Artemissia-Phoebe Nifli

Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action

IntroductionThe oncoprotective role of food-derived polyphenol antioxidants has been described but the implicated mechanisms are not yet clear. In addition to polyphenols, phenolic acids, found at high concentrations in a number of plants, possess antioxidant action. The main phenolic acids found in foods are derivatives of 4-hydroxybenzoic acid and 4-hydroxycinnamic acid.MethodsThis work concentrates on the antiproliferative action of caffeic acid, syringic acid, sinapic acid, protocatechuic acid, ferulic acid and 3,4-dihydroxy-phenylacetic acid (PAA) on T47D human breast cancer cells, testing their antioxidant activity and a number of possible mechanisms involved (interaction with membrane and intracellular receptors, nitric oxide production).ResultsThe tested compounds showed a time-dependent and dose-dependent inhibitory effect on cell growth with the following potency: caffeic acid > ferulic acid = protocatechuic acid = PAA > sinapic acid = syringic acid. Caffeic acid and PAA were chosen for further analysis. The antioxidative activity of these phenolic acids in T47D cells does not coincide with their inhibitory effect on tumoral proliferation. No interaction was found with steroid and adrenergic receptors. PAA induced an inhibition of nitric oxide synthase, while caffeic acid competes for binding and results in an inhibition of aryl hydrocarbon receptor-induced CYP1A1 enzyme. Both agents induce apoptosis via the Fas/FasL system.ConclusionsPhenolic acids exert a direct antiproliferative action, evident at low concentrations, comparable with those found in biological fluids after ingestion of foods rich in phenolic acids. Furthermore, the direct interaction with the aryl hydrocarbon receptor, the nitric oxide synthase inhibition and their pro-apoptotic effect provide some insights into their biological mode of action.

Polyphenols and cancer cell growth

Polyphenols constitute an important group of phytochemicals that gained increased research attention since it was found that they could affect cancer cell growth. Initial evidence came from epidemiologic studies suggesting that a diet that includes regular consumption of fruits and vegetables (rich in polyphenols) significantly reduces the risk of many cancers. In the present work we briefly review the effects of polyphenols on cancer cell fate, leading towards growth, differentiation and apoptosis. Their action can be attributed not only to their ability to act as antioxidants but also to their ability to interact with basic cellular mechanisms. Such interactions include interference with membrane and intracellular receptors, modulation of signaling cascades, interaction with the basic enzymes involved in tumor promotion and metastasis, interaction with oncogenes and oncoproteins, and, finally, direct or indirect interactions with nucleic acids and nucleoproteins. These actions involve almost the whole spectrum of basic cellular machinery--from the cell membrane to signaling cytoplasmic molecules and to the major nuclear components--and provide insights into their beneficial health effects. In addition, the actions justify the scientific interest in this class of compounds, and provide clues about their possible pharmaceutical exploitation in the field of oncology.

Activation of membrane estrogen receptors induce pro-survival kinases.

Experimental and epidemiological data suggest a neuroprotective role for estrogen (E(2)). We have recently shown that, in PC12 cells, non-permeable estradiol conjugated to bovine serum albumin (BSA) prevent serum-deprivation induced apoptosis through activation of specific membrane estrogen receptors (mER). In the present study, we explored in detail the early signaling events involved in this anti-apoptotic action, downstream to activation of mER. Our findings suggest that mER is associated to G-proteins, and its activation with non-permeable E(2)-BSA results in the activation of the following downstream pro-survival kinases pathways: (1) the PKB/Akt pathway, (2) the Src-->MEK-->ERK kinases and finally (3) the MAPK-->ERK kinases. Activation of these pro-survival signals leads to CREB phosphorylation and NFkappaB nuclear translocation, two transcription factors controlling the expression of anti-apoptotic Bcl-2 proteins. These data suggest that major pro-survival kinases are involved in the mER-mediated anti-apoptotic effects of estrogen. This is further supported by experiments with specific kinases inhibitors, which partially but significantly reversed the mER-mediated anti-apoptotic effect of E(2)-BSA. Our findings suggest that estrogen act via mER as potent cytoprotective factors, downstream activating pro-survival kinases, assuring thus an efficient and multipotent activation of the anti-apoptotic machinery.

Polyphenol interaction with the T47D human breast cancer cell line

Experimental and epidemiological studies indicate that antioxidant food polyphenols could have antimitotic activities, interfering with cancer initiation, progression or mortality. Circulating polyphenols are far lower than the nominal value in foods. In the rare studies dealing with polyphenol bioavailability, it was noted that their active concentrations in the blood are <1% of their food concentration. In the present study we investigated the effect of four polyphenols (resveratrol, and the flavonoids quercetin, catechin and epicatechin, major constituents of wine) in the hormone-sensitive human cancer cell line T47D, at concentrations compatible with their calculated plasma concentrations after ingestion of a moderate quantity of wine (nM or pM). Our results indicate that cell growth was decreased, with cells being arrested at the S phase of the cycle. In addition, we provide evidence of a bimodal modulation of the NO/NOS system, affecting its activity and transcription. We show that modulation of this system is sufficient to explain polyphenol action on this cell line. This result suggests a potential importance of wine ingestion and possibly the consumption of other polyphenol-rich dietary foods and drinks in the control of breast cancer cell growth.