Natural Plant Polyphenol Research Articles

The novel resveratrol analogue HS-1793 induces apoptosis via the mitochondrial pathway in murine breast cancer cells

Resveratrol (3,4′,5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. Several studies were undertaken to obtain synthetic analogues of resveratrol with potent anticancer activity. The aim of the present study was to investigate the effect of HS-1793 as a new resveratrol analog on apoptosis via the mitochondrial pathway in murine breast cancer cells. A pharmacological dose (1.3–20 μM) of HS-1793 exerted a cytotoxic effect on murine breast cancer cells resulting in apoptosis. HS-1793-mediated cytotoxicity in FM3A cells by several apoptotic events including mitochondrial cytochrome c release, activation of caspase-3 and PARP occurred. In addition, HS-1793 induced collapse of ΔΨm and enhanced AIF and Endo G release from mitochondria while undergoing apoptosis. These results demonstrate that the cytotoxicity by HS-1793 in FM3A cells can mainly be attributed to apoptosis via a mitochondrial pathway by caspase activation or contributions of AIF and Endo G.

Rottlerin and curcumin: a comparative analysis

Rottlerin and curcumin are natural plant polyphenols with a long tradition in folk medicine. Over the past two decades, curcumin has been extensively investigated, while rottlerin has received much less attention, in part, as a consequence of its reputation as a selective PKCδ inhibitor. A comparative analysis of genomic, proteomic, and cell signaling studies revealed that rottlerin and curcumin share a number of targets and have overlapping effects on many biological processes. Both molecules, indeed, modulate the activity and/or expression of several enzymes (PKCδ, heme oxygenase, DNA methyltransferase, cyclooxygenase, lipoxygenase) and transcription factors (NF-κB, STAT), and prevent aggregation of different amyloid precursors (α-synuclein, amyloid Aβ, prion proteins, lysozyme), thereby exhibiting convergent antioxidant, anti-inflammatory, and antiamyloid actions. Like curcumin, rottlerin could be a promising candidate in the fight against a variety of human diseases.

P38 Inhibitor SB203580 sensitizes the resveratrol‐induced apoptosis in human lung adenocarcinoma (A549) cells

Based on our recent findings that resveratrol, a natural plant polyphenol found in red grape skins as well as other food products, induces apoptosis via a caspase-independent intrinsic pathway in human lung adenocarcinoma cells, this study is designed to explore whether SB203580, a p38 inhibitor, potentiates the resveratrol-induced apoptosis of human lung adenocarcinoma (A549) cells. We found that pretreatment with SB203580 enhanced the resveratrol-induced apoptosis by accelerating the intrinsic apoptotic pathway including Bax activation, loss of mitochondrial membrane potential, and activation of both caspase-9 and -3. Although treatment with resveratrol alone did not induce caspase-8 activation, cotreatment with both SB203580 and resveratrol not only enhanced FasL cleavage but also activated caspase-8, indicating that the extrinsic apoptotic pathway may be involved in the synergistic effect. Collectively, we for the first time demonstrate that SB203580 synergistically enhances the resveratrol-induced apoptosis by accelerating Bax-mediated intrinsic pathway and initiating extrinsic pathway, suggesting a possible alternative therapeutic strategy for human lung cancer.

The chemopreventive and clinically used agent curcumin sensitizes HPV- but not HPV+ HNSCC to ionizing radiation, in vitro and in a mouse orthotopic model

Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV- cell lines was significantly higher than the HPV+ cell lines used in our study. Notably, all of the HPV- cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV- cell lines it had no effect on the HPV+ cells. Based on these findings we employed an orthotopic, HPV- HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV- HNSCC.

Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells

Our recent study have shown that resveratrol (RV), a natural plant polyphenol found in red grape skins as well as other food product, induced apoptosis via the downstream factors, caspase-independent AIF and to lesser extent caspase-9, of intrinsic apoptosis pathway in human lung adenocarcinoma (ASTC-a-1) cells. This report is designed to explore the roles of the upstream mediators of the intrinsic pathway, such as Bak/Bax, Bim, Puma and Noxa, during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines. RV treatment remarkably induced the activation of Bak but not Bax, and silencing Bak but not Bax by shRNA almost completely prevented RV-induced cell death, mitochondrial dysfunction and also largely prevented RV-induced AIF release, demonstrating the preferential engagement of Bak but not Bax during RV-induced apoptosis. In addition, although RV treatment induced a significant degradation of Mcl-1, knockdown of Mcl-1 by shRNA only modestly increased RV-induced Bak activation. Interestingly, silencing Bim but not Puma and Noxa remarkably attenuated RV-induced cell death, loss of mitochondrial membrane potential, and Bak activation, suggesting the important roles of Bim. Collectively, our findings for the first time demonstrate that RV induces apoptosis dominantly via a Bak- but not Bax-mediated AIF-dependent mitochondrial apoptotic signaling pathway in which Bim but not Puma and Noxa may supply the force to trigger Bak activation and subsequent apoptosis in both ASTC-a-1 and A549 cell lines.

