Dual Effect of Tamoxifen, an Anti-Breast-Cancer Drug, on Intracellular Ca2+ and Cytotoxicity in Intact Cells

Jan, Chung Ren; Cheng, Jin; Chou, Kang Ju; Wang, Shiou Ping; Lee, Kam Chung; Tang, Kwong Yui; Tseng, Li Ling; Chiang, Hung

doi:10.1006/taap.2000.9011

Cited by 13 publications

(23 citation statements)

References 22 publications

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“…This value is similar to the 10 lM observed in breast cancer cells, bladder cancer cells and renal tubular cells (Chang et al 2001(Chang et al , 2002Jan et al 2000). Tamoxifen increased [Ca 2+ ] i by releasing store-Ca 2+ and causing Ca 2+ influx because removing extracellular Ca 2+ partly reduced the tamoxifen-induced [Ca 2+ ] i increase.…”

Section: Discussionsupporting

confidence: 84%

“…However, evidence accumulates that tamoxifen expresses additional effects such as inducing an immediate increase in [Ca 2+ ] i in several cell types in a manner unrelated to estrogen receptors. These cell types include renal tubular cells, bladder cancer cells, neutrophils, prostate cancer cells and glioma cells (Chang et al 2001(Chang et al , 2002Jan et al 2000). Because an unregulated [Ca 2+ ] i increase can alter many cell functions, the [Ca 2+ ] i -elevating effect of tamoxifen in cells from different tissues may be associated with the diverse in vivo effects of tamoxifen in different tissues.…”

Section: Discussionmentioning

confidence: 98%

“…Because an unregulated [Ca 2+ ] i increase can alter many cell functions, the [Ca 2+ ] i -elevating effect of tamoxifen in cells from different tissues may be associated with the diverse in vivo effects of tamoxifen in different tissues. Indeed, tamoxifen has been shown to cause cell death in bladder cancer cells, renal tubular cells (Chang et al 2001;Jan et al 2000), hepatoblastoma cells (Kim et al 1999), breast cancer cells (Cameron et al 2001), etc. Tamoxifen has been thought to act as an antiestrogen in breast and other tissues by binding to estrogen receptors (Fournier et al 1996;Jones et al 1999). However, our data suggest that tamoxifen increases [Ca 2+ ] i via non-estrogen receptor-mediated pathways because its action was not affected by a widely used estrogen receptor antagonist.…”

Section: Discussionmentioning

confidence: 98%

“…Given that acute (<30 min) incubation with tamoxifen in bladder cells and renal tubular cells induces cell death, as assayed by trypan blue exclusion (Chang et al 2001;Jan et al 2000), experiments were performed to examine the effect of overnight incubation with tamoxifen on the proliferation of ovary cells. In control groups, the cell number per well increased by 23.2±1.6% (from 10,002±12 to 12,300±208; n=3; six replicates in each experiment; P<0.05).…”

Section: Effect Of Tamoxifen On the Proliferation Of Cho-k1 Cellsmentioning

confidence: 99%

“…In breast cancer cells, bladder cancer cells and renal tubular cells, it has been shown that tamoxifen (>5 lM) increases basal [Ca 2+ ] i and triggers cell death (Chang et al 2001(Chang et al , 2002Jan et al 2000). However, tamoxifen has been shown to inhibit Ca 2+ currents in neurosecretory cells (Greenberg et al 1987;Sartor et al 1988).…”

Section: Introductionmentioning

confidence: 96%

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The anti-breast cancer drug tamoxifen alters Ca2+ movement in Chinese hamster ovary (CHO-K1) cells

