The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alteration of the cell cycle

Pozo‐Guisado, Eulalia; Alvarez-Barrientos, Alberto; Mulero‐Navarro, Sonia; Santiago-Josefat, Belen; Fernandez-Salguero, Pedro

doi:10.1016/s0006-2952(02)01296-0

Cited by 210 publications

(164 citation statements)

References 31 publications

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“…RES induced apoptosis in estrogen-responsive MCF-7, but not in estrogen-unresponsive MDA-MB-231, cells, and this cell-specific effect was related to differential regulation of the cell cycle. 8 We later suggested that apoptosis induction by RES in ERa-positive MCF-7 cells could be mediated by the interference of this molecule with the ERa-dependent PI3K pathway. 14 In the present work, we have attempted to identify the molecular mechanisms involved in RES-induced apoptosis by analyzing downstream targets from PI3K.…”

Section: Discussionmentioning

confidence: 99%

“…8,14 PI3K inhibition leads to decreased cell survival and increased apoptosis by altering the activity of downstream proteins, among them the transcriptional regulator NF-kB. Decreased NF-kB activity, however, results in lower levels of Bcl-2, a major antiapoptotic protein.…”

Section: Apoptosis Induction By Res Is Mediated By a Decrease In Bcl-mentioning

confidence: 99%

“…As shown in Figure 1a, RES decreased Bcl-2 protein content in MCF-7 cells in a concentration-dependent manner, reaching very low levels at concentrations of this molecule (around 150 mM) at which apoptosis was observed. 8 The contribution of Bcl-2 to RES-induced apoptosis was further analyzed using the cell line MCF-7-Bcl-2, stably transfected to overexpress this protein. Flow-cytometric analysis revealed that Bcl-2 overexpression markedly inhibited apoptosis induction by RES (Fig.…”

Section: Apoptosis Induction By Res Is Mediated By a Decrease In Bcl-mentioning

confidence: 99%

“…7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis.…”

mentioning

confidence: 99%

“…14 The effect of RES on GSK-3 activity could also help to explain the changes in expression and activity of the cell cycle regulatory proteins cyclin D1 and CDK4. 8,14 NF-kB is involved in cell proliferation and survival and in apoptosis induction. Constitutive activation of NF-kB leads to autoimmune disease and cancer, thus revealing this protein as a potential target for disease treatment.…”

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Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

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210

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionmentioning

confidence: 99%

Section: Apoptosis Induction By Res Is Mediated By a Decrease In Bcl-mentioning

confidence: 99%

Section: Apoptosis Induction By Res Is Mediated By a Decrease In Bcl-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

Self Cite

210

143

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Effects of Dietary Natural Compounds on DNA Methylation Related to Cancer Chemoprevention and Anticancer Epigenetic Therapy

Stefańska

Fabianowska‐Majewska

2009

Epigenetics and Human Health

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Aberrations in function and expression of a wide variety of genes are the hallmarks of cancer cells. A growing body of evidence shows that these aberrations are affected by genetics and epigenetics which cooperate at all stages of cancer development. Epigenetic alterations (especially DNA hypermethylation) resulting in the silencing of key tumor suppressor genes have attracted signifi cant attention. In contrast to genetic changes, epigenetic modifi cations are reversible and responsive to developmental, physiological, environmental, dietary, and pathological signals. A number of studies provide evidence that some natural bioactive compounds found in food and herbs can infl uence gene expression via modulation of the DNA methylation process. It has been demonstrated that some polyphenols (i.e., catechins, quercetin, myricetin, genistein, resveratrol) and vitamins (i.e., retinoic acid, vitamin D 3 ) exert a profound inhibitory effect on DNA methyltransferase enzyme activity and/or DNA methyltransferase gene expression and contribute to reactivation of methylation -silenced tumor suppressor genes in cancer cells leading to blocking of cancer development. This raises the possibility that the natural compounds can be a new approach to anticancer therapy. Moreover, their presence in widely available food products can bring about the high effi cacy of the compounds in cancer chemoprevention. This chapter gives a short overview of the mechanisms of DNA methylation inhibition by the selected bioactive food components and their potential use in cancer prevention and/or epigenetic therapy.

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Dendron‐Based Micelles for Topical Delivery of Endoxifen: A Potential Chemo‐Preventive Medicine for Breast Cancer

Yang

Pearson

Lee

et al. 2014

Adv Funct Materials

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Endoxifen (EDX) is an active metabolite of tamoxifen that has been proven effective in the prevention and treatment of estrogen-positive breast cancer; however, oral administration of tamoxifen often causes severe side effects. Here, the topical delivery of EDX is explored using polymeric micelles to achieve localized drug delivery with potentially minimal side effects. EDX is encapsulated into dendron micelles (DM) with various surface groups (-NH 2 , -COOH, or -Ac) and into cationic liposomes as a control. End-group modification signifi cantly affects the drug loading, where the DM-COOH micelles allow the most effi cient encapsulation. Furthermore, unlike the burst release from the liposomes, all DMs show sustained release of EDX over 6 days. Each formulation is evaluated for its potential to deliver EDX across the skin layers. DMs substantially enhance the permeation of EDX through both mouse (up to 20-fold) and human (up to 4-fold) skin samples relative to ethanol, a chemical penetration enhancer. Franz diffusion cell experiments reveal that DM-COOH induces the highest fl ux of EDX among all groups. The enhanced drug loading, controlled release profi les, and enhanced skin permeation all demonstrate that DMs are a useful platform for the topical delivery of EDX, offering a potential alternative administration route for chemoprevention.

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The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alteration of the cell cycle

Cited by 210 publications

References 31 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Effects of Dietary Natural Compounds on DNA Methylation Related to Cancer Chemoprevention and Anticancer Epigenetic Therapy

Dendron‐Based Micelles for Topical Delivery of Endoxifen: A Potential Chemo‐Preventive Medicine for Breast Cancer

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