Clotrimazole, an Antimycotic Drug, Inhibits the Sarcoplasmic Reticulum Calcium Pump and Contractile Function in Heart Muscle

Šnajdrová, Lenka; Xu, A.; Narayanan, Njanoor

doi:10.1074/jbc.273.43.28032

Cited by 40 publications

(40 citation statements)

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“…The particular susceptibility of enamel cell SERCA2b to proteolysis, as revealed by phosphoenzyme analysis, might also have contributed to the low thapsigargin sensitivity although a mechanistic basis for this is not known. Increased confidence about inhibitor specificity can be gained by comparing the effects of several such compounds ( Figure 5), since each has distinctive pharmacological properties [14][15][16]35]. It is plausible that our microsome preparations also contained significant amounts of thapsigargin-insensitive Ca# + -ATPases (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…70 %), and to a lesser extent by cyclopiazonic acid and tbuBHQ (55 % and 35 % respectively). Clotrimazole, recently characterized as a SERCA inhibitor [35], also gave partial inhibition equivalent to tbuBHQ. A similar pattern was obtained for brain microsomes, but the inhibition was more profound in all cases ( Figure 5).…”

Section: Atpase Activity and Inhibitor Sensitivity Of Enamel Cell Sercamentioning

confidence: 99%

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Endoplasmic reticulum Ca2+-ATPase pump is up-regulated in calcium-transporting dental enamel cells: a non-housekeeping role for SERCA2b

Franklin

Winz

Hubbard

2001

Biochemical Journal

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Dental enamel-forming cells face a major challenge to avoid the cytotoxic effects of excess calcium. We have characterized sarcoplasmic/endoplasmic reticulum calcium-ATPase pumps (SERCA) in rat enamel cells to address the proposal that non-mitochondrial calcium stores play a dominant role in transcellular calcium transport. A single major isoform, SERCA2b, was detected during the protein-secretory and calcium-transport stages of enamel formation using reverse-transcriptase PCR, cDNA cloning, Northern analysis and immunoblotting. Most importantly, SERCA2b exhibited a specific 3-fold up-regulation to high expression levels during calcium transport, as determined by quantitative immunoblotting and ATPase assays. Sensitivity of the calcium-dependent ATPase to thapsigargin and three other SERCA inhibitors was characterized. These findings indicate that enamel cells are well-equipped to sequester calcium in endoplasmic reticulum stores and so protect against calcium toxicity, associate SERCA with transcellular calcium transport for the first time, and establish SERCA2b as a molecular and pharmacological target for future investigations of calcium transcytosis. The observed physiological regulation in enamel cells contradicts the widespread perception that SERCA2b is restricted to general housekeeping duties.

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Section: Discussionmentioning

confidence: 99%

Section: Atpase Activity and Inhibitor Sensitivity Of Enamel Cell Sercamentioning

confidence: 99%

Endoplasmic reticulum Ca2+-ATPase pump is up-regulated in calcium-transporting dental enamel cells: a non-housekeeping role for SERCA2b

Franklin

Winz

Hubbard

2001

Biochemical Journal

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“…CLT has been shown to have a multiplicity of effects on cell proliferation (32), steroid metabolism (33)(34)(35), and sickle cell dehydration (36,37). The mechanism of these actions has been variously attributed to its inhibitory effect on cytochrome P450-dependent enzymes (38), sarcoplasmic reticulum Ca 2ϩ pump (39), capacitative Ca 2ϩ channels (32,40,41), and the intermediate-conductance Gardos channel (18). The diversity of reported actions suggests that CLT may act independently on a surprising variety of targets.…”

Section: Discussionmentioning

confidence: 99%

“…Oxygen enhances the antimalarial activity of some imidazoles; the imidazole drug ketoconazole has a greater antimalarial effect in older red cells, which are more susceptible to oxidative stress, than in younger red cells (31), effects that may be shared by CLT. The antiproliferative action of CLT results mainly from inhibition of the sarcoplasmic reticulum Ca 2ϩ pump and capacitative Ca 2ϩ channels (32,39,49), which induces depletion of intracellular Ca 2ϩ stores. Store depletion activates protein kinase R, causing phosphorylation of the eukaryotic translation initiation factor 2␣ and inhibition of protein synthesis (49).…”

