DNC News


Taxol and Quercetin:

August 15, 2006

Jacob Schor, ND


There is a warranted concern about combining the plant extract quercetin with the chemotherapy drug Taxol. This stems from a 2001 paper by Marone and colleagues working at the Catholic University in Rome which suggests that quercetin may interfere with Taxol's cancer killing effect. [i] This was an in vitro study, watching the behavior of cancer cells in a test tube.


Taxol is the trademarked name for Paclitaxel a chemotherapy agent isolated from the bark of the Pacific Yew tree. First shown to have anticancer effect in the early 1960's, it wasn't until 1977 that a mechanism was proposed to explain the effect. Taxol interferes with cell division by binding to the protein tubulin, which is a key factor in mitosis. Unlike some other cancer drugs which prevented tubulin from assembling into microtubules, Taxol binds to assembled microtubules and blocks them from disassembling. The process of cell division and growth is stopped. Making Taxol from Yew bark was difficult, only small concentrations are present. When Bristol-Meyers took over Taxol from the National Cancer Institute, the collection of yew bark from Oregon and Washington was expanded to run drug trials. At their peak, Pacific yew bark collections were several hundred thousand pounds of bark per year. The bark from a single tree only yielded enough Taxol for about one dose of the drug. Currently a cell culture method is used to produce Taxol. Docetaxel is a closely related drug and is sold under the brand name Taxotere. For the purpose of this discussion I take the liberty of lumping all of these Taxane drugs together and refer to them all as Taxol acknowledging that technically this isn't accurate.


Quercetin is a yellow isoflavonoid commonly found in the pigments of onions and apples. Commercial extracts are prepared from some sort of palm tree. It is commonly used to treat hay fever and allergic asthma; it has wide application in cancer treatment.


For example querceetin will stop breast cancer cells in their tracks, preventing cell division and triggering apoptosis, or what can be described as cell suicide. [ii] It can block the stimulation of breast cancer cells by environmental estrogens, [iii] an action akin to that of tamoxifen. In fact giving quercetin along with tamoxifen increases the tamoxifen's bioavailability possibly making it more effective, [iv]


Tamoxifen isn't the only anti cancer drug that works better in combination with quercetin. Quercetin creates a synergistic action with carboxyamidotriazole when used to treat human breast carcinoma cells. [v] Same story with Tiazofurin and ovarian cancer; adding quercetin to the mix creates a synergistic action. [vi] Again, a similar story exists with Cisplatin; quercetin and Cisplatin have a synergistic effect at killing leukemia cells. [vii]

A similar benefit is seen using this combination together for treating ovarian cancer. [viii] Quercetin changes a cell's chemistry so that previously drug resistant cells become sensitive again to cisplatin. [ix]


The same sort of benefits are seen when combining quercetin with Adryamycin (aka Doxorubicin). The two together inhibit metastasis of murine melanoma cells. [x] [xi] Apparently quercetin may actually work better on its own with these types of melanoma cells. Quercetin causes apoptosis in murine melanoma cells by injuring the mitochondria BUT this action is blocked by Doxorubicin. [xii] This is an unusual situation. Typically we worry about supplements blocking chemotherapy's benefit. In this particular case it appears that chemotherapy blocks quercetin's action.


Again as with Cisplatin, quercetin overcomes Adryamycin drug resistance reversing it so that cancer cells again become sensitive. [xiii] [xiv] [xv] Same thing happens for drug resistance to Vincristine or Vinblastine [xvi] and Gemcitabine and Topotecan resistant breast cancer cells. [xvii]


Quercetin also has a synergistic action with natural supplements. For example it increases the cancer killing effect of ellagic acid. [xviii] [xix]


Looking at how useful quercetin is when taken in conjunction with other chemotherapy drugs, it is difficult to accept that Taxol would be an exception. In reality it isn't clear that it is. This is anything but simple. For one thing quercetin slows biliary excretion of paclitaxel by 76%. [xx] In other words taking the two together keeps the chemo drug in the body much longer. Quercetin also slows the breakdown of the active chemotherapy drug into its inactive metabolites [xxi] and may increase blood concentrations of the active drug during chemotherapy. [xxii] Thus combined with quercetin, Taxol (and its close drug relative, Taxotere) may stay in the body and continue to act much longer when taken with quercetin. So on one hand quercetin makes Taxol less toxic; on the other it stays active in the body longer. How do you calculate the sum of these two opposing actions? Does the longer exposure offset the lowered toxicity? What's the bottom line? It's far from clear at this point. The study that triggered this caution was an in vitro study. Perhaps an animal experiment will eventually tell us which of these effects wins out. Until then the question remains of whether the combination is a problem or an asset in treating cancer.


