Comparison between inhibition of protein kinase C and antagonism of calmodulin by tamoxifen analogues

Rowlands, Martin; Budworth, Joanna; Jarman, Michael; Hardcastle, Ian R.; McCague, Raymond; Gescher, Andreas J.

doi:10.1016/0006-2952(95)00186-4

Cited by 32 publications

(19 citation statements)

References 20 publications

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“…This class of compounds has been previously shown to have antifungal activity by a number of groups (41,42). Tamoxifen has been the most widely studied of these and has been found to have a number of additional targets in mammalian cells, including calmodulin and protein kinase C (43). In addition, tamoxifen is thought to directly interact with lipids in membranes (44).…”

Section: Discussionmentioning

confidence: 99%

Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

Jacobs

DiDone

Jobson

et al. 2013

Antimicrob Agents Chemother

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bAdenylate kinase (AK) is a ubiquitous intracellular enzyme that is released into the extracellular space upon cell lysis. We have shown that AK release serves as a useful reporter of bactericidal agent activity and can be exploited for antimicrobial screening purposes. The AK assay exhibits improved sensitivity over that of growth-based assays and can detect agents that are active against bacteria in clinically relevant growth states that are difficult to screen using conventional approaches, such as small colony variants (SCV) and bacteria within established biofilms. The usefulness of the AK assay was validated by screening a library of off-patent drugs for agents that exhibit antimicrobial properties toward a variety of bacterial species, including Escherichia coli and all members of the "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The assay detected antibiotics within the library that were expected to be active against the organism screened. Moreover, 38 drugs with no previously reported antibacterial activity elicited AK release. Four of these were acquired, and all were verified to exhibit antimicrobial activity by standard susceptibility testing. Two of these molecules were further characterized. The antihistamine, terfenadine, was active against S. aureus planktonic, SCV population, and biofilm-associated cells. Tamoxifen, an estrogen receptor antagonist, was active toward E. faecium in vitro and also reduced E. faecium pathogenesis in a Galleria mellonella infection model. Our data demonstrate that the AK assay provides an attractive screening approach for identifying new antimicrobial agents. Further, terfenadine and tamoxifen may represent novel antimicrobial drug development scaffolds.

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Section: Discussionmentioning

confidence: 99%

Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

Jacobs

DiDone

Jobson

et al. 2013

Antimicrob Agents Chemother

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“…However, in MCF-7 cells, the reported findings on the effect of tamoxifen are controversial. Rowlands et al tested the inhibitory potential of several tamoxifen analogues in MCF-7 cells (29). In 2003, one group observed a reduction of PKC activity by tamoxifen, whereas in another report, an increased PKC activity and induction of PKC translocation to the plasma membrane in response to tamoxifen was observed (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…Because tamoxifen was shown to affect protein kinase C (PKC) activity in MCF-7 cells and several possible serin/threonine phosphorylation sites can be predicted on TRPV6, we tested whether PKC inhibition could be involved in the effect of tamoxifen on TRPV6 activity (29). We found that activation of PKC with 200 nmol/L phorbol 12-myristate 13-acetate (PMA) promptly elevated intracellular calcium in transfected cells, whereas the effect was much smaller in nontransfected cells.…”

Section: Determination Whether Protein Kinase C Plays a Role In The Omentioning

confidence: 99%

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Bolanz

Kovács

Landowski

et al. 2009

Molecular Cancer Research

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The epithelial calcium channel TRPV6 is upregulated in breast carcinoma compared with normal mammary gland tissue. The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy. Previously, we showed that tamoxifen inhibits calcium uptake in TRPV6-transfected Xenopus oocytes. In this study, we examined the effect of tamoxifen on TRPV6 function and intracellular calcium homeostasis in MCF-7 breast cancer cells transiently transfected with EYFP-C1-TRPV6. TRPV6 activity was measured with fluorescence microscopy using Fura-2. The basal calcium level was higher in transfected cells compared with nontransfected cells in calcium-containing solution but not in nominally calcium-free buffer. Basal influxes of calcium and barium were also increased. In transfected cells, 10 μmol/L tamoxifen reduced the basal intracellular calcium concentration to the basal calcium level of nontransfected cells. Tamoxifen decreased the transport rates of calcium and barium in transfected cells by 50%. This inhibitory effect was not blocked by the estrogen receptor antagonist, ICI 182,720. Similarly, a tamoxifen-induced inhibitory effect was also observed in MDA-MB-231 estrogen receptor-negative cells. The effect of tamoxifen was completely blocked by activation of protein kinase C. Inhibiting protein kinase C with calphostin C decreased TRPV6 activity but did not alter the effect of tamoxifen. These findings illustrate how tamoxifen might be effective in estrogen receptor-negative breast carcinomas and suggest that the therapeutic effect of tamoxifen and protein kinase C inhibitors used in breast cancer therapy might involve TRPV6-mediated calcium entry. This study highlights a possible role of TRPV6 as therapeutic target in breast cancer therapy.

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“…Other ER-independent effects include perturbations in membrane structure (Clarke et al, 1990b), changes in protein kinase C activation and subcellular localization (O'Brian et al, 1986;Gundimeda et al, 1996), and inhibition of the intracellular Ca þ þ binding protein calmodulin (Rowlands et al, 1995). Some of these effects may be inter-related, since inhibition of protein kinase C also blocks calmodulin-dependent EGFR transactivation (Tebar et al, 2002).…”

Section: Estogen Receptor-independent Cell Signaling In Antiestrogen mentioning

confidence: 99%

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

et al. 2003

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Comparison between inhibition of protein kinase C and antagonism of calmodulin by tamoxifen analogues

Cited by 32 publications

References 20 publications

Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

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