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs demands a continuous effort to develop new antimalarial agents. In this quest, the identification of antimalarial effects of drugs already in use for other therapies represents an attractive approach with potentially rapid clinical application. We have found that the extensively used antimycotic drug clotrimazole (CLT) effectively and rapidly inhibited parasite growth in five different strains of P. falciparum, in vitro, irrespective of their chloroquine sensitivity. The concentrations for 50% inhibition (IC50), assessed by parasite incorporation of [ 3 H]hypoxanthine, were between 0.2 and 1.1 M. CLT concentrations of 2 M and above caused a sharp decline in parasitemia, complete inhibition of parasite replication, and destruction of parasites and host cells within a single intraerythrocytic asexual cycle (Ϸ48 hr). These concentrations are within the plasma levels known to be attained in humans after oral administration of the drug. The effects were associated with distinct morphological changes. Transient exposure of ring-stage parasites to 2.5 M CLT for a period of 12 hr caused a delay in development in a fraction of parasites that reverted to normal after drug removal; 24-hr exposure to the same concentration caused total destruction of parasites and parasitized cells. Chloroquine antagonized the effects of CLT whereas mefloquine was synergistic. The present study suggests that CLT holds much promise as an antimalarial agent and that it is suitable for a clinical study in P. falciparum malaria. In the course of an investigation on the homeostasis of human red cells infected in vitro with the human malaria parasite Plasmodium falciparum, we found that clotrimazole (CLT), an imidazole derivative used as an antifungal agent (1), had a powerful growth-inhibiting effect on the parasite. The vast clinical experience, proven tolerance, and unique lack of acquired fungal resistance to CLT prompted a detailed investigation of its antimalarial effects in cultures of P. falciparum to assess its clinical potential. In this study, we report the in vitro effects of CLT on P. falciparum cultures by assessing the timeand concentration-dependent changes in parasite growth, parasite morphology, stage-specific development, and parasite replication. Materials and MethodsCultures. Five different laboratory strains of P. falciparum [A4 (2), W2, NF54, HB3, and FCR] were cultured in human erythrocytes by standard methods (3) under a low oxygen atmosphere. The culture medium was RPMI 1640, supplemented with 40 mM Hepes, 25 mg͞liter gentamicin sulfate, 10 mM D-glucose, 2 mM glutamine, and either 8.5% (vol͞vol) pooled human serum (A4 clone), or 10% heat-inactivated plasma (strains W2, NF54, HB3, and FCR). Culture media, with or without CLT, were changed daily, unless otherwise indicated. Parasites were synchronized at the ring stage with D-sorbitol (4) for all experiments. Initial parasitemias varied between 2% and 7% for the different e...

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“…Particularly, clotrimazole, an antifungal agent with imidazole and triarylmethyl groups, inhibits the growth of cancer cells in culture [3] as well as in cancerous mouse models [3,4]. The mode of action of this triarylmethyl motif underlies in its ability to inhibit translation mediated by depletion of intracellular Ca +2 concentrations and also by inhibition of glycolysis by prompting the detachment of mitochondrial bound hexokinase [3,5]. 3,3-diaryl-1,3-dihyroindoles, an indole modified triarylmethanes, possess antiproliferative activity against cancer cell lines in cell culture [6,7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Docking Studies of 4, 4’-Diaminotriphenylmethanes (DATPMs)

Shah¹,

Jabeen²,

Khan³

et al. 2017

Med chem

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DATPMs were synthesized by the acid-catalysed Baeyer condensation of 4-substituted benzaldehydes and aniline in good yields. The materials were purified by column chromatography and characterized by FTIR, 1 H-13 CNMR and elemental analysis. The optimized ligands were docked with the IKKα, (PDB code: 3BRT) using the MOE-Dock module and are found to obey Lipinski's Ro5 cut-off limits. The computational results revealed that the DATPMs, like other derivatives of TPM, could be potential anticancer drugs. Moderate protein kinase inhibitory activity was exhibited by samples 2 and 3 by displaying inhibition bald zone of 10 and 9 mm respectively against the Streptomyces 85E strain.

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Clotrimazole, an Antimycotic Drug, Inhibits the Sarcoplasmic Reticulum Calcium Pump and Contractile Function in Heart Muscle

Cited by 40 publications

References 39 publications

Endoplasmic reticulum Ca2+-ATPase pump is up-regulated in calcium-transporting dental enamel cells: a non-housekeeping role for SERCA2b

Endoplasmic reticulum Ca2+-ATPase pump is up-regulated in calcium-transporting dental enamel cells: a non-housekeeping role for SERCA2b

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Synthesis, Characterization and Docking Studies of 4, 4’-Diaminotriphenylmethanes (DATPMs)

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