Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of seven isoquinoline derivatives in overcoming resistance to vinblastine in Adriamycin-resistant mouse leukemia P388/ADR cells and human myelogeneous leukemia K562/ADR cells. N-(2-Methylpiperazyl)-5-isoquinoline-sulfonamide (H-7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) did not reverse resistance to vinblastine in these resistant cells. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5- isoquinolinesulfonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]- amino]ethyl]-5-isoquinolinesulfonamide (H-87) caused significant accumulation of intracellular vinblastine and marked reversal of the resistance to vinblastine in both resistant cell lines. Addition of a formyl group at the terminal amino group of H-86 (H-85) or addition of an aminoethyl group to the nitrogen atom at the sulfonamide group of H-86 (W-66) reduced those activities. The activity on vinblastine accumulation seems to correlated with the hydrophobicity of the compounds. The compounds that effectively reversed resistance to vinblastine inhibited [3H]vinblastine efflux and photoaffinity labeling of P-glycoprotein with a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I]iodo)-salicyl)-N'-beta-aminoethylvindesine. Although these isoquinoline derivatives inhibited protein kinase A and protein kinase C with various potencies, these inhibitory activities did not correlate with the reversal of drug resistance. These results indicate that hydrophobic isoquinoline derivatives reverse multidrug resistance due to the suppression of drug binding to P-glycoprotein, without involvement of their activities on protein kinase A and protein kinase C.
Mol Pharmacol 1992 Jun
PMID:Overcoming of vinblastine resistance by isoquinolinesulfonamide compounds in adriamycin-resistant leukemia cells. 161 7

The therapeutic use of doxorubicin (an antitumoral antibiotic belonging to the anthracycline group) is limited by its cardiotoxicity. Adriamycin (DXR) causes myocardial subcellular damage, such as myocytolysis, disarray of actin filaments, and alterations in the Z-band with loss of sarcomeric organization. We studied the effect of stoichiometrical concentrations of DXR on the interaction between cardiac actin and alpha-actinin in solution. Doxorubicin inhibits the formation of alpha-actinin/actin tridimensional networks and bundles. The main effect of the drug seems to be on the size of the actin polymers.
Exp Mol Pathol 1992 Jun
PMID:Interaction of cardiac alpha-actinin and actin in the presence of doxorubicin. 163 82

Morphologic changes in Doxorubicin (DXR)-induced cardiomyopathy are characterized by marked dilatation of the sarcoplasmic reticulum (SR). DXR was administered to New Zealand White rabbits for 5 or 8 weeks and the three-dimensional structure of the sarcotubular system in cardiac muscle cells from each rabbit was examined under a field-emission type scanning electron microscope (SEM) after removal of cytoplasmic matrices by the osmium-DMSO-osmium procedure. Five weeks after the initial injection of DXR, partial dilatation of the SR and damaged mitochondria with lysis of cristae were observed three-dimensionally. After 8 weeks, the three-dimensional structure of the SR showed extensive spherical ballooning which could be seen clearly in bold relief. Thus, we could directly visualize structural alterations of the sarcotubular system in DXR-induced cardiomyopathy using the SEM.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Ultrastructural alterations of the myocardium induced by doxorubicin. A scanning electron microscopic study. 167 75

Doxorubicin (Adriamycin, ADR) is an effective antineoplastic agent with a major side effect of dilated cardiomyopathy. Previously we showed ADR selectively decreased alpha cardiac (alpha c) actin mRNA in the rat heart when compared to other mRNAs examined in heart and skeletal muscle. The present study determined if this effect was selective for mRNAs within the thin filament, related to inhibitory effects on mitochondrial transcription, and modified by pretreatment with the cardioprotective chelating agent ICRF-187. Adult Sprague-Dawley rats received ADR at 8 mg/kg intraperitoneally (ip) with or without pretreatment with ICRF-187 given at 80 mg/kg ip. After 3 days, rats were killed and myocardial RNA was extracted, electrophoresed, transferred to nitrocellulose, and hybridized with the [32]cDNA probes alpha c actin, troponin C (TnC), BamHI fragment of mouse mitochondria (MM), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Results showed a major depressive effect of ADR on rat myocardial alpha c actin mRNA. No depression of the other mRNAs examined (TnC, MM, or G3PD) was seen. ICRF-187 did not modify the effect. We conclude that the ADR-induced decrease in alpha c actin mRNA was: (1) selective within the thin filament; (2) not related to inhibitory effects on mitochondrial transcription; and (3) not related to free radical formation. Possible subcellular mechanisms are discussed.
Exp Mol Pathol 1991 Apr
PMID:Selective alterations in rat cardiac mRNA induced by doxorubicin: possible subcellular mechanisms. 170 8

