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)

In both mouse sarcoma 180 and human KB cells selected for the multiple drug resistance (MDR) phenotype, there is an elevation in the steady state mRNA level of c-fos. There is no detectable gene amplification for c-fos, nor is there any significant change in the rate of mRNA transcription or degradation, suggesting that other factors are responsible for the increased expression level in resistance. Cells selected for resistance to methotrexate, a drug not in the MDR group, do not have an increase in c-fos mRNA expression. When drug-sensitive cells are exposed for 30 min to an ED50 concentration of vinblastine, Adriamycin, colchicine, or VP-16, but not to methotrexate or cisplatin, there is a 3-6-fold induction in the level of c-fos message. Because the former drugs are members of the MDR class and the latter are not, the results are consistent with the hypothesis that induction of c-fos by low levels of cytotoxic drugs may be an early event in the acquisition of the MDR phenotype. If this were the case, then c-fos would be expected to act in concert with c-jun to control transcription by binding to a specific DNA regulatory site. Consistent with this explanation is the existence of an AP-1 sequence in the promotor region for the P-glycoprotein gene (mdr1), as well as the fact that c-jun is also overexpressed in MDR cells.
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PMID:Expression of c-fos in human and murine multidrug-resistant cells. 135 51

Sarcoma 180 (S180) cells pretreated with verapamil increase their resistance to doxorubicin in vitro. This result could be confirmed by in vivo experiments using P388 cells. The mechanism for this resistance is different from the P-glycoprotein-mediated mechanism characteristic for multidrug-resistant cells.
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PMID:Resistance to doxorubicin in tumor cells in vitro and in vivo after pretreatment with verapamil. 167 49

Among the many phenotypic characteristics of multidrug resistance (MDR), the presence of P-glycoprotein is nearly always observed, and it appears that the plasma membrane of the multidrug resistant cell is integrally involved in controlling drug resistance. Another membrane-associated protein kinase, protein kinase C (PKC), has been shown to regulate the flow of information to the cell interior and to control the efflux of a number of different compounds. We therefore initiated a study of PKC and MDR. We found that multidrug resistant sublines from both mouse sarcoma 180 and human KB lines exhibited 80-90% increases in basal PKC activity. The mechanism of the increase appears to be quite different in the two cell lines. The human KB cells overexpress the alpha isozyme of PKC, commensurate with the increase in alpha-PKC protein, whereas the mouse cells do not overexpress alpha-mRNA but increase alpha-PKC protein. Furthermore, it appears that PKC activity plays a functional role in drug resistance, since inhibition of endogenous PKC activity by staurosporine resulted in decreased resistance to Adriamycin. We also found that phosphorylation of MDR cell membrane vesicles by purified PKC, followed by immunoprecipitation of P-glycoprotein with monoclonal antibody C219, resulted in a level of phosphorylation of P-glycoprotein that was greater than the endogenous phosphorylation level. The data presented indicate that MDR cells of diverse species exhibited enhanced PKC activity but that the mechanisms were different. The increased kinase activity may have biological relevance to MDR since PKC appears to be coupled to P-glycoprotein function.
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PMID:Human multidrug resistant KB cells overexpress protein kinase C: involvement in drug resistance. 257 53

Resistance of tumor cells to doxorubicin is a multifactorial phenomenon. In the present investigation, the ability of resistance modifiers against different resistance mechanisms was analysed. Substances which block P-glycoprotein (P-170) function circumvented resistance of doxorubicin-resistant sarcoma 180 (S180) cells completely (verapamil, thioridazine) or partially (hycanthone), whereas inhibitors of glutathione S-transferase (ethacrynic acid, N-ethylmaleimide, buthionine sulfoximine), and protein kinase C (staurosporine, acridine orange) caused only a partial reversion of resistance. In contrast, an inhibitor of alkaline phosphatase (levamisole) did not overcome doxorubicin-resistance. These results indicate that P-glycoprotein blockers might be more effective to modulate doxorubicin-resistance of S180 cells as compared to other modifiers. Further investigations using other MDR cell lines are required to clarify the generality of these findings.
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PMID:Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms. 810 93

The expression of alkaline phosphatase (AP) was analyzed in multidrug-resistant (MDR) tumor cells (sarcoma 180, lung carcinoma, and renal cell carcinoma cell lines) by means of immunocytochemistry. MDR cell cultures showed an overexpression of AP and a cross-resistance to 6-thioguanine (6-TG, CAS 154-42-7). Significant correlations between AP expression and doxorubicin or vincristine resistance and P-glycoprotein (P-170) expression were found in these cell cultures. A specific AP inhibitor, levamisole, reversed resistance to 6-TG, but not to doxorubicin. This indicates that 6-TG resistance is certainly associated to P-170 but a causal function of AP for the development of MDR does not exist.
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PMID:Increase of alkaline phosphatase in multidrug-resistant tumor cells and their cross-resistance to 6-thioguanine. 826 80

