Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular insensitivity to vinca alkaloids is suggested to be primarily due to drug efflux by P-glycoprotein (P-gp). The anti-epileptic phenytoin (DPH), which does not bind to P-gp, can selectively enhance vincristine (VCR) cytotoxicity in wild-type (WT) or multidrug-resistant (MDR) cells. We now demonstrate that the protein phosphatase inhibitor okadaic acid (OKA) can mimic the effect of DPH by selectively enhancing cytotoxicity of vinblastine (VBL), but not taxol and doxorubicin, in human leukaemia HL-60 cells. Both DPH and OKA potentiate the anti-mitotic effects of VBL by enhanced damage to the mitotic spindle, resulting in prolonged growth arrest. Also, unlike VBL alone, in human leukaemia or non-small-cell lung carcinoma cells treated with VBL plus DPH, recovery from damage to the mitotic spindle is compromised in drug-free medium and cell death by apoptosis in interphase ensues. Since protein phosphatases are involved with the regulation of metaphase to anaphase transit of cells during the mitotic cycle, enhanced VBL cytotoxicity in the presence of DPH or OKA may involve effects during metaphase on the mitotic spindle tubulin leading to growth arrest and apoptosis in interphase. These novel results suggest that DPH or OKA could be powerful tools to study cellular effects of vinca alkaloids and possibly for the development of novel therapeutic strategies.
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PMID:Modulation of vinblastine cytotoxicity by dilantin (phenytoin) or the protein phosphatase inhibitor okadaic acid involves the potentiation of anti-mitotic effects and induction of apoptosis in human tumour cells. 854 4

Microcystins (MC) are a group of amphiphatic peptide hepatotoxins and protein phosphatase inhibitors produced by certain cyanobacteria (blue-green algae). Microcystins are believed to require an active transport mechanism to penetrate the plasma membranes of animal cells. In this study the surface barostat technique showed that two more hydrophobic microcystins MC-LF, containing Leu and Phe, and MC-LW, containing Leu and Trp, had a higher surface activity on an egg phosphatidylcholine-cholesterol (7:3, molar ratio) monolayer as compared to that of a more hydrophilic variant MC-LR, containing Leu and Arg. Fluorescence anisotropy measurements of 1-[4-(trimethylamine)phenyl]-hexa-1,3,5-trien (TMA-DPH) were used to assess changes in the fluidity or lipid packing of model membranes in the presence of toxins. All three toxins caused a decrease in the steady-state anisotropy of TMA-DPH, suggesting that the toxins interacted with the membranes. The change in anisotropy was more pronounced for MC-LF and MC-LW than for MC-LR. Moreover, the fluorescence emission maximum of Trp in MC-LW was shifted slightly towards a shorter wavelength and the intensity was enhanced when allowed to interact with lipid vesicles, suggesting that the single Trp in MC-LW moved into a more unpolar environment when interacting with the vesicles. The differences between hydrophilic and hydrophobic microcystins could result in changes in organotropism, toxicokinetics and bioaccumulation.
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PMID:Interaction between microcystins of different hydrophobicities and lipid monolayers. 1256 58

Common practice to evaluate the efficacy of any compound as drug is done in cell-based in vitro system followed by in vivo murine model prior to clinical trial in human. Cardiac glycosides are very effective to kill human cells, but not murine cells. In this report, we describe the comparative molecular mechanism of oleandrin, a cardiac glycoside action in human and murine cells. Treatment with oleandrin facilitated nuclear translocation of FKHR in human, but not murine cells by dephosphorylating Akt. It activated MAPK and JNK in human, but not in murine cells and also induced expression of FasL leads to apoptosis in human cells as detected by assaying caspases activation, PARP cleavage, nuclear fragmentation, and annexin staining. Oleandrin interacted with human plasma membrane as evaluated by HPLC, altered its fluidity as detected by DPH binding, inhibited Na+/K+-ATPase activity, and increased intracellular free Ca2+ level followed by calcineurin activity only in human, but not in murine cells. Results suggest that human plasma membrane might be different than murine, which interact with oleandrin that disturb Na+/K+-ATPase pump resulting in the calcification followed by induction of Ca2+-dependent cellular responses such as apoptosis.
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PMID:Oleandrin induces apoptosis in human, but not in murine cells: dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity. 1717 71