Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen; Correlations with cytotoxicity

Rowlands, Martin; Parr, Iris B.; McCague, Raymond; Jarman, Michael; Goddard, Phyllis M.

doi:10.1016/0006-2952(90)90689-i

Cited by 75 publications

(35 citation statements)

References 19 publications

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“…It has, however, become increasingly apparent that many biological activities of tamoxifen are potentiated in a manner divorced from estrogen receptor machinery [3]. Examples of activities promoted by tamoxifen include protection against lipid peroxidation [4], induction of transforming growth factor-[3 [5], modification of protein kinase C activity [6 8], activation of lipid second messenger signaling [9], and antagonism of calmodulin [10]. Along these lines, the utility of tamoxifen in non-breast related disease, e.g.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

et al. 1996

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In this study we provide evidence that tamoxifen, the widely used breast cancer drug, is a potent antagonist of glycolipid metabolism. When added to the medium of cultured multidrug resistant (MDR) KB-V-I carcinoma cells, tamoxifen, at 5.0 pM, drastically lowered the levels of glucosylceramide (glc-cer), as evidenced by a reduction in glc-cer mass. In a similar fashion, in cultured human melanoma cells grown with [3H]galactose, tamoxifen inhibited formation of glc-cer by 44%, and retarded lactosylceramide and ganglioside formation by 50 and 35%, respectively. When glc-cer synthase of melanoma was assayed in cell-free incubations, the inclusion of tamoxifen, at a I :I0 molar ratio with ceramide, inhibited glc-cer synthesis by 50%. These results clearly reveal a new action of tamoxifen and thereby pose intriguing questions regarding mechanisms of action in the realm of estrogen receptor-independent modalities, including effects on MDR.

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Section: Introductionmentioning

confidence: 99%

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

et al. 1996

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“…Figure 5 shows (Hait, 1987), futher variation of the alkylaminoethoxy side chain of tamoxifen to obtain even greater inhibition of calmodulin is in progress. Previous studis with the same series of compounds have shown a similar correlation between calmodulin inhibition and cytotoxicty for oestrogen receptor-positive MCF-7 human breast cancer cells but no such correlation for murine L1210 or rat Walker cells (Rowlands et al, 1990).…”

Section: Activity Of Idoxifene Against Acquired Cisplatin-resistant Cmentioning

confidence: 79%

“…Furthermore, the synergy observed in the T-289 melanoma cell line did not appear to be related to effects on calmodulin (or protein kinase C) (McClay et al, 1993a). Nevertheless, as idoxifene is a more effective inhibitor of calmodulin than tamoxifen (Rowlands et al, 1990) …”

Section: Activity Of Idoxifene Against Acquired Cisplatin-resistant Cmentioning

confidence: 99%

“…The results (Figure 2a for 41M lnes and Figure 2b for CHI lines) showed a strong correlation between the inhibition of calmodulin-dependent cyclic AMP phosphodiestase [vahls taken from previous determinations (Rowlands et al, 1990) In preliminary experiments, the highest non-toxic concentration of the resistance modifiers (<10% cell kill in any one cell line; continuous drug exposure) was determined as 6 9AM for verapamiL 4 JM for tamoxifen and 2 M for idoxifene.…”

Section: Reismentioning

confidence: 99%

“…It has also been shown that idoxifene has a greater ability to inhibit calmodulin-dependent cyclic AMP phosphodiesterase than tamoxifen itself (IC50 of 1.4 1LM vs 6.75 jpM for tamoxifen) (Rowlands et al, 1990). Idoxifene is currently undergoing phase I clinical evaluation in advanced breast cancer (Quigley et al, 1993).…”

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Effects of a new antioestrogen, idoxifene, on cisplatin- and doxorubicin-sensitive and -resistant human ovarian carcinoma cell lines

Sharp

Rowlands²,

Jarman³

et al. 1994

Br J Cancer

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Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells

et al. 1998

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Tamoxifen, a synthetic antiestrogen, is known for its antitumoral action in vivo; however, it is well accepted that many tamoxifen effects are elicited via estrogen receptor‐independent routes. Previously, we reported that tamoxifen induces PKC translocation in fibroblasts. In the present study, we investigated the influence of tamoxifen, and several triphenylethylene derivatives, on protein kinase C (PKC) in MCF‐7 human breast cancer cells. As measured by Western blot analysis, tamoxifen elicited isozyme‐specific membrane association of PKC‐ϵ, which was time‐dependent (as early as 5 min post‐treatment) and dose‐dependent (5.0–20 μM). Tamoxifen did not influence translocation of α, β, γ, δ or ζ PKC isoforms. Structure‐activity relationship studies demonstrated chemical requirements for PKC‐ϵ translocation, with tamoxifen, 3‐OH‐tamoxifen and clomiphene being active. Compounds without the basic amino side chain, such as triphenylethylene, or minus a phenyl group, such as N,N‐dimethyl‐2‐[(4‐phenylmethyl)phenoxy]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent‐induced PKC‐ϵ translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. Since PKC‐ϵ has been associated with cell differentiation and cellular growth‐related processes, the antiproliferative influence of tamoxifen on MCF‐7 cells may be related to the interaction with PKC‐ϵ. Int. J. Cancer 77:928–932, 1998.© 1998 Wiley‐Liss, Inc.

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Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen; Correlations with cytotoxicity

Cited by 75 publications

References 19 publications

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

Tamoxifen retards glycosphingolipid metabolism in human cancer cells

Effects of a new antioestrogen, idoxifene, on cisplatin- and doxorubicin-sensitive and -resistant human ovarian carcinoma cell lines

Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells

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