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1.

001-es BibID:BIBFORM002233
035-os BibID:WOS:000242995600010
Első szerző:Goda Katalin (biofizikus)
Cím:Complete inhibition of P-glycoprotein by simultaneous treatment with a distinct class of modulators and the UIC2 monoclonal antibody / Katalin Goda, Ferenc Fenyvesi, Zsolt Bacsó, Henrietta Nagy, Teréz Márián, Attila Megyeri, Zoltán Krasznai, István Juhász, Miklós Vecsernyés, Gábor Szabó
Dátum:2007
Megjegyzések:P-glycoprotein (Pgp) is one of the active efflux pumps that are able to extrude a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance. The conformation-sensitive UIC2 monoclonal antibody potentially inhibits Pgp-mediated substrate transport. However, this inhibition is usually partial, and its extent is variable because UIC2 binds only to 10 to 40% Pgp present in the cell membrane. The rest of the Pgp molecules become recognized by this antibody only in the presence of certain substrates or modulators, including vinblastine, cyclosporine A (CsA), and SDZ PSC 833 (valspodar). Simultaneous application of any of these modulators and UIC2, followed by the removal of the modulator, results in a completely restored steady-state accumulation of various Pgp substrates (calcein-AM, daunorubicin, and 99mTc-hexakis-2- methoxybutylisonitrile), indicating near 100% inhibition of pump activity. Remarkably, the inhibitory binding of the antibody is brought about by coincubation with concentrations of CsA or SDZ PSC 833 20 times lower than what is necessary for Pgp inhibition when the modulators are applied alone. The feasibility of such a combinative treatment for in vivo multidrug resistance reversal was substantiated by the dramatic increase of daunorubicin accumulation in xenotransplanted Pgp tumors in response to a combined treatment with UIC2 and CsA, both administered at doses ineffective when applied alone. These observations establish the combined application of a class of modulators used at low concentrations and of the UIC2 antibody as a novel, specific, and effective way of blocking Pgp function in vivo.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
UIC2 monoclonal antibody
P-glycoprotein
Megjelenés:The Journal of Pharmacology and Experimental Therapeutics 320 : 1 (2007), p. 81-88. -
További szerzők:Fenyvesi Ferenc (1977-) (gyógyszerész, gyógyszertechnológus) Bacsó Zsolt (1963-) (biofizikus) Nagy Henrietta Márián Teréz (1950-) (radiobiológus) Megyeri Attila (1968-) (orvos) Krasznai Zoltán (1950-) (biofizikus) Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Vecsernyés Miklós (1959-) (gyógyszertechnológus, endokrinológus) Szabó Gábor (1980-) (orvos) jr
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2.

001-es BibID:BIBFORM014288
Első szerző:Pacher Pál
Cím:Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure / Pacher P., Liaudet L., Bai P., Virag L., Mabley J. G., Haskó G., Szabó C.
Dátum:2002
ISSN:0891-5849 (Print)
Megjegyzések:Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.Nitroxyl (NO(-)/HNO), has been proposed to be one of the NO(*)-derived cytotoxic species. Although the biological effect of nitroxyl is largely unknown, it has been reported to cause DNA breakage and cytotoxicity. We have therefore investigated whether NO(-)/HNO-induced DNA single-strand breakage activates the nuclear nick sensor enzyme poly(ADP-ribose) polymerase (PARP) and whether PARP activation affects the mode of NO(-)/HNO- induced cell death. NO(-)/HNO generated from Angeli's salt (AS, sodium trioxodinitrate) (0-300 microM) induced DNA single-strand breakage, PARP activation, and a concentration-dependent cytotoxicity in murine thymocytes. AS-induced cell death was also accompanied by decreased mitochondrial membrane potential and increased secondary superoxide production. The cytotoxicity of AS, as measured by propidium iodide uptake, was abolished by electron acceptors potassium ferricyanide, TEMPOL, the intracellular calcium chelator BAPTA-AM, and by PARP inhibitors 3-aminobenzamide (3-AB) and PJ-34. The cytoprotective effect of 3-AB was paralleled by increased output of AS-induced apoptotic parameters such as phosphatidylserine exposure, caspase activation, and DNA fragmentation. No significant increase in tyrosine nitration could be observed in AS-treated thymocytes as opposed to peroxynitrite-treated cells, indicating that tyrosine nitration is not likely to contribute to NO(-)/HNO-induced cytotoxicity. Our results demonstrate that NO(-)/HNO-induced PARP activation shifts the default apoptotic cell death toward necrosis in thymocytes. However, as total PARP inhibition resulted only in 30% cytoprotection, PARP-independent mechanisms dominate NO(-)/HNO-induced cytotoxicity in thymocytes.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acute Disease
Animals
Antibiotics, Antineoplastic
Creatine Kinase/metabolism
Doxorubicin
Enzyme Activation/drug effects
Heart Failure/ chemically induced/pathology/physiopathology
Hemodynamics/drug effects
L-Lactate Dehydrogenase/metabolism
Male
Metalloendopeptidases/metabolism
Mice
Mice, Inbred BALB C
Mice, Knockout
Poly(ADP-ribose) Polymerases/ genetics/ metabolism
Survival Analysis
Ventricular Function, Left/genetics
Apoptosis
Benzamides/ pharmacology
Caspases/metabolism
Cells, Cultured
DNA Damage/drug effects
DNA Fragmentation/drug effects
Enzyme Activation/drug effects/physiology
Enzyme Inhibitors/ pharmacology
Mice, Inbred C57BL
Mitochondria/ drug effects
Nitrates
Nitrites/toxicity
Nitrogen Oxides/ toxicity
Poly(ADP-ribose) Polymerases/ antagonists & inhibitors/metabolism
Protective Agents/ pharmacology
Thymus Gland/cytology/ drug effects
Tyrosine
Megjelenés:The Journal of Pharmacology and Experimental Therapeutics. - 300 : 3 (2002), p. 862-867. -
További szerzők:Liaudet, Lucas Bai Péter (1976-) (biokémikus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Mabley, Jon G. Haskó György (1967-) (biokémikus) Szabó Csaba
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3.

