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Published in: Cancer Chemotherapy and Pharmacology 5/2011

01-11-2011 | Original Article

Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells

Authors: Davide Staedler, Elita Idrizi, Blanka Halamoda Kenzaoui, Lucienne Juillerat-Jeanneret

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2011

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Abstract

Purpose

Doxorubicin is a first-line chemotherapeutic for breast cancer; however, it is associated with severe side effects to non-tumoral tissues. Thus, it is necessary to develop new therapeutic combinations to improve doxorubicin effects at lower concentration of the drug associated with protective effects for non-tumoral cells. In this work, we evaluated whether the plant-derived flavonoid quercetin may represent such an agent.

Methods

The effects of doxorubicin and quercetin as single agents and in combination were evaluated on cell survival, DNA and protein synthesis, oxidative stress, migratory potential and cytoskeleton and nucleus structure in highly invasive and poorly invasive human breast cancer cells in comparison with non-tumoral human breast cells.

Results

In human breast cancer cells, quercetin potentiated antitumor effects of doxorubicin specifically in the highly invasive breast cancer cells and attenuated unwanted cytotoxicity to non-tumoral cells. Quercetin interfered with cell metabolism, GST activity, cytoskeleton and invasive properties specifically in breast tumor cells compared with non-tumoral breast cells. Doxorubicin induced DNA damage in tumor and non-tumor cells; however, quercetin reduced this damage only in non-tumoral cells, thus offering a protective effect for these cells. Quercetin also induced polynucleation in aggressive tumor cells, which was maintained in combination with doxorubicin.

Conclusions

By combining quercetin with doxorubicin, an increase in doxorubicin effects was obtained specifically in the highly invasive breast cancer cells, while in non-tumoral cells quercetin reduced doxorubicin cytotoxic side effects. Thus, quercetin associated with doxorubicin demonstrated very promising properties for developing chemotherapeutics combinations for the therapy of breast cancer.
Literature
2.
go back to reference Andreetta C, Minisini AM, Miscoria M, Puglisi F (2010) First-line chemotherapy with or without biologic agents for metastatic breast cancer. Crit Rev Oncol Hematol 76:99–111PubMedCrossRef Andreetta C, Minisini AM, Miscoria M, Puglisi F (2010) First-line chemotherapy with or without biologic agents for metastatic breast cancer. Crit Rev Oncol Hematol 76:99–111PubMedCrossRef
3.
go back to reference Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRef Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRef
4.
go back to reference Gajewski E, Gaur S, Akman SA, Matsumoto L, van Balgooy JN, Doroshow JH (2007) Oxidative DNA base damage in MCF-10A breast epithelial cells at clinically achievable concentrations of doxorubicin. Biochem Pharmacol 73:1947–1956PubMedCrossRef Gajewski E, Gaur S, Akman SA, Matsumoto L, van Balgooy JN, Doroshow JH (2007) Oxidative DNA base damage in MCF-10A breast epithelial cells at clinically achievable concentrations of doxorubicin. Biochem Pharmacol 73:1947–1956PubMedCrossRef
5.
6.
go back to reference Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2:659–668PubMed Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2:659–668PubMed
7.
go back to reference Moon YJ, Wang L, DiCenzo R, Morris ME (2008) Quercetin pharmacokinetics in humans. Biopharm Drug Dispos 29:205–217PubMedCrossRef Moon YJ, Wang L, DiCenzo R, Morris ME (2008) Quercetin pharmacokinetics in humans. Biopharm Drug Dispos 29:205–217PubMedCrossRef
8.
go back to reference Rodgers EH, Grant MH (1998) The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells. Chem Biol Interact 116:213–228PubMedCrossRef Rodgers EH, Grant MH (1998) The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells. Chem Biol Interact 116:213–228PubMedCrossRef
9.
go back to reference Paliwal S, Sundaram J, Mitragotri S (2005) Induction of cancer-specific cytotoxicity towards human prostate and skin cells using quercetin and ultrasound. Br J Cancer 92:499–502PubMed Paliwal S, Sundaram J, Mitragotri S (2005) Induction of cancer-specific cytotoxicity towards human prostate and skin cells using quercetin and ultrasound. Br J Cancer 92:499–502PubMed
10.
go back to reference Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ (2006) Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem 54:9798–9804PubMedCrossRef Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ (2006) Distinctive antioxidant and antiinflammatory effects of flavonols. J Agric Food Chem 54:9798–9804PubMedCrossRef
11.
go back to reference Bach A, Bender-Sigel J, Schrenk D, Flugel D, Kietzmann K (2010) The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal 13:437–448PubMedCrossRef Bