A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines

Vessières, Anne; Corbet, Cyril; Heldt, Jan Martin; Lories, Nicolas; Jouy, Nathalie; Laı̈os, Ioanna; Leclercq, Guy; Jaouen, Gérard; Toillon, Robert‐Alain

doi:10.1016/j.jinorgbio.2009.12.020

Cited by 70 publications

(63 citation statements)

References 39 publications

(40 reference statements)

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“…Growing evidence on the mechanism of TAM-induced cancer inhibition have led to the discovery of many signaling intermediates that may play critical roles in this process (50). However, mechanisms underlying TAM-induced apoptosis and TAM resistance are still not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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Abstract. This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells. IntroductionBreast cancer is a common malignancy in females and the second cause of death from cancer in women today (1). Treatment for breast cancer includes surgery, chemotherapy, radiotherapy and endocrine therapy. Tamoxifen (TAM), an antagonist of the estrogen receptor (ER), is a selective ER modulator (SERM). TAM is a front-line endocrine therapeutic drug for ER-positive breast cancers. Results from TAM therapy showed a 40-50% reduction in the risk of cancer recurrence and cancer mortality (2). Recently, TAM has been demonstrated to be effective for some ER-negative breast cancers, as well as other types of cancers, including gliomas. These data suggest that TAM may also be implicated in ER-independent antitumor mechanisms (3,4). Of note, some advanced breast cancers that initially respond well to TAM eventually become refractory to treatment (5-9). Thus, the traditional mechanism of TAM action through the ER is challenged, and other noncanonical pathways need to be explored.Protein kinase C (PKC), a family of serine/threonine kinases, is involved in many important cellular functions, including cell proliferation, migration, differentiation, and apoptosis (10-12). Twelve PKC isoforms have been discovered in various cell types, including conventional PKCs (cPKCα, βI/βII and γ), novel PKCs (nPKCδ, ε, η), and atypical PKCs (aPKCζ) (13,14). The expression of PKCα, δ, ε, η, γ, μ, and ζ has been detected in MCF-7 cells (15,16); PKCα is a marker for anti-estrogen resistance and is involved in the growth of TAM-resistant human breast cancer cell...

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Section: Discussionmentioning

confidence: 99%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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“…4HT likely induces reactive oxygen species (ROS) which in turn cause DNA damage and subsequently cellular senescence [211-213]. Similar levels of cellular senescence were observed in MCF-7 and MCF7/DoxR cells when they were cultured in medium containing 4HT.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

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Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.

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“…These organometallic species can operate on cancerous cells via the signaling pathways of senescence [23,24] or apoptosis, with markedly different effects depending on the concentration at which they are used and the type of cell involved, while healthy cells are affected only slightly or not at all [25].…”

Section: Introductionmentioning

confidence: 99%

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

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Lee

et al. 2016

Journal of Inorganic Biochemistry

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ABSTRACT:To complete our study of the iron, ruthenium and osmium metallocene triad derived from hydroxytamoxifen, we report here the synthesis and study of the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen- within the cell and that inhibition of thioredoxin reductase is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.

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A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines

Cited by 70 publications

References 39 publications

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

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