Molecular mechanisms of the neuroprotective neurorescue action of multi-target green tea polyphenols

Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.

The importance of the multiple target action of green tea polyphenols for neuroprotection

Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multipharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.

Facile Synthesis of Size-Controlled Silver Nanoparticles Using Plant Tannin Grafted Collagen Fiber As Reductant and Stabilizer for Microwave Absorption Application in the Whole Ku Band

Size-controlled silver nanoparticles (AgNPs) were facilely synthesized on collagen fiber (CF), in which bayberry tannin (BT), a natural plant polyphenol, was grafted on CF to act as a reductant and stabilizer without any additional reagent (surfactant, template, and capping agent) or treatment (heat and photoirradiation) needed. The as-synthetic AgNPs-BT@CF was well characterized via combined techniques including SEM, HTEM, XRD, XPS, and FT-IR. The particle diameter and size distribution of AgNPs in BT@CF matrix are feasible to adjust by varying the grafting degree of BT on the CF surface. When the grafting degree of BT was 0.4, the particle size of AgNPs is as small as 5.2 ± 1.9 nm. Furthermore, the complex permittivity, and complex permeability of the AgNPs-BT@CF were also investigated in detail. It was found that with the increase of grafting degree of BT on CF the imaginary part (ε″) of complex permittivity was dramatically increased, whereas the real part (μ′) and imaginary part (μ″) of complex permittivity were not obviously changed. The reflection loss (RL) of AgNPs-BT@CF exceeding −10 dB was achieved in the whole Ku band (12.5–18 GHz).

Plant polyphenols attenuate hepatic injury after hemorrhage/resuscitation by inhibition of apoptosis, oxidative stress, and inflammation via NF-kappaB in rats

Oxidative stress and inflammation contribute to hepatic injury after hemorrhage/resuscitation (H/R). Natural plant polyphenols, i.e., green tea extract (GTE) possess high anti-oxidant and anti-inflammatory activities in various models of acute inflammation. However, possible protective effects and feasible mechanisms by which plant polyphenols modulate pro-inflammatory, apoptotic, and oxidant signaling after H/R in the liver remain unknown. Therefore, we investigated the effects of GTE and its impact on the activation of NF-kappaB in the pathogenesis of hepatic injury induced by H/R. Twenty-four female LEWIS rats (180-250g) were fed a standard chow (ctrl) or a diet containing 0.1% polyphenolic extracts (GTE) from Camellia sinensis starting 5days before H/R. Rats were hemorrhaged to a mean arterial pressure of 30±2mmHg for 60min and resuscitated (H/R and GTE H/R groups). Control groups (sham, ctrl, and GTE) underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested. Plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increased 3.5-fold and fourfold, respectively, in vehicle-treated rats as compared to GTE-fed rats. Histopathological analysis revealed significantly decreased hepatic necrosis and apoptosis in GTE-fed rats after H/R. Real-time PCR showed that GTE diminished gene expression of pro-apoptotic caspase-8 and Bax, while anti-apoptotic Bcl-2 was increased after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as systemic IL-6 level and hepatic IL-6 mRNA were markedly reduced in GTE-fed rats compared with controls after H/R. Plant polyphenols also decreased the activation of both JNK and NFκB. Taken together, GTE application blunts hepatic damage, apoptotic, oxidative, and pro-inflammatory changes after H/R. These results underline the important roles of JNK and NF-kappaB in inflammatory processes after H/R and the beneficial impact of plant polyphenols in preventing their activation.

Resveratrol induces mitochondria-mediated AIF and to a lesser extent caspase-9-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells

Resveratrol (RV), a natural plant polyphenol widely present in foods such as grapes, wine, and peanuts, has an ability to inhibit various stages of carcinogenesis in vitro and in vivo. In this report, we explored the roles of intrinsic and extrinsic apoptotic pathways during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cells. After exposure of cells to different concentrations of RV, we found that RV induced concentration-dependent apoptosis. Fluorometric substrates assay and western blotting (WB) analysis showed that caspase-8 was not activated, which was further verified by monitoring the cleavage of Bid to tBid using fluorescence resonance energy transfer (FRET) microscopy imaging inside single living cells, indicating that extrinsic apoptotic pathway was not involved in RV-induced apoptosis. In addition, inhibition of caspases-3 or -9 but not caspase-8 using the specific inhibitors of caspases modestly but significantly attenuated RV-induced apoptosis. Moreover, flow cytometry (FCM) analysis showed that RV treatment induced time-dependent loss of mitochondrial membrane potential (∆ψ(m)), in combination with the activation of caspases-3 and -9; we therefore concluded that RV-induced apoptosis involved the intrinsic apoptotic pathway. It is noteworthy that RV treatment induced translocation of AIF from mitochondria to nucleus in a time dependent manner, and that knockdown of AIF remarkably attenuated RV-induced apoptosis. Collectively, our findings demonstrate that RV induces caspase-8-independent apoptosis via AIF and to a lesser extent caspase-9-dependent mitochondrial pathway in ASTC-a-1 cells.

Catalytic hydrogenation of quinoline over recyclable palladium nanoparticles supported on tannin grafted collagen fibers

Black wattle tannin (BT), a typical natural plant polyphenol, was grafted onto collagen fiber (CF) to act as the stabilizer and carrier of Pd nanoparticles, and as a result, a recyclable heterogeneous Pd catalyst (Pd-BT-CF) was synthesized. The main physicochemical properties of the Pd-BT-CF catalyst were characterized by Scanning Electron Microscopy (SEM), X-ray Photoelectron Spectroscopy (XPS), and Transmission Electron Microscopy (TEM). It was found that the catalyst was in an ordered fibrous state, on which Pd nanoparticles with diameter of 4 nm were highly dispersed. Subsequently, the Pd-BT-CF catalyst was employed for the hydrogenation of quinoline. The influences of reaction time, temperature, H 2 pressure and solvent on the catalytic hydrogenation of quinoline were systematically investigated. The experimental results suggested that the Pd-BT-CF catalyst exhibited high catalytic activity and selectivity for quinoline hydrogenation. The average turnover frequency (TOF) of Pd-BT-CF was as high as 165.3 mol mol −1 h −1, and the selectivity to 1,2,3,4-tetrahydroquinoline was 100% when the reaction was carried out at 60 °C and 2.0 MPa for 1.0 h. Moreover, the activity and selectivity of Pd-BT-CF catalyst were not significantly reduced after being reused 6 times, exhibiting a satisfied reusability. Further XPS, Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and TEM analyses confirmed that the Pd species were stabilized by the hydroxyls of BT-CF, which prevented the aggregation and leakage of Pd during the reaction.

One-step room-temperature synthesis of Au@Pd core–shell nanoparticles with tunable structure using plant tannin as reductant and stabilizer

Bayberry tannin (BT), a natural plant polyphenol, is used for the one-step synthesis of Au@Pd core–shell nanoparticles (Au@Pd NPs) in aqueous solution at room temperature. Due to its mild and stepwise reduction ability, BT was able to preferentially reduce Au3+ to Au NPs when placed in contact with an Au3+/Pd2+ mixture, and subsequently, the formed Au NPs served as in situ seeds for the growth of a Pd shell, resulting in the formation of Au@Pd NPs. Importantly, it is feasible to adjust the morphology of the Pd shell by varying the Pd2+/Au3+ molar ratio. Au@Pd NPs with a spherical Pd shell were formed when the Pd2+/Au3+ molar ratio was 1/50, while Au@Pd NPs with cubic Pd shell predominated when the ratio was increased to 2/1. The core–shell structure of synthesized Au@Pd NPs was characterized by TEM, HAADF-STEM, EDS mapping, an EDS line scan, and EDS point scan. Furthermore, density functional theory (DFT) calculations suggested that the localization of BT molecules on the surface of the Au clusters was the crucial factor for the formation of Au@Pd NPs, since the BT molecules increased the surface negative charges of the Au NPs, favoring the attraction of Pd2+ over Au NPs and resulting in the formation of a Pd shell.