ADR-529 protects against anthracycline cardiotoxicity, possibly by preventing free radical induction. We hypothesize that this occurs by ADR-529 forming a ternary anthracycline-iron-ADR-529 complex. This study used 200-MHz Fourier-transformed NMR to demonstrate the ability of ADR-529 to do this. Peak assignments were by proton-correlated spectroscopy and proton-carbon heteronuclear-correlated spectroscopy. Ga3+ served as a probe for Fe3+, and D2O was the system solvent. Doxorubicin and epirubicin were the studied drugs. Proton spectra of multiple combinations (including pure standards as controls) were obtained. Both Ga3+ plus ADR-529 and Ga3+ plus doxorubicin showed evidence of complexation, as seen by appropriate peak shifts and changes in the associated coupling constants. Ga3+ plus ADR-529 plus epirubicin showed complexation different from that of Ga3+ plus ADR-529 or Ga3+ plus doxorubicin and consistent with the proposed structure. We conclude that ADR-529 would be able to form a ternary complex with an existing anthracycline-Fe3+ complex in an isolated aqueous environment.
Mol Pharmacol 1992 Jan
PMID:In vitro evidence for direct complexation of ADR-529/ICRF-187 [(+)-1,2-bis-(3,5-dioxo-piperazin-1-yl)propane] onto an existing ferric-anthracycline complex. 173 25

Doxorubicin (DXR), an anthracycline antineoplastic drug, is mainly metabolized to the C-13 dihydroderivative doxorubicinol (DXR-ol), which displays cytotoxic activity on various cell lines. To better characterize the cytotoxic activity of this metabolite, we have studied the effect of DXR (0.1-10 micrograms/ml) or DXR-ol (1-100 micrograms/ml) on the transformed fibroblast cell line V79/AP4 by means of the clonogenic assay, cytofluorescence, and light and electron microscopy. Both DXR and DXR-ol displayed a dose-dependent inhibition of colony formation with an IC50 factor DXR-ol/DXR of 19.5. A striking nuclear fluorescence was observed after DXR but not after DXR-ol. A low number of mitoses and a decrease in nucleoli staining affinity were the most evident alterations induced by DXR. Electron microscopy showed both nuclear and cytoplasmic changes in DXR treated cells: nucleolar segregation, cytoplasmic vacuoles, and mitochondrial swelling with dense needle-shaped material were observed. Exposure to formic acid confirmed the calcific nature of the mitochondrial bodies. Only the highest dose of DXR-ol brought about nuclear and cytoplasmic ultrastructural changes similar to those induced by DXR. Our data describe new in vitro findings on the cytotoxicity and morphological alterations induced by both DXR and DXR-ol, with a lower activity of DXR-ol against V79/AP4 fibroblasts.
Exp Mol Pathol 1991 Dec
PMID:Comparative activity of doxorubicin and its major metabolite, doxorubicinol, on V79/AP4 fibroblasts: a morphofunctional study. 174 13

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
Mol Pharmacol 1990 Jun
PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

