Effects of drugs on calmodulin-mediated enzymatic actions

Ovádi, Judit

doi:10.1007/978-3-0348-9146-2_11

Cited by 19 publications

(8 citation statements)

References 132 publications

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“…In contrast, W‐7 and J‐8, two closely related substances [16], inhibited Ca 2+ entry both when applied before and after the thapsigargin‐induced Ca 2+ transient, suggesting the possibility of a direct blocking action of these substances on the Ca 2+ entry channel in addition to their described effects on CAM. The differential effects of this series of compounds is consistent with the respective potency and selectivity of the drugs, which was reported to be significantly higher for calmidazolium and CGS 9343B than for W‐7 [23].…”

Section: Resultssupporting

confidence: 81%

Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes

Cao

Chatton

1998

FEBS Letters

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Section: Resultssupporting

confidence: 81%

Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes

Cao

Chatton

1998

FEBS Letters

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“…Enzymatic assay CaM can modulate the activity of numerous enzymes, which can be abolished by CaM antagonists. CaM can stimulate (e.g., phosphodiesterase) or inhibit (e.g., PFK) the activities of enzymes (Orosz et al , 1988b; Ovádi, 1989) and references therein). We found that the inhibitory potency of drugs to suppress the modulating effect of CaM manifested itself in both phosphodiesterase and PFK tests (Orosz et al , 1990).…”

Section: Resultsmentioning

confidence: 99%

“…Since Ca 2+ is also implicated in the regulation or modulation of cell division and initiation of DNA synthesis, CaM is an extraordinarily versatile Ca 2+ ‐binding protein, thus the Ca 2+ ‐CaM complex could have a central role in many cellular events. It is also present in the soluble fraction and influences cell metabolism by activating/inhibiting regulatory enzymes (Migliaccio et al , 1984; Ovádi, 1989). Indeed, CaM can be found in most eukaryotic cells, its concentration varies in different tissues and the highest level has been found in the brain (500 mg kg −1 tissue) (Nairn & Perry, 1979).…”

Section: Introductionmentioning

confidence: 99%

The interaction of a new anti‐tumour drug, KAR‐2 with calmodulin

Orosz

Vértessy

Salerno³

et al. 1997

British J Pharmacology

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KAR‐2 (3′′‐(β‐chloroethyl)‐2′′,4′′‐dioxo‐3,5′′‐spiro‐oxazolidino‐4‐deacetoxy‐vinblastine) is a semisynthetic bis‐indol derivative, with high anti‐microtubular and anti‐tumour activities but with low toxicity. KAR‐2, in contrast to other biologically active bis‐indols (e.g. vinblastine), did not show anti‐calmodulin activity in vitro (enzyme kinetic, fluorescence anisotropy and immunological tests). Direct binding studies (fluorescence resonance energy transfer, circular dichroism) provided evidence for the binding of KAR‐2 to calmodulin. The binding affinity of KAR‐2 to calmodulin (dissociation constant was about 5 μM) in the presence of Ca2+ was comparable to that of vinblastine. KAR‐2 was able to interact with apo‐calmodulin as well; in the absence of Ca2+ the binding was of cooperative nature. The effect of drugs on Ca2+ homeostasis in human neutrophil cells was investigated by means of a specific fluorescent probe. Trifluoperazine extensively inhibited the elevation of intracellular Ca2+ level, vinblastine did not appreciably affect it, KAR‐2 stimulated the Ca2+ influx and after a transient enhancement the Ca2+ concentration reached a new steady‐state level. Comparison of the data obtained with KAR‐2 and bis‐indols used in chemotherapy suggests that the lack of anti‐calmodulin potency resides on the spiro‐oxazolidino portion of KAR‐2. This character of KAR‐2 manifested itself in various systems and might result in its low in vivo toxicity, established in an anti‐tumour test.

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“…The results are summarized in Table 1. According to expectation (Ovádi, 1989), the inhibitory effect of calmodulin on PFK activity was significantly attenuated by trifluoperazine, but not at all by KAR-2 (Orosz et al, 1997b). As shown in Table 1, KAR-4, similar to KAR-2 (both are vinblastine derivatives), does not display anticalmodulin activity in the PFK assay, whereas KAR-3 can extensively reduce the calmodulin-mediated inactivation of PFK by about 50% suggesting its significant anti-calmodulin potency.…”

Section: Anti-calmodulin Activitiesmentioning

confidence: 80%

New semisynthetic vinca alkaloids: chemical, biochemical and cellular studies

et al. 1999

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Summary A new semisynthetic anti-tumour bis-indol compound, KAR-2 [3′-(β-chloroethyl)-2′,4′-dioxo-3,5′-spiro-oxazolidino-4-deacetoxyvinblastine] with lower toxicity than vinca alkaloids used in chemotherapy binds to calmodulin but, in contrast to vinblastine, does not exhibit anti-calmodulin activity. To investigate whether the modest chemical modification of bis-indol structure is responsible for the lack of anticalmodulin potency and for the different pharmacological effects, new derivatives have been synthesized for comparative studies. The synthesis of the KAR derivatives are presented. The comparative studies showed that the spiro-oxazolidino ring and the substitution of a formyl group to a methyl one were responsible for the lack of anti-calmodulin activities. The new derivatives, similar to the mother compounds, inhibited the tubulin assembly in polymerization tests in vitro, however their inhibitory effect was highly dependent on the organization state of microtubules; bundled microtubules appeared to be resistant against the drugs. The maximal cytotoxic activities of KAR derivatives in in vivo mice hosting leukaemia P388 or Ehrlich ascites tumour cells appeared similar to that of vinblastine or vincristine, however significant prolongation of life span could be reached with KAR derivatives only after the administration of a single dose. These studies plus data obtained using a cultured human neuroblastoma cell line showed that KAR compounds displayed their cytotoxic activities at significantly higher concentrations than the mother compounds, although their antimicrotubular activities were similar in vitro. These data suggest that vinblastine/vincristine damage additional crucial cell functions, one of which could be related to calmodulin-mediated processes.

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Effects of drugs on calmodulin-mediated enzymatic actions

Cited by 19 publications

References 132 publications

Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes

Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes

The interaction of a new anti‐tumour drug, KAR‐2 with calmodulin

New semisynthetic vinca alkaloids: chemical, biochemical and cellular studies

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Effects of drugs on calmodulin-mediated enzymatic actions

Cited by 19 publications

References 132 publications

Involvement of calmodulin in the activation of store‐operated Ca2+ entry in rat hepatocytes

Involvement of calmodulin in the activation of store‐operated Ca2+ entry in rat hepatocytes

The interaction of a new anti‐tumour drug, KAR‐2 with calmodulin

New semisynthetic vinca alkaloids: chemical, biochemical and cellular studies

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Product

Resources

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Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes

Involvement of calmodulin in the activation of store‐operated Ca²⁺ entry in rat hepatocytes