Hippocrates' ghost hangs over us as we weigh this question and the answer though is simple: “primo, non nocere.” Or translated, “First off, don't hurt them.” As long as there is any question about the benefit of combining Taxol and quercetin and as long as there is any hint that the quercetin may lower the tumor killing ability of Taxol, we will list quercetin as contraindicated with Taxol and its closely related drug cousins. As future research is published this advisement may change.






[i] Exp Cell Res. 2001 Oct 15;270(1):1-12.

Quercetin abrogates taxol-mediated signaling by inhibiting multiple kinases.

Marone M, D'Andrilli G, Das N, Ferlini C, Chatterjee S, Scambia G.


Laboratory of Anti-neoplastic Pharmacology, Catholic University , Rome , Italy .


Cell cycle block in G(2)/M initiates apoptosis, but the mechanism of this signaling cascade are largely unknown. The microtubule-perturbing agent Taxol has multiple effects on this signaling pathway and is a potent inducer of apoptosis. The specific pathways activated by low, clinically relevant concentrations of the drug are still largely unknown and are dependent on cell type and drug concentration. In this work, we have investigated why HeLa cells respond to Taxol by undergoing complete apoptosis, whereas MCF-7 cells remain in an intermediate phase with reduced death. Three phases were distinguished in these apoptotic pathways. The initial phase characterized by cellular detachment is followed by a second phase which includes the onset of apoptotic morphology, and p38 and Bcl-2 phosphorylation. These two phases are common to both cell lines. HeLa cells then proceed to the third and final execution phase, which culminates in death, whereas MCF-7 cells do not progress. Interestingly, the isoflavonoid Quercetin, a known general kinase inhibitor and an antioxidant, was able to prevent the onset of Taxol-induced cellular detachment and to protect from cell death . Moreover, it blocked Taxol-induced phosphorylation of p38 and Bcl-2, and prevented a Taxol-induced change in relative mobility of the apoptosis signal-regulating kinase 1 (Ask1). Our data elucidate the signaling pathways activated by Taxol at low clinically relevant concentrations. Copyright 2001 Academic Press.


PMID: 11597122 [PubMed - indexed for MEDLINE]


[ii] Int J Oncol. 2001 Oct;19(4):837-44

Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin.

Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS, Lee SJ.


Laboratory of Radiation Effect, Korea Cancer Center Hospital , Seoul 139-706, Korea .


Quercetin, a widely distributed bioflavonoid, has been shown to induce growth inhibition in certain cancer cell types. In the present study we have pursued the mechanism of growth inhibition in MCF-7 human breast cancer cells. Quercetin treatment resulted in the accumulation of cells specifically at G2/M phase of the cell cycle. Mitotic index measured by MPM2 staining clearly showed that cells were transiently accumulated in M phase, 24 h after treatment. The transient M phase accumulation was accompanied by a transient increase in the levels of cyclin B1 and Cdc2 kinase activity. However, 24 h or longer treatment caused a marked accumulation of cells in G2 instead of M phase. Levels of cyclin B1 and cyclin B1-associated Cdc2 kinase activity were also decreased. We also found that quercetin markedly increased Cdk-inhibitor p21CIP1/WAF1 protein level after treatment for 48 h or longer, and the induction of p21CIP1/WAF1 increased its association with Cdc2-cyclin B1 complex, however, up-regulation of p53 by quercetin was not observed. Quercetin also induced significant apoptosis in MCF-7 cells in addition to cell cycle arrest, and the induction of apoptosis was markedly blocked by antisense p21CIP1/WAF1 expression. The present data, therefore, demonstrate that a flavonoid quercetin induces growth inhibition in the human breast carcinoma cell line MCF-7 through at least two different mechanisms; by inhibiting cell cycle progression through transient M phase accumulation and subsequent G2 arrest, and by inducing apoptosis.


PMID: 11562764 [PubMed - indexed for MEDLINE]


[iii] In Vitro Cell Dev Biol Anim. 2001 May;37(5):275-82.

Inhibition of environmental estrogen-induced proliferation of human breast carcinoma MCF-7 cells by flavonoids.

Han D, Tachibana H, Yamada K.


Department of Bioscience and Biotechnology, Graduate School , Kyushu University , Fukuoka , Japan .


In the present study, we evaluated the individual and combined effects of environmental estrogens and flavonoids on the proliferation of human breast carcinoma MCF-7 cells. These compounds are as follows: (1) pharmaceutical chemicals such as diethylstilbestrol, 17alpha-ethynylestradiol (17ES), tamoxifen, mestranol, and clomiphene, (2) industrial chemicals such as bisphenol A (BisA), 4-octylphenol (OP), 4-nonylphenol (NP), and p,p'-biphenol, and (3) flavonoids such as daidzein (D), genistein (G), quercetin (Q), and luteolin (L). We found that nanomolar concentrations of 17ES, BisA, OP, and NP were sufficient to stimulate the proliferation of MCF-7 cells. Among them, 1 microM BisA exhibited cell proliferation-stimulating activity as strong as 10 nM 17beta-estradiol; and D and G exhibited cell proliferation-stimulating activity at 10 nM. On the other hand, Q and L exhibited cell proliferation-inhibiting activity. We also found that 10 nM flavonoids, such as D, G, Q, and L, were able to inhibit the proliferation-stimulating activity in MCF-7 cells by 1 microM environmental estrogens.