et al. 2002

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The anti-breast cancer drug tamoxifen has recently been shown to cause an increase in intracellular free-Ca(2+) concentrations ([Ca(2+)](i)) in renal tubular cells, breast cells and bladder cells. Because tamoxifen is known to alter ovary function in human patients and in rats, the present study was aimed at exploring whether tamoxifen could alter Ca(2+) movement in Chinese hamster ovary (CHO-K1) cells. Cytosolic free-Ca(2+) levels in populations of cells have been explored by using fura-2 as a fluorescent Ca(2+) indicator. Tamoxifen at concentrations above 1 micro M increased [Ca(2+)](i) in a concentration-dependent manner with an EC(50) value of 8 micro M. The Ca(2+) signal was reduced by removing extracellular Ca(2+), but was not affected by nifedipine, verapamil, diltiazem or ICI 182,780 (an estrogen receptor antagonist). Pretreatment with 1 micro M thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+) abolished 10 micro M tamoxifen-induced Ca(2+) release. Neither inhibition of phospholipase C with 2 micro M U73122 nor depletion of ryanodine-sensitive Ca(2+) stores with 50 micro M ryanodine affected tamoxifen-induced Ca(2+) release. Cell proliferation assays using ELISA revealed that overnight incubation with 5-10 micro M tamoxifen inhibited cell proliferation by 20%, and 20 micro M tamoxifen killed all cells. Together, the results suggest that, in CHO-K1 cells, tamoxifen induced a [Ca(2+)](i) increase by causing store-Ca(2+) release from the endoplasmic reticulum in an phospholipase C-independent manner, and by inducing Ca(2+) influx. The action of tamoxifen appears to be dissociated from estrogen receptor activation. Longer incubation with tamoxifen (>5 micro M) was cytotoxic.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Effect Of Tamoxifen On the Proliferation Of Cho-k1 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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The anti-breast cancer drug tamoxifen alters Ca2+ movement in Chinese hamster ovary (CHO-K1) cells

et al. 2002

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BioGPS: Navigating biological space to predict polypharmacology, off-targeting, and selectivity

et al. 2015

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The structural comparison of protein binding sites is increasingly important in drug design; identifying structurally similar sites can be useful for techniques such as drug repurposing, and also in a polypharmacological approach to deliberately affect multiple targets in a disease pathway, or to explain unwanted off-target effects. Once similar sites are identified, identifying local differences can aid in the design of selectivity. Such an approach moves away from the classical "one target one drug" approach and toward a wider systems biology paradigm. Here, we report a semiautomated approach, called BioGPS, that is based on the software FLAP which combines GRID Molecular Interactions Fields (MIFs) and pharmacophoric fingerprints. BioGPS comprises the automatic preparation of protein structure data, identification of binding sites, and subsequent comparison by aligning the sites and directly comparing the MIFs. Chemometric approaches are included to reduce the complexity of the resulting data on large datasets, enabling focus on the most relevant information. Individual site similarities can be analyzed in terms of their Pharmacophoric Interaction Field (PIF) similarity, and importantly the differences in their PIFs can be extracted. Here we describe the BioGPS approach, and demonstrate its applicability to rationalize off-target effects (ERα and SERCA), to classify protein families and explain polypharmacology (ABL1 kinase and NQO2), and to rationalize selectivity between subfamilies (MAP kinases p38α/ERK2 and PPARδ/PPARγ). The examples shown demonstrate a significant validation of the method and illustrate the effectiveness of the approach.

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Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast

Parsons

López

Givoni

et al. 2006

Cell

467

496

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Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of "chemical-genetic interaction" profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular pathways and proteins affected, we applied both a hierarchical clustering and a factorgram method, which allows a gene or compound to be associated with more than one group. In particular, tamoxifen, a breast cancer therapeutic, was found to disrupt calcium homeostasis and phosphatidylserine (PS) was recognized as a target for papuamide B, a cytotoxic lipopeptide with anti-HIV activity. Further, the profile of crude extracts resembled that of its constituent purified natural product, enabling detailed classification of extract activity prior to purification. This compendium should serve as a valuable key for interpreting cellular effects of novel compounds with similar activities.

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Dual Effect of Tamoxifen, an Anti-Breast-Cancer Drug, on Intracellular Ca2+ and Cytotoxicity in Intact Cells

Cited by 13 publications

References 22 publications

The anti-breast cancer drug tamoxifen alters Ca2+ movement in Chinese hamster ovary (CHO-K1) cells

The anti-breast cancer drug tamoxifen alters Ca2+ movement in Chinese hamster ovary (CHO-K1) cells

BioGPS: Navigating biological space to predict polypharmacology, off-targeting, and selectivity

Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast

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