5-(3-Aminopropyl)amino-7,10-dihydroxy-2-(2-hydroxethyl)-aminoethyl -6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxy-chloride (KW-2170), a novel derivative of pyrazoloacridone, was selected and evaluated for its antitumor activity and toxicity in mice. KW-2170 exhibited antitumor activity superior to adriamycin (ADM) against Sarcoma 180, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in mice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed significant antitumor activity against 17 human tumor xenografts of a total of 24 tumors tested and the total tumor response rate by treatment with KW-2170 was significantly higher than that by ADM (70.8 versus 58.3%). In particular, human lung carcinoma was highly sensitive to KW-2170, and a marked tumor regression was observed on Lu-65 and Lu-99 human lung carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also high on these human carcinoma models in comparison with that of ADM. The best antitumor efficacy of KW-2170 was observed by a weekly treatment schedule followed by a single treatment schedule and a successive administration schedule also tended to be toxic to the hosts. KW-2170 exhibited very low cross-resistance against four lines of multidrug resistant tumors expressing high levels of P-glycoprotein, and the drug showed significant antitumor activity against ADM-resistant human ovary carcinoma A2780/ADM and against nasopharynx carcinoma KB-A1 xenografts which were not sensitive to ADM. These results indicate that KW-2170 has a very potent antitumor activity and is feasible as a new antitumor drug against ADM-refractory solid tumors in clinics.
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PMID:Antitumor activity of KW-2170, a novel pyrazoloacridone derivative. 962 37

The inhibitory effects of vincristine (VCR) with or without verapamil (VER) on angiogenesis in mouse subcutaneous fascia induced by mouse sarcoma 180 cells were assessed using the dorsal air sac method. VCR combined with VER had inhibitory effects on tumor-induced angiogenesis, but VCR alone did not inhibit capillarization. The chemosensitivity of human umbilical vein endothelial cells (HUVEC) and tumor-derived endothelial cells from rat KMT-17 fibrosarcoma (TEC) was examined using the microculture tetrazolium assay. VCR and taxol had strong anti-proliferative activity against HUVEC, but only weakly inhibited the proliferation of TEC. In combination with VER, VCR and Taxol inhibited the proliferation of TEC. Cisplatin, mitomycin C, and 5-fluorouracil had weakly anti-proliferative activity against both HUVEC and TEC. Expression of P-glycoprotein (P-gp) was found in TEC, but not in HUVEC using western blot analysis. These findings indicate that drug resistance and P-gp expression appeared on newly formed capillaries induced by rodents tumors.
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PMID:Drug resistance and P-glycoprotein expression in endothelial cells of newly formed capillaries induced by tumors. 971 95

Mouse sarcoma 180 cell with a 25-fold higher cisplatin (CDDP) resistance, termed S-180cisR, is newly established. S-180cisR cells grow quite slowly in the presence of CDDP with high concentration. This may show that S-180cisR cells modulate the cell cycle to acquire CDDP resistance. P-Glycoprotein is selectively expressed on the surface of S-180cisR, which is not on CDDP-sensitive S-180 parent cells. In an experiment using an inhibitor (verapamil) of P-glycoprotein, cytotoxicity of CDDP against S-180cisR is significantly increased (viz., IC(50) value is decreased) and accumulation of CDDP in S-180cisR cells is also increased. These results indicate that enhanced pumping-out of CDDP by P-glycoprotein should be one of the reasons for the CDDP resistance of S-180cisR. A platinum(II) complex with a cyclometalated 2-phenylpyridine ligand and a nonchelated one (complex 5) is synthesized, and its structure is determined by X-ray structural analysis. Complex 5 has a cyctotoxicity against S-180cisR higher than that of CDDP and its derivatives with 2- or 3-substituted pyridine ligands (complexes 2-4, 6, 7). Complex 5 is incorporated in S-180cisR to an enormously greater extent than CDDP; that is, the ratio of accumulated platinum amount after 3 h is 61.9. In S-180 parent cells, on the other hand, the ratio remains 8.1. This high accumulation of complex 5 into S-180cisR must account for the higher activity of complex 5 against S-180cisR compared to CDDP.
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PMID:Mononuclear platinum(II) complex with 2-phenylpyridine ligands showing high cytotoxicity against mouse sarcoma 180 cells acquiring high cisplatin resistance. 1174 83

The aim of this investigation was to analyze whether or not ionizing radiation can induce the expression of resistance- and oncoproteins in murine sarcoma 180 cells and several human carcinoma cell lines. For assessment of the proteins the streptavidin-biotin peroxidase-complex method was performed using specific antibodies. Expression of glutathione S-transferase-pi and thymidylate-synthase was increased after a single dose of irradiation which was accompanied by a lower sensitivity against cisplatin and 5-fluorouracil. No differences in protein expression could be detected for P-glycoprotein 170 and topoisomerase II. Differences in the expression of the oncoproteins c-Fos and c-ErbB1 were also found after irradiation. In contrast, a decreased expression of topoisomerase II was found after fractionated irradiation. This was confirmed by mRNA analysis.
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PMID:Induction of resistance-proteins and oncoproteins in murine and human tumor-cell lines after irradiation. 2159 37