PMID: 11513082 [PubMed - indexed for MEDLINE]


[iv] Int J Pharm. 2006 Apr 26;313(1-2):144-9. Epub 2006 Mar 3.

Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats.


* Shin SC,

* Choi JS,

* Li X.


College of Pharmacy , Chonnam National University , Bukgu, Gwangju 500-757, Republic of Korea .


Orally administered tamoxifen undergoes a first-pass metabolism and substrates for multidrug resistance (MDR) transporters efflux in the liver and intestines, which obstructs its systemic exposure. This study investigated the effect of quercetin, a dual inhibitor of CYP3A4 and P-gp, on the bioavailability and pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen in plasma were determined after orally administering tamoxifen (10 mg/kg) with or without quercetin (2.5, 7.5 and 15 mg/kg). The coadministration of quercetin (2.5 and 7.5 mg/kg) significantly (p < 0.05) increased the absorption rate constant (K(a)), peak concentration (C(max)) and the areas under the plasma concentration-time curve (AUC) of tamoxifen. The absolute bioavailability (AB%) of tamoxifen with 2.5 and 7.5 mg/kg quercetin ranged from 18.0% to 24.1%, which was significantly higher than the control group, 15.0% (p < 0.05). The relative bioavailability (RB%) of tamoxifen coadministered with quercetin was 1.20-1.61 times higher than the control group. The coadministration of quercetin caused no significant changes in the terminal half-life (t(1/2)) and the time to reach the peak concentration (T(max)) of tamoxifen. Compared with the control group, the coadministration of 7.5 mg/kg quercetin significantly (p < 0.05) increased the AUC of 4-hydroxytamoxifen. However, the metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower (p < 0.05). This suggests that quercetin inhibits the both MDR transporters efflux and first-pass metabolism of tamoxifen. The enhanced bioavailability of tamoxifen as a result of its coadministration with quercetin might be due to the effect of quercetin promoting the intestinal absorption and reducing the first-pass metabolism of tamoxifen. If the results are further confirmed in the clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with quercetin or quercetin-containing dietary supplements in order to avoid potential drug interactions.


PMID: 16516418 [PubM


[v] Life Sci. 1995;57(13):1285-92.

Quercetin: synergistic action with carboxyamidotriazole in human breast carcinoma cells.

Yeh YA, Herenyiova M, Weber G.


Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200 , USA .


Quercetin, a plant flavonoid, blocks signal transduction pathways by inhibiting 1-phosphatidylinositol 4-kinase (EC, PI kinase) and 1-phosphatidylinositol 4-phosphate 5-kinase (EC, PIP kinase), resulting in a reduction of inositol 1,4,5-trisphosphate (IP3) concentration which decreases the release of calcium from intracellular sources. Carboxyamidotriazole (CAI), a novel anticancer agent, inhibits calcium entry into cells. Because both drugs reduce cytosolic calcium levels, we tested the action of quercetin and CAI in human carcinoma cells. Human breast carcinoma MDA-MB-435 cells were grown in minimum essential medium with 10% fetal bovine serum. In growth inhibition assay the IC50s for quercetin and CAI were 55 and 4.8 microM, respectively; in clonogenic assay, 28 and 1.4 microM, respectively. When quercetin and CAI were added to the cultures, synergism was observed in isobolograms in growth inhibition and clonogenic assays. In growth inhibition assay, the best combination was 20 microM quercetin with 4 microM CAI; in clonogenic assay, 30 microM quercetin with 1.2 microM CAI. Since these drugs are in phase I trials the synergistic action of quercetin and CAI may be of interest in clinical trials for breast carcinoma.


PMID: 7674820 [PubMed - indexed for MEDLINE]



[vi] Life Sci. 1999;64(21):1869-76.

Synergistic down-regulation of signal transduction and cytotoxicity by tiazofurin and quercetin in human ovarian carcinoma cells.


Shen F, Herenyiova M, Weber G.


Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis 46202-5119 , USA .