001-es BibID:BIBFORM073728
Első szerző:Patai Zoltán (molekuláris biológus)
Cím:Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models / Patai Z., Guttman A., Mikus E. G.
Dátum:2016
ISSN:1521-0103
Megjegyzések:Drotaverine is considered an inhibitor of cyclic-3',5'-nucleotide-phophodiesterase (PDE) enzymes; however, published receptor binding data also support the potential L-type voltage- operated calcium channel (L-VOCC) blocking effect of drotaverine. Hence, in this work, we focus on the potential L-VOCC blocking effect of drotaverine by using L-VOCC-associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. Drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca2+- induced contraction in a concentration- dependent fashion. The PDE inhibitor theophylline had no effect on the KCl-evoked contractions, indicating its lack of inhibition on inward Ca2+ flow. Drotaverine was also tested on the L-VOCC-mediated resting Ca2+ refill model. In this model, the extracellular Ca2+ enters the cells to replenish the emptied intracellular Ca2+ stores. Drotaverine and L-VOCC blocker reference molecules inhibited Ca2+ replenishment of Ca2+-depleted preparations detected by agonist-induced contractions in post-Ca2+ replenishment Ca2+-free medium. Theophylline did not modify the Ca2+ store replenishment after contraction. It seems that drotaverine, but not theophylline, inhibits inward Ca2+ flux. The addition of CaCl2 to Ca2+-free medium containing the agonist induced inward Ca2+ flow and subsequent contraction of Ca2+-depleted tracheal preparations. Drotaverine, similar to the L-VOCC blockers, inhibited inward Ca2+ flow and blunted the slope of CaCl2-induced contraction in agonist containing Ca2+-free medium with Ca2+-depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but, unlike PDE inhibitors using L-VOCC associated in vitro experimental models.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Pharmacology and Experimental Therapeutics 359 : 3 (2016), p. 442-451. -
További szerzők:Guttman András (1954-) (vegyészmérnök) Mikus Endre G.
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4.

001-es BibID:BIBFORM049062
Első szerző:Rocchetti, Marcella
Cím:Modulation of Sarcoplasmic Reticulum Function by Na+/K+ Pump Inhibitors with Different Toxicity: Digoxin and PST2744 [(E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione Hydrochloride] / Marcella Rocchetti, Alessandra Besana, Gaspare Mostacciuolo, Rosella Micheletti, Patrizia Ferrari, Sandor Sarkozi, Csaba Szegedi, Istvan Jona, Antonio Zaza
Dátum:2004
ISSN:0022-3565
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény hazai lapban
Megjelenés:Journal Of Pharmacology And Experimental Therapeutics. - 313 : 1 (2004), p. 207-215. -
További szerzők:Besana, Alessandra Mostacciuolo, Gaspare Micheletti, Rosella Ferrari, Patrizia Sárközi Sándor (1966-) (élettanász) Szegedi Csaba Jóna István (1948-) (élettanász, fizikus) Zaza, Antonio
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