Rat cardiac membrane vesicles enriched in biochemical markers of the junctional region of sarcoplasmic reticulum (SR) and exhibiting ruthenium red-sensitive rapid Ca2+ release have been prepared. Doxorubicin and seven congeners are shown to enhance the binding of [3H]ryanodine to the ryanodine receptor with a strong structural requirement. Doxorubicin enhances the binding of [3H]ryanodine to SR membranes and soluble receptor preparations and induces Ca2+ release from SR vesicles in a highly Ca2(+)-dependent manner, suggesting that anthraquinones promote the open state of the junctional Ca2+ release channel by increasing the affinity of the Ca2+ activator site for Ca2+. Doxorubicin reduces the Kd of [3H]ryanodine binding solely by enhancing the rat of association. Caffeine competes for the same site with anthraquinones, because the caffeine-activated binding of [3H]ryanodine is inhibited by doxorubicin and vice versa. The acute effect of doxorubicin on the cardiac Ca2+ release channel is fully reversible; however, long term treatment (up to 24 hr) with doxorubicin increases the sensitivity of the preparation to subsequent acute challenge with doxorubicin. The thiol-reductive agent dithiothreitol enhances, whereas the reactive disulfide 4,4'-dithiodipyridine reduces, the doxorubicin-enhanced binding of [3H]ryanodine. These results demonstrate that the acute and chronic cardiotoxicity of anthraquinones may be accounted for by a receptor-mediated mechanism. Our findings suggest that the chronic effects observed with the clinical use of anthraquinones may be the result of a receptor-mediated shift in the redox equilibrium of allosteric thiols at the ryanodine receptor complex, which in turn leads to long term sensitization of the Ca2+ release channel.
Mol Pharmacol 1990 Apr
PMID:Anthraquinone-sensitized Ca2+ release channel from rat cardiac sarcoplasmic reticulum: possible receptor-mediated mechanism of doxorubicin cardiomyopathy. 215 59

The XAD-2 resin concentration/elution system for concentration of mutagens contained in urines was optimized for cancer patients who had been administered such antineoplastic agents as adriamycin (ADR; doxorubicin), cyclophosphamide (CP), methotrexate, vincristine, and 5-fluorouracil. In the reverse mutation assay, Salmonella typhimurium strains TA1535 and TA98 differentiated between CP (with S9 fraction) and ADR (without S9), respectively. No dose-response for CP was observed. There was a dose-response to ADR by TM677 in the presence of S9 using a forward mutation assay. However, while the reverse mutation assays successfully detected ADR and CP administration in the presence of each other in terms of urine mutagenicity, the forward mutation assay did not, since unidentified CP metabolites were also detected in the latter. None of these systems detected mutagenic urines from tobacco smokers, although reaction of these urines with beta-glucuronidase allowed this type of source to be detected also.
Environ Mol Mutagen 1990
PMID:Mutagenesis assays on urines produced by patients administered adriamycin and cyclophosphamide. 220 75

The effects of doxorubicin (adriamycin, ADR) and daunorubicin (daunomycin, DAU), two anthracyclinic antibiotics, on a human breast carcinoma cell line (CG5) were studied by cytochemical and morphological methods. Both ADR and DAU were capable of inducing the multinucleation and spreading phenomena, associated with a decrease of the cell growth rate. DAU appeared to be more effective than ADR at the tested concentrations (10(-5), 5 x 10(-5) mM), in affecting the cell growth as well as in inducing multinucleation. As revealed by scanning electron microscopy, spreading and multinucleation were accompanied by a remarkable redistribution of surface structures. Moreover, a dose- and time-dependent rearrangement of the underlying cytoskeletal components was clearly detected. In addition, both ADR and DAU at 5 x 10(-5) mM seemed to favor the rebuilding of microtubules after treatment with colcemid, while a higher dose (10(-4) mM) exerted the opposite effect. Furthermore, both anthracyclines prevented the action of the antimicrotubular agent. When recovered after treatment with cytochalasin B, in presence of ADR (or DAU) (5 x 10(-5), 10(-4) mM), cells showed a microfilament pattern rearranged differently as compared to that of cells recovered in anthracycline-free medium. The results reported here strongly suggest the involvement of actin and tubulin in CG5 cell response to ADR and DAU treatments. Thus, the cytoskeletal apparatus is confirmed as another target involved in the mechanism of action of anthracyclines.
Exp Mol Pathol 1990 Aug
PMID:Interaction of anthracyclinic antibiotics with cytoskeletal components of cultured carcinoma cells (CG5). 220 8


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