Ovarian carcinoma is one of the most common causes of cancer death in women. Tiazofurin, a C-nucleoside, arrests the cell cycle at S phase and reduces the activities of PI (phosphatidylinositol) utilizing enzymes in signal transduction by depleting cellular GTP concentration. Quercetin (QN), a flavonoid, attacks the cell cycle at the G1 and S phase boundary and mainly inhibits PI kinase (1-phosphatidylinositol 4-kinase, EC activity in the signal transduction pathway. Because tiazofurin and QN attack different biochemical targets and arrest different phases of the cell cycle, we tested the hypothesis that the two drugs might be synergistic against human carcinoma cells. In human ovarian carcinoma OVCAR-5 cells in growth inhibition assay, the IC50s (drug concentration that inhibits 50% of cell proliferation) for tiazofurin and QN were (mean +/- SE) 13 +/- 1.2 and 66 +/- 3.0 microM; in clonogenic assays they were 6 +/- 0.5 and 15 +/- 1.2 microM, respectively. When tiazofurin was added to cells followed 12 h later by QN, synergism was observed in both growth inhibition and clonogenic assays. The combination also yielded synergistic reduction of IP3 (inositol 1,4,5-trisphosphate) concentration in the cells which may explain, at least in part, the synergistic action of tiazofurin and QN in OVCAR-5 cells. The protocols yielding synergism may have implications in the clinical treatment of human ovarian carcinoma.


PMID: 10353585 [PubMed - indexed for MEDLINE]


[vii] Leuk Res. 2003 Jan;27(1):65-72.

Effects of flavonoids on cisplatin-induced apoptosis of HL-60 and L1210 leukemia cells.


Cipak L, Rauko P, Miadokova E, Cipakova I, Novotny L.


Cancer Research Institute, Vlarska 7, 833 91, Bratislava , Slovak Republic .


Effects of three flavonoids, quercetin (QU), galangin (GA), and chrysin (ChR) on cisplatin (cis-Pt)-induced apoptosis of human promyelocytic leukemia HL-60 cells and murine leukemia L1210 cells were investigated. The quantitative analysis of apoptotic DNA fragmentation was used to show that preincubation of cells with flavonoids can influence cis-Pt-induced apoptosis in different way. ChR had no effect, QU enhanced, and GA reduced apoptotic DNA fragmentation. It is also shown that combined treatment with QU and cis-Pt showed synergistic effect, however, GA combined with cis-Pt exhibited antagonism on cytotoxicity in L1210 murine leukemia cells. We assume that tested flavonoids affect the important biological activities connected with cancer chemotherapy and chemoprevention as they differently modulated the sensitivity of cells to cis-Pt treatment. QU is presented as pro-apoptotic agent and GA as agent with anti-apoptotic potential.


PMID: 12479854 [PubMed - indexed for MEDLINE]


[viii] J Cell Physiol. 2003 Jan;194(1):63-70.  

Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents

Chan MM ,Fong D , Soprano KJ , Holmes WF , Heverling H .

Department of Microbiology and Immunology, Temple University School of Medicine, North Broad Street, Philadelphia , Pennsylvania 19140 , USA . marionc@astro.temple.edu

The polyphenolic compounds curcumin and quercetin increased sensitivity of ovarian cancer cells (CAOV3 and SKOV3) to cisplatin. The effect was obtained when the compounds were added simultaneously with cisplatin, as well as when they were added 24 h before. High serum levels of certain cytokines, for example interleukin-6 (IL-6), have been associated with poor prognosis and cisplatin resistance in various forms of cancer. Furthermore, it has been hypothesized that cytokines may increase proliferation, metastasis, and stimulate production of detoxification enzymes and multi-drug resistant proteins. Curcumin inhibits the production of many cytokines. The two ovarian cell lines differ significantly in IL-6 production, and correspondingly the high producer, CAOV3, was less susceptible to cisplatin. Curcumin inhibited the production of IL-6 in this cell suggesting that one of the mechanisms for synergy between cisplatin and curcumin was by reducing the autologous production of IL-6. However, the synergy was also observed in the low IL-6 producer, SKOV3, indicating that the action was most probably a result of multiple targeting. In sum, this study suggests that the compounds, curcumin and quercetin, potentially may be useful for enhancing drug sensitivity in certain cancer. Copyright 2002 Wiley-Liss, Inc.

PMID: 12447990 [


[ix] Biochem Pharmacol. 2005 May 1;69(9):1343-50.

The effect of quercetin on pro-apoptotic activity of cisplatin in HeLa cells .Jakubowicz-Gil J, Paduch R, Piersiak T, Glowniak K, Gawron A, Kandefer-Szerszen M.