Modification of collagen with a natural cross-linker, procyanidin

We have investigated the modification of collagen with a natural plant polyphenol, procyanidin under acidic conditions. Fourier transform infrared spectroscopy (FTIR) and Atomic force microscopy (AFM) studies demonstrate that the hydrogen bond interactions between collagen and procyanidin does not destroy the triple helix conformation of collagen, and the fibril aggregation occurs because of the cross-linking with procyanidin. The water contact angle (WCA) tests indicate that the hydrophobicity of the procyanidin modified collagen films can be improved. Whereas, the water vapor permeability (WVP) of the films decrease with the increasing procyanidin content due to the formation of denser structure. Moreover, differential scanning calorimetry (DSC) and thermogravimetric (TG) measurements reveal that the collagen/procyanidin films have improved thermal stability in comparison with pure collagen. The present study reveals that procyanidin stabilizes collagen as a cross-linker and preserves its triple helical structure. [Display omitted]

Preparation of platinum nanoparticles supported on bayberry tannin grafted silica bead and its catalytic properties in hydrogenation

Bayberry tannin (BT), a natural plant polyphenol, was used as a stabilizer to prepare supported platinum catalysts. Bayberry tannin was first grafted onto aminated SiO 2 beads and subsequently coordinate with Pt(IV) species. Then a series of heterogeneous Pt–bayberry tannin–SiO 2 (Pt–BT–SiO 2) catalysts was obtained after reduction with NaBH 4. The catalysts were characterized by UV–DR, XRD and TEM, and the coordination state of Pt(IV) with BT grafted on SiO 2 beads was investigated by XPS. It was found that the Pt–BT–SiO 2 catalysts were highly active and stable in aqueous hydrogenation of acrylic acid, α-methacrylic acid, allyl alcohol and 2-methyl-3-buten-2-ol. Moreover, the Pt–BT–SiO 2 catalysts could be conveniently recovered from the reaction systems simply by filtration, and be reused at least five times without loss of activity.

One-step, size-controlled synthesis of gold nanoparticles at room temperature using plant tannin

Bayberry tannin (BT), a natural plant polyphenol, was used for one-step synthesis of gold nanoparticles (AuNPs) in aqueous solution at room temperature. During the synthetic process, BT simultaneously serves as a reducing agent and stabilizing agent, while no additional reagent (surfactant, template, and capping agent) or treatment (heat and photo-irradiation) is needed. The particle diameter and size distribution of BT-stabilized AuNPs (BT-AuNPs) can be facilely controlled by varying the concentration of BT, and the particle size of BT-AuNPs is as small as 1.8 ± 0.3 nm when the BT concentration was 800 mg L−1. Furthermore, this green approach for the auto-reduction synthesis of AuNPs can be completed in several minutes and exhibits high reproducibility, which shows great potential for practical applications.

Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation

Resveratrol (RES), a natural plant polyphenol, is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, RES has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventive and anti-tumor agent in vivo. The chemopreventive and chemotherapeutic properties associated with resveratrol offer promise for the design of new chemotherapeutic agents. However, the mechanisms by which RES mediates its effects are not yet fully understood. In this study, we showed that RES caused cell cycle arrest and proliferation inhibition via induction of unfolded protein response (UPR) in human leukemia K562 cell line. Treatment of K562 cells with RES induced a number of signature UPR markers, including transcriptional induction of GRP78 and CHOP, phosphorylation of eukaryotic initiation factor 2α (eIF2α), ER stress-specific XBP-1 splicing, suggesting the induction of UPR by RES. RES inhibited proliferation of K562 in a concentration-dependent manner. Flow cytometric analyses revealed that K562 cells were arrested in G1 phase upon RES treatment. Salubrinal, an eIF2α inhibitor, or overexpression of dominant negative mutants of PERK or eIF2α, effectively restored RES-induced cell cycle arrest, underscoring the important role of PERK/eIF2α branch of UPR in RES-induced inhibition of cell proliferation.

Electrostatic assembles and optical properties of Au–CdTe QDs and Ag/Au–CdTe QDs

Au–CdTe and Ag/Au–CdTe assembles were firstly investigated through the static interaction between positively charged cysteamine-stabilized CdTe quantum dots (QDs) and negatively charged Au or core/shell Ag/Au nano-particles (NCs). The CdTe QDs synthesized in aqueous solution were capped with cysteamine which endowed them positive charges on the surface. Both Au and Ag/Au NCs were prepared through reducing precursors with gallic acid obtained from the hydrolysis of natural plant poly-phenols and favored negative charges on the surface of NCs. The fluorescence spectra of CdTe QDs exhibited strong quenching with the increase of added Au or Ag/Au NCs. Railey resonance scattering spectra of Au or Ag/Au NCs increased firstly and decreased latter with the concentration of CdTe QDs, accompanied with the solution color changing from red to purple and colorless at last. Experimental results on the effects of gallic acid, chloroauric acid tetrahydrate and other reagents demonstrated the static interaction occurred between QDs and NCs. This finding reveals the possibilities to design and control optical process and electromagnetic coupling in hybrid structures.

