Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen sulfide (H(2)S) is now recognised as an important endogenous antihypertensive molecule and is synthesised in the vasculature primarily by endothelial cystathionine gamma lyase. Activity of this enzyme, and the production of other vasoactive substances by the endothelium, are subject to modulation by changes of [Ca(2+)](i). Here, we have used microfluorimetry to investigate whether H(2)S can regulate human endothelial [Ca(2+)](i). H(2)S (applied via the donor NaHS, 5-500 microM) caused concentration-dependent rises of [Ca(2+)](i) which were attributable to release from an ATP- and 4-CEP sensitive intracellular pool. Rises of [Ca(2+)](i) evoked by H(2)S were essentially abolished by prior pool depletion. In the absence of external Ca(2+), H(2)S slowed the decay phase of responses to cyclopiazonic acid, but this could not be attributed to the inhibition of Ca(2+) extrusion since the effects of H(2)S were at least additive with the Na(+)/Ca(2+) exchange inhibitors bepridil and SEA 0400 and the Ca(2+) ATPase inhibitor, carboxyeosin. In some but not all the cells, re-exposure to extracellular Ca(2+) following the addition and removal of H(2)S activated capacitative Ca(2+) entry (CCE), and H(2)S increased ATP-evoked (but not thapsigargin-evoked) CCE. Effects of H(2)S were not mediated by energy depletion or production of cyclic ADP ribose. Our data indicate that H(2)S can modulate endothelial [Ca(2+)](i) via multiple mechanisms, and such effects are likely to contribute to this gasotransmitter's beneficial actions.
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PMID:Modulation of Ca(2+) signalling in human vascular endothelial cells by hydrogen sulfide. 1987 15

Cancer can be cured by platinum-based chemotherapy, but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutation in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologues, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild-type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms, and suggest that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.
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PMID:ASNA-1 activity modulates sensitivity to cisplatin. 2096 25

The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.
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PMID:CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function. 2505 26