Department of Comparative Anatomy and Anthropology, Maria Curie-Sklodowska University , Akademicka 19, 20-033 Lublin , Poland . jjgil@biotop.umcs.lublin.pl


It is well known that some tumour cells are very resistant to chemotherapy-induced cell death which indicate poor prognosis for patients. Thus the aim of the present study was to investigate the effect of quercetin on pro-apoptotic activity of cisplatin in human cervix carcinoma cells (HeLa). Three variants of experiments were performed. In the first one cells were incubated with studied drugs separately for 8 and 24h. In the second, drugs were added to the culture medium simultaneously. In third cisplatin or quercetin addition was followed by subsequent quercetin or cisplatin treatment, respectively. We observed different apoptotic effects, dependent on the drug succession. Preincubation of cells with quercetin followed by cisplatin treatment appeared to be the most effective and was correlated with strong activation of caspase-3 and inhibition of both heat shock proteins (Hsp72) and multi-drug resistance proteins (MRP) levels . Our results indicate that quercetin pretreatment sensitizes HeLa cells to cisplatin-induced apoptosis in HeLa cells.


PMID: 15826605 [PubMed - indexed for MEDLINE]


[x] Clin Exp Metastasis. 2000;18(5):415-21.

Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression. Zhang X, Xu Q, Saiki I.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, The People's Republic of China.


Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2-M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-XL. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression.


PMID: 11467774 [PubMed - indexed for MEDLINE]


[xi] Cancer Chemother Pharmacol. 2004 Jan;53(1):82-8. Epub 2003 Oct 30.

Quercetin inhibits the invasion of murine melanoma B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.Zhang XM, Huang SP, Xu Q.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences , Nanjing University , Nanjing 210093, The People's Republic of China .


PURPOSE: On the basis of the inhibitory effect of quercetin on the invasion of melanoma B16-BL6 cells previously reported by us, the mechanisms of quercetin-mediated inhibition of invasion were further investigated in the present study. METHODS: The ability of B16-BL6 cells to invade and migrate was evaluated in terms of the numbers of cells penetrating a reconstituted basement membrane in the Transwell coculture system. The relative levels and activities of matrix metalloproteinase-9 (MMP-9) and MMP-2 were determined by gelatin zymography and quantified using LabWorks 4.0 software. RESULTS: The quercetin-mediated inhibition of invasion was partially blocked by phorbol-12,13-dibutyrate (PDB), a PKC (protein kinase C) activator, and by doxorubicin, a PKC inhibitor. Only the proforms of MMP-9 (92 kDa) and MMP-2 (72 kDa) were detected by gelatin zymography. Quercetin dose-dependently decreased the gelatinolytic activity of pro-MMP-9. Doxorubicin also markedly reversed the quercetin-induced decrease. Quercetin showed a dose-dependent antagonism of increases in gelatinolytic activity of pro-MMP-9 induced by PDB and free fatty acid (another PKC activator). CONCLUSIONS: Together with the report that quercetin directly reduces PKC activity, the results reported here suggest that quercetin may inhibit the invasion of B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.


PMID: 14593496 [PubMed - indexed for MEDLINE]

[xii] Cancer Chemother Pharmacol. 2005 Mar;55(3):251-62. Epub 2004 Nov 5.

Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alpha and translocating PKC-delta .Zhang XM, Chen J, Xia YG, Xu Q.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China.


PURPOSE: In our previous study, quercetin was found to induce apoptosis of murine melanoma B16-BL6 cells. The cellular and molecular mechanism of quercetin-induced apoptosis was investigated in the present study. METHODS: Nuclear morphology was determined by fluorescence microscopy. DNA fragmentation was analyzed by electrophoresis and quantified by the diphenylamine method. The transmembrane potential of mitochondria was measured by flow cytometry. Bcl-2, Bcl-X(L), PKC-alpha, PKC-beta, and PKC-delta were detected by Western blotting. Caspase activity was determined spectrophotometrically. RESULTS: Quercetin induced the condensation of nuclei of B16-BL6 cells in a dose-dependent pattern as visualized by Hoechst 33258 and propidium iodide dying. Phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly enhanced apoptosis induced by quercetin, while doxorubicin, a PKC inhibitor, markedly decreased it. Both PMA and doxorubicin showed a consistent effect on the fragmentation of nuclear DNA caused by various dosages of quercetin. Quercetin dose-dependently led to loss of the mitochondrial membrane potential, which was also significantly reinforced or antagonized by PMA and doxorubicin, respectively. Moreover, PMA showed reinforcement, while doxorubicin showed significant antagonization, of the quercetin-mediated decrease in the expression of Bcl-2. Quercetin promoted caspase-3 activity in a dose-dependent manner, which was also regulated by PMA and doxorubicin with a pattern similar to that seen in their effect on apoptosis, mitochondrial membrane potential and Bcl-2 expression, but none of these were directly affected by PMA and doxorubicin. Free fatty acid and chlorpromazine, a PKC activator and inhibitor, respectively, did not interfere with these effects of quercetin. B16-BL6 cells expressed PKC-alpha, PKC-beta, and PKC-delta. Quercetin dose-dependently inhibited the expression of PKC-alpha but not that of PKC-beta and PKC-delta. Doxorubicin almost completely blocked the effect of quercetin on the expression of PKC-alpha. Quercetin was also involved in the translocation of PKC-delta from the cytosol to the nucleus. PMA enhanced the effect of quercetin on the translocation of PKC-delta. CONCLUSIONS: These results indicate that quercetin induced apoptosis of murine melanoma B16-BL6 cells by injuring their mitochondria, increasing the activity of caspase-3, inhibiting the expression of Bcl-2 and PKC-alpha, and inducing the translocation of PKC-delta. Doxorubicin inhibited these effects of quercetin by blocking the decreased expression of PKC-alpha induced by quercetin while PMA increased these effects by enhancing the translocation of PKC-delta induced by quercetin.