Modulatory potential of ellagic acid, a natural plant polyphenol on altered lipid profile and lipid peroxidation status during alcohol‐induced toxicity: A pathohistological study

Polyphenol-rich dietary foodstuffs, consumed as an integral part of vegetables, fruits, and beverages have attracted attention due to their antioxidant and anticancer properties. Ellagic acid (EA), a polyphenolic compound widely distributed in fruits and nuts, has been reported to scavenge free radicals and inhibit lipid peroxidation. Chronic consumption of alcohol potentially results in serious illness including hepatitis, fatty liver, hypertriglyceridemia, and cirrhosis. A little is known about the influence of EA on alcohol toxicity in vivo. Accordingly, in the present study, we have evaluated the protective effects of EA on lipid peroxidation and lipid levels during alcohol-induced toxicity in experimental rats. Forty female albino Wistar rats, which were weighing between 150-170 g were used for the study. The toxicity was induced by administration of 20% alcohol orally (7.9 g/kg body wt.) for 45 days. Rats were treated with EA at three different doses (30, 60, and 90 mg/kg body wt.) via intragastric intubations together with alcohol. At the end of experimental duration, liver marker enzymes (i.e., aspartate transaminase, alanine transaminase), lipid peroxidative indices (i.e., thiobarbituriacid reactive substances and hydroperoxides) in plasma, and lipid levels (i.e., cholesterol, free fatty acids, triglycerides and phospholipids) in tissues were analyzed to evaluate the antiperoxidative and antilipidemic effects of EA. Liver marker enzymes, lipid peroxidative indices, and lipid levels, i.e., cholesterol, triglycerides and free fatty acids, were significantly increased whereas phospholipid levels were significantly decreased in the alcohol-administered group. EA treatment resulted in positive modulation of marker enzymes, peroxidative indices, and lipid levels. EA at the dose of 60 mg/kg body wt. was found to be more effective when compared to the other two doses. Histological changes observed were also inconsistent with the biochemical parameters. Our study suggests that EA exerts beneficial effects at the dosage of 60 mg/kg body wt. against alcohol-induced damage, and it can be used as a potential drug for the treatment of alcohol-abuse ailments in the near future.

Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer

Resveratrol (RES), a natural plant polyphenol, has gained interest as a nontoxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms of RES-induced apoptosis are not well defined. Using the human breast cancer cell lines MDA-MB-231 and MCF-7, we demonstrate that RES is antiproliferative and induces apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of mitochondrial membrane potential by directly targeting mitochondria. This is followed by release of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) into the cytoplasm and substantial increase in the activities of caspases-9 and -3 in MDA-MB-231 cells. In addition, live cell microscopy demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca2+]i), probably resulting from depletion of the endoplasmic reticulum stores in breast cancer cells. In caspase-3-deficient MCF-7 cells, apoptosis is mediated by the Ca2+-activated protease, calpain, leading to the degradation of plasma membrane Ca2+-ATPase isoform 1 and fodrin; the degradation is attenuated by buffering [Ca2+]i and blocked by calpain inhibitors. Mitochondrial permeability transition pore antagonists also blocked calpain activation. In vivo mouse xenograft studies demonstrate that RES treatment inhibits breast cancer growth with no systemic toxicities. Together, these results suggest a critical role for mitochondria not only in the intrinsic apoptotic pathway but also in the Ca2+ and calpain-dependent cell death initiated by RES. Thus, RES may prove useful as a nontoxic alternative for breast cancer treatment.

Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells.

BackgroundThe natural plant polyphenol resveratrol present in some foods including grapes, wine, and peanuts, has been implicated in the inhibition, delay, and reversion of cellular events associated with heart diseases and tumorigenesis. Recent work has suggested that the cancer chemoprotective effect of the compound is primarily linked to its ability to induce cell division cycle arrest and apoptosis, the latter possibly through the activation of pro-apoptotic proteins such as Bax.MethodsThe expression, subcellular localization, and importance of Bax for resveratrol-provoked apoptosis were assessed in human HCT116 colon carcinoma cells and derivatives with both bax alleles inactivated.ResultsLow to moderate concentrations of resveratrol induced co-localization of cellular Bax protein with mitochondria, collapse of the mitochondrial membrane potential, activation of caspases 3 and 9, and finally, apoptosis. In the absence of Bax, membrane potential collapse was delayed, and apoptosis was reduced but not absent. Resveratrol inhibited the formation of colonies by both HCT116 and HCT116 bax -/- cells.ConclusionResveratrol at physiological doses can induce a Bax-mediated and a Bax-independent mitochondrial apoptosis. Both can limit the ability of the cells to form colonies.