Unidentified ? I thought the Medline links were quite clear.
These are what are sometimes called "naked links" There's not even any way to tell what the link means until you go there. The best way to support an argument is to quote the abstract, and put the relevant parts in bold so people can quickly see what you're talking about.
It's not just inhibition of PPAR gamma alone, but resveratrol's
upregulation of SIRT1, the reverse of which is desired in fighting
cancer.
what's the evidence for this? Is there enough evidence to overwhelm the evidence for high dose resveratrol being pro-apoptotic?
http://www.imminst.o...o...st&p=305414
This is a link to an imminst post by blutarsky where he shows a poor understanding of resveratrol. He thinks it's just an "antioxidant", and is therefore contraindicated in cancer. That's just wrong.
http://www.imminst.o...mp;#entry298229
Another blutarsky post which led to among other things, a link to this paper:
Cancer Res. 2005 Nov 15;65(22):10183-7.
Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1.
Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A.
Department of Pediatrics, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.
Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA-mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.
PMID: 16288004
They show that sirt1 is upregulated in drug-resistant cell lines. Chicken or egg?
They show that cells from cancer patients who had chemotherapy express more sirt1. Does that mean we shouldn't use chemotherapy?
siRNA down-regulation of sirt1 significantly reduces the PGP/MDR phenotype. That is interesting.
Ectopic overexpression of sirt1 induced expression of PGP. That is interesting, and sheds light on the chicken/egg question, as does the siRNA experiment.
However, does resveratrol increase PGP? I don't think we have any evidence to that effect. Does resveratrol increase the expression of sirt1? I thought the main mechanism of action was changing the energetics of sirt1-induced deacetylation.
There appears to be evidence in the literature that resveratrol
inhibits PGP and other transporters implicated in multidrug resistance. Therefore, I think that the connection between sirt1 and PGP expression, while interesting, does not imply that resveratrol is contraindicated in cancer.
Pharmazie. 2009 Jan;64(1):49-52.Links
Effect of resveratrol on the pharmacokinetics of oral and intravenous nicardipine in rats: possible role of P-glycoprotein inhibition by resveratrol.
Choi JS, Choi BC, Kang KW.
College of Pharmacy, Chosun University, Gwangju, Korea.
The present study aimed to assess the effect of resveratrol on the bioavailability of nicardipine in rats. Nicardipine was administered orally (12 mg kg(-1)) or intravenously (4 mg kg(-1)) with or without oral administration of resveratrol (0.5, 2.5 or 10 mg kg(-1)). The oral administration of 2.5 or 10 mg kg(-1) of resveratrol significantly increased both the area under the plasma concentration-time curve (AUC) (P < 0.01, 111-126%) and the peak plasma concentration (Cmax) (P < 0.01, 105-121%), and significantly decreased the total body clearance (CL/F) (P < 0.01, 52.8-55.8%) of orally administered nicardipine. In contrast, resveratrol did not significantly change the pharmacokinetic parameters of i.v. nicardipine. Resveratrol significantly reduced rhodamine123 efflux via P-gp in MCF-7/ADR cells overexpressing P-gp. Resveratrol also inhibits CYP3A4, suggesting that the enhanced oral bioavailability of nicardipine by resveratrol may result from decreased P-gp-mediated efflux or inhibition of intestinal CYP3A4 metabolism. Based on these results, nicardipine dosage should be adjusted when given with supplements containing resveratrol.
PMID: 19216231
Biomed Pharmacother. 2008 Nov;62(9):622-9. Epub 2008 Aug 28.Click here to read Links
Reversal effect of resveratrol on multidrug resistance in KBv200 cell line.
Quan F, Pan C, Ma Q, Zhang S, Yan L.
Department of ENT & Head and Neck Surgery, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an 710061, PR China. quanfang2008@sina.com.cn
A multidrug-resistant clone of human oral epidermoid carcinoma KB cells was isolated by stepwise selection on exposure to increasing doses of vincristine. The final clone, KBv200, obtained after ethylmethane sulfonate mutagenesis showed 156-fold higher resistance to vincristine than KB cells. The cells were also cross-resistant to paclitaxel and adriamycin. The aim of this study was to explore the reversal effect and potential mechanism of resveratrol on KBv200 cells. MTT assay was used to investigate the reversal index of resveratrol to vincristine, adriamycin and paclitaxel. Cell apoptosis was measured by flow cytometry. RT-PCR and western blot were used to detect mRNA and protein expression of multidrug-resistant gene MDR1 and apoptosis-suppressing gene Bcl-2. Resveratrol produced a synergistic effect combined with the chemotherapeutic agents and reversed the multidrug-resistant phenotype of KBv200 cells. Flow cytometry confirmed that the percentage of apoptotic cell increased when KBv200 cells were exposed to resveratrol. The results of gene detection showed that the expression levels of MDR1 and Bcl-2 were decreased upon resveratrol treatment. Resveratrol can efficiently reverse multidrug resistance in KBv200 cells. The potential mechanism may be via inhibiting the multidrug-resistant gene expressions and/or promoting cell apoptosis.
PMID: 18804944
Biochem Biophys Res Commun. 2004 Apr 23;317(1):269-75.
Interaction of the breast cancer resistance protein with plant polyphenols.
Cooray HC, Janvilisri T, van Veen HW, Hladky SB, Barrand MA.
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Multidrug transporters influence drug distribution in vivo and are often associated with tumour drug resistance. Here we show that plant-derived polyphenols that interact with P-glycoprotein can also modulate the activity of the recently discovered ABC transporter, breast cancer resistance protein (BCRP/ABCG2). In two separate BCRP-overexpressing cell lines, accumulation of the established BCRP substrates mitoxantrone and bodipy-FL-prazosin was significantly increased by the flavonoids silymarin, hesperetin, quercetin, and daidzein, and the stilbene resveratrol (each at 30 microM) as measured by flow cytometry, though there was no corresponding increase in the respective wild-type cell lines. These compounds also stimulated the vanadate-inhibitable ATPase activity in membranes prepared from bacteria (Lactococcus lactis) expressing BCRP. Given the high dietary intake of polyphenols, such interactions with BCRP, particularly in the intestines, may have important consequences in vivo for the distribution of these compounds as well as other BCRP substrates.
PMID: 15047179
