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At least 91 records · Page 5Linked to original sources
PubMed1990

Comparison of the efficacy of a phenothiazine and a bisquinaldinium calmodulin antagonist against multidrug-resistant P388 cell lines.

Dequalinium belongs to a group of cationic lipophilic drugs believed to be selectively cytotoxic to malignant cells of epithelial origin by virtue of their accumulation in mitochondria. In addition, they are potent inhibitors of calmodulin and, therefore, might sensitize multidrug-resistant cells to chemotherapeutic agents. We compared the responsiveness of multidrug-resistant cells to the effect of dequalinium with that to trifluoperazine, a potent phenothiazine inhibitor of calmodulin. In addition, we studied the effect of these drugs on the responsiveness of multidrug-resistant cell lines to doxorubicin. The effect of drugs on P388 murine leukemic cells was determined by cell counting, [3H]thymidine incorporation into DNA, or soft agar cloning. Drug accumulation was measured by fluorescence spectrophotometry. We found that multidrug-resistant lines were less sensitive than parental cell lines to the intrinsic growth inhibitory effects of dequalinium (IC50, 4.4 versus 0.3 microM in multidrug-resistant and sensitive P388 cells, respectively), whereas they were equally sensitive as the parental line to the effects of trifluoperazine. Following a 3-h exposure of P388/doxorubicin-resistant cells to 0-100 microM doxorubicin with or without either 10 microM dequalinium or 10 microM trifluoperazine, the latter increased the sensitivity to doxorubicin whereas the former had little effect (IC50 values were doxorubicin, 30 microM; doxorubicin plus dequalinium, 25 microM; doxorubicin plus trifluoperazine, 4 microM). Calmodulin prepared from resistant cells were equally sensitive to inhibition by dequalinium and trifluoperazine. P388/doxorubicin-resistant cells accumulated 4.5-fold less dequalinium than P388 cells whereas trifluoperazine was accumulated equally in both. The addition of 4 microM trifluoperazine to resistant cells exposed to 0-100 microM dequalinium completely reversed the alteration in accumulation and resistance to the dequalinium. These studies demonstrate that certain multidrug-resistant lines are cross-resistant to dequalinium and that sensitivity can be completely restored by nontoxic concentrations of trifluoperazine. The resistance appears to be due to changes in drug accumulation and not to be related to an altered sensitivity of calmodulin.

Animals↗
PubMed1998

Deletion analysis of protein kinase Calpha reveals a novel regulatory segment.

Using a combined pharmacological and genetic approach, we have identified aa 260-280 in the C2 region as a critical factor in the catalytic function of protein kinase Calpha (PKCalpha). Progressive truncations from the N-terminus as well as selected internal deletion mutants were expressed in Saccharomyces cerevisiae and tested for altered sensitivity to dequalinium, a PKC inhibitor whose target site was previously mapped to the catalytic domain. PKC mutants representing truncations of up to 158 amino acid residues (aa) from the N-terminus (ND84 and ND158) displayed 60-63% inhibition of kinase activity by 50 microM dequalinium, somewhat more sensitive than the wild-type PKCalpha enzyme (45% inhibition). Mutant ND262, lacking N-terminal aa 1-262, was inhibited by almost 72% with 50 microM dequalinium, but mutant ND278, which lacked an additional 16 aa, was inhibited by only 9% of total activity. This result suggests that a C-terminal segment of the C2 region (aa 263-278) influences inhibition by dequalinium at low micromolar concentrations. An internal deletion mutant (D260-280) which retains the entire primary structure of PKCalpha except for aa 260-280, was similarly inhibited by only 4% with 50 microM dequalinium. In the absence of dequalinium and despite the presence of a nearly complete regulatory domain, this mutant exhibited constitutive activity (both in vitro and in a phenotypic assay with S. cerevisiae) that could not be further stimulated even by the potent activator TPA. Taken together, our findings suggest that, in the native structure of PKCalpha, the segment described by aa 260-280 regulates PKCalpha activity and influences the sensitivity of PKCalpha to dequalinium.

Animals↗
PubMed1986

Selective antimitochondrial agents inhibit calmodulin.

Certain cationic-lipophilic compounds are known to selectively accumulate in tumor mitochondria and inhibit energy production. Since these substances bear a structural resemblance to known inhibitors of calmodulin, we studied whether rhodamine-123 or a bis-4-aminoquinaldinium could antagonize the action of calmodulin. Rhodamine-123 (IC50 = 58 microM) and dequalinium (IC50 = 1 microM) inhibited the activity of a calmodulin-stimulated cyclic nucleotide phosphodiesterase. Propylinium, a compound similar to dequalinium except for having a 3 rather than 10 carbon alkyl bridge connecting two non-substituted quinoline rings, had no inhibitory effect. Kinetic analysis showed that dequalinium competitively inhibited calmodulin's activation of phosphodiesterase. We also studied the antiproliferative effects of the compounds on the C6 astrocytoma cell line. Rhodamine-123 and dequalinium inhibited the proliferation of this cell line while propylinium had no effect. These studies demonstrate that rhodamine-123 and dequalinium are calmodulin-antagonists and inhibit cellular proliferation.

Animals↗
PubMed1996

Discrimination between subtypes of apamin-sensitive Ca(2+)-activated K+ channels by gallamine and a novel bis-quaternary quinolinium cyclophane, UCL 1530.

1. Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.

Alkanes↗