not kill by induction of apoptosis.
...
PMID:Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells. 1184 68

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>