PMID: 15538571 [PubMed - indexed for MEDLINE]

[xiii] Cancer Lett. 2002 Mar 8;177(1):89-93.

Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells .Ikegawa T, Ohtani H, Koyabu N, Juichi M, Iwase Y, Ito C, Furukawa H, Naito M, Tsuruo T, Sawada Y.

Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University , Maidashi, Higashi-ku, Fukuoka 812-8582, Japan .


We investigated the effects of natural flavones, quercetin and morin, and their pentamethyl, pentaethyl, pentapropyl, pentabutyl and pentaallyl ethers, on the function of P-glycoprotein (P-gp) assessed by an increase in the uptake of [3H]vincristine by human myelogenous leukemia (K562) cells and adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Pentamethyl, pentaethyl, pentapropyl and pentaallyl ethers of morin and quercetin (20 microM) all increased the uptake of [3H]vincristine by K562/ADM cells, while quercetin, morin and their pentabutyl ethers had no effect. Pentamethylquercetin, pentaallylquercetin and pentaethylmorin remarkably increased the uptake of [3H]vincristine by K562/ADM cells by 10.6, 10.8 and 14.4-fold, respectively. These inhibitory potencies for P-gp were more potent than typical P-gp inhibitors, cyclosporine A and verapamil. Taking into consideration that these flavonoid derivatives possess antitumor promoter activity, they may become candidates of effective multidrug resistance-reversing agents in cancer chemotherapy.


PMID: 11809535 [PubMed - indexed for MEDLINE]



[xiv] Anticancer Res. 2000 Jul-Aug;20(4):2477-83.

Effects of quercetin on the cell growth and the intracellular accumulation and retention of adriamycin .Asaum J, Matsuzaki H, Kawasak S, Kuroda M, Takeda Y, Kishi K, Hiraki Y.

Department of Oral Radiology, Okayama University Dental School , Japan .


In this study, we examined the inhibitory effects on cell growth and the effects of quercetin on intracellular accumulation of adriamycin (ADR) in wild type Ehrlich ascites tumor cells (wild EAT cells) and their ADR-resistant strain. Quercetin strongly inhibited growth in both strains. Cell growth reached a plateau at 3.5 days in the wild type EAT cells and at 7 days in the ADR-resistant strain. The inhibitory concentration in 50% of the ADR-resistant cells on day 7 (24 microM) was twice that of the wild type EAT cells on day 4 (12 microM) after continuous treatment with quercetin. Quercetin decreased the ADR accumulation in the wild type cells but did not affect it in the ADR-resistant cells. Further, quercetin did not affect the retention of ADR in either strain. These results indicated that quercetin decreased ADR accumulation without extruding ADR in the wild type EAT cells. ADR accumulation in the ADR-resistant cells treated with quercetin for 7 days was increased with increasing concentrations of quercetin. Moreover, ADR accumulation in the ADR-resistant cells treated with 50 microM quercetin for 7 days, increased to 186.6% and to 181.9% of that in untreated cells after 60 minutes and 120 minutes incubation, respectively, whilst it increased to 70% from 37.5% of that in the wild type EAT cells after 60 minutes incubation. These findings indicated that quercetin might reverse ADR-resistance.


[xv] Cancer Chemother Pharmacol. 1994;34(6):459-64.

Comment in:

Cancer Chemother Pharmacol. 1995;36(5):448-50.

Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target .Scambia G, Ranelletti FO, Panici PB, De Vincenzo R, Bonanno G, Ferrandina G, Piantelli M, Bussa S, Rumi C, Cianfriglia M, et al.

Department of Gynecology, Catholic University , Rome , Italy .


This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 microM. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3',4',7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 microM Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anti-cancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.


PMID: 7923555 [PubMed - indexed for MEDLINE]


[xvi] Exp Mol Med. 1998 Jun 30;30(2):87-92

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells.


Kim SH, Yeo GS, Lim YS, Kang CD, Kim CM, Chung BS.


Department of Biochemistry, College of Medicine , Pusan National University , Korea .


MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.


PMID: 9873828 [PubMed - indexed for MEDLINE]



[xvii] Br J Cancer. 1996 Jul;74(2):172-7. Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy.


Sliutz G, Karlseder J, Tempfer C, Orel L, Holzer G, Simon MM.


Department of Gynaecology and Obstetrics, University of Vienna , Medical School , Austria .


Heat shock proteins have been reported to confer resistance to certain antineoplastic drugs. We investigated the impact of hsp70 overexpression on the efficacy of two new anti-cancer drugs, topotecan and gemcitabine. We used the fibrosarcoma WEHI-S cells stably transfected to overexpress the hsp70 cDNA from the constitutive SV40 promoter and appropriate control cells. After topotecan and gemcitabine treatment hsp70-overexpressing cells showed a marked elevation in cell survival, suggesting that hsp70 overexpression was sufficient to confer resistance to the drugs. In addition, hsp70-overexpressing cells were capable of starting cell proliferation after treatment with drug dosages that were lethal to control cells. Our results demonstrate that hsp70 overexpression represents a possible cause of drug resistance. In order to transfer these data to tumour cells constitutively expressing stress hsp70 due to the constitutive activity of the original hsp70 promoter we sought to supress the heat shock response pathway by the natural flavonoid quercetin, known to inactivate the heat shock transcription factor (HSF). Using a suitable cell line, we demonstrated the sensitising activity of quercetin. We found that antineoplastic drug concentrations exerting cytotoxic activity were markedly lower when cells were pretreated with quercetin. Concomitantly, hsp70 expression was strongly down-regulated under quercetin treatment. Our data indicate that quercetin may be useful as a sensitiser in chemotherapeutically treated patients suffering from hsp70-overexpressing tumours.


PMID: 8688318 [PubMed - indexed for MEDLINE]


[xviii] J Nutr. 2003 Aug;133(8):2669-74.

Low concentrations of quercetin and ellagic acid synergistically influence proliferation, cytotoxicity and apoptosis in MOLT-4 human leukemia cells. Mertens-Talcott SU, Talcott ST, Percival SS.

Food Science and Human Nutrition Department, University of Florida , Gainesville , FL 32611 , USA .


Little information is available regarding possible synergistic or antagonistic biochemical interactions among polyphenols contained in fruits and vegetables. Identifying potential interactions among these compounds may help to define the efficiency of polyphenol-containing foods in cancer prevention as related to structure-function activity of the compounds. The objective of this study was to investigate interactions between quercetin and ellagic acid, two polyphenolics that are present predominantly in small fruits, on cell death and proliferation-related variables in the MOLT-4 human leukemia cell line. Assays were performed to determine cell cycle kinetics, proliferation, apoptotic DNA-fragmentation and caspase-3-activity after 12, 24 and 48 h . Ellagic acid significantly potentiated the effects of quercetin (at 5 and 10 micro mol/L each) in the reduction of proliferation and viability and the induction of apoptosis. Significant alterations in cell cycle kinetics were also observed. The synergy was confirmed by an isobolographic analysis of the cell proliferation data. The interaction of ellagic acid and quercetin demonstrated an enhanced anticarcinogenic potential of polyphenol combinations, which was not based solely on the additive effect of individual compounds, but rather on synergistic biochemical interactions.


PMID: 12888656 [PubMed - indexed for MEDLINE]


[xix] J Nutr. 2005 Mar;135(3):609-14. Links

Ellagic acid potentiates the effect of quercetin on p21waf1/cip1, p53, and MAP-kinases without affecting intracellular generation of reactive oxygen species in vitro.Mertens-Talcott SU, Bomser JA, Romero C, Talcott ST, Percival SS.

Department of Food Science and Human Nutrition, Institute of Food and Agricultural Sciences, University of Florida , Gainesville , FL 32611-0370 , USA .


Anticarcinogenic effects attributed to polyphenols in fruits may be based on synergistic, additive, or antagonistic interactions of many compounds. In a previous study, it was demonstrated that quercetin and ellagic acid interacted synergistically in the induction of apoptosis in the human leukemia cell line, MOLT-4. To investigate possible cellular mechanisms, this study evaluated whether synergistic effects might be detectable within proapoptotic or antiproliferative signal transduction pathways. We found that quercetin and combinations of quercetin and ellagic acid nonsynergistically increased p53 protein levels. In contrast, ellagic acid potentiated the effects of quercetin for p21(cip1/waf1) protein levels and p53 phosphorylation at serine 15, possibly explaining the synergistic effect observed in apoptosis induction. Phosphorylation of the mitogen-activated protein (MAP) kinases, c-jun N-terminal (JNK)1,2 and p38, was also increased by the combination of ellagic acid and quercetin, whereas quercetin alone induced only p38. We further evaluated whether the generation of reactive oxygen species (ROS) and/or quercetin stability were influenced by interactions of ellagic acid with quercetin. Quercetin increased the generation of ROS, which was neither potentiated nor inhibited by ellagic acid. The stability of intracellular and extracellular quercetin was not influenced by the presence of ellagic acid . In summary, quercetin and ellagic acid combined increase the activation of p53 and p21(cip1/waf1) and the MAP kinases, JNK1,2 and p38, in a more than additive manner, suggesting a mechanism by which quercetin and ellagic acid synergistically induce apoptosis in cancer cells.


[xx] Anticancer Drugs. 2005 Jul;16(6):675-82. Links

Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs.Bun SS, Giacometti S, Fanciullino R, Ciccolini J, Bun H, Aubert C.

Laboratory of Pharmacokinetics and Toxicokinetics, Faculty of Pharmacy, Marseille , France . siya.bun@pharmacie.univ-mrs.fr


The objective of this study was to evaluate the in vivo metabolic profile of paclitaxel and to examine the effect of potential co-administered drugs on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. We first investigated in vitro paclitaxel metabolism using liver microsomes obtained from various species to identify the most suitable animal model with a similar metabolism to humans. Then, in vivo paclitaxel metabolism was investigated in male guinea-pigs. The levels of paclitaxel and its metabolites were measured by high-performance liquid chromatography in bile samples from guinea-pigs after paclitaxel i.v. injection (6 mg/kg). We further evaluated the effects of various drugs (quercetin, ketoconazole, dexamethasone, cotrimoxazole) on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. This work demonstrated significant in vitro interspecies differences in paclitaxel metabolism. Our findings showed both in vitro and in vivo similarities between human and guinea-pig biotransformation of paclitaxel. 6alpha-Hydroxypaclitaxel, the main human metabolite of paclitaxel, was found in guinea-pig bile. After paclitaxel combination with ketoconazole or quercetin in guinea-pigs, the cumulative biliary excretion of paclitaxel and its metabolites up to 6 h was significantly decreased by 62 and 76%, respectively. The co-administration of cotrimoxazole or pretreatment with dexamethasone did not alter significantly cumulative biliary excretion. The guinea-pig is a suitable model to study metabolism and biliary excretion of paclitaxel, and to investigate in vivo drug interactions.


PMID: 15930897 [PubMed

[xxi] J Chemother. 2003 Jun;15(3):266-74.

Drug interactions of paclitaxel metabolism in human liver microsomes.Bun SS, Ciccolini J, Bun H, Aubert C, Catalin J.

Laboratory of Pharmacokinetics and Toxicokinetics, Faculty of Pharmacy, 27 boulevard Jean Moulin, 13385 Marseille , France . siya.bun@pharmacie.univ-mrs.fr


The human liver metabolism of paclitaxel (Taxol), an anticancer drug, leads to three metabolites: 6alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel. The inter-individual variability of paclitaxel metabolism was investigated first in vitro using 22 human liver microsomes. Three metabolites have been detected by HPLC. This preliminary work revealed marked inter-individual differences in paclitaxel metabolism. The amount of major metabolite 6alpha-hydroxypaclitaxel formed varied 16-fold (0.7 to 11.5 nmol/mg/h). We next studied the effect of 29 compounds (antineoplastics, antiemetics, histamine-2 receptor antagonist, antalgics, antifungals, antivirals, psychotropics, antibiotic, corticoid, antiarrhythmic, calcium channel blocker) on paclitaxel metabolism in human liver microsomes. Among the compounds studied, quercetin, antifungal drugs such as ketoconazole and miconazole, and the antineoplastic drug doxorubicin inhibited formation of 6alpha-hydroxypaclitaxel. Dixon plots indicated that quercetin and doxorubicin inhibited 6alpha-hydroxypaclitaxel formation through a competitive mechanism with a Ki of 10.1 microM and 64.8 microM, respectively. The inhibition of this metabolite by ketoconazole was through a noncompetitive mechanism with a Ki of 11.8 microM. Our data thus suggest that special attention should be paid when these drugs are combined in clinical practice.


PMID: 12868554 [PubMed

[xxii] Naunyn Schmiedebergs Arch Pharmacol. 2003 Sep;368(3):200-9. Epub 2003 Aug 14.

Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants.Vaclavikova R, Horsky S, Simek P, Gut I.

Centre of Occupational Diseases, National Institute of Public Health, Srobarova 48, 100 42, Prague 10, Czech Republic . rvaclavikova@szu.cz


Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.


PMID: 12920504 [PubMed - indexed for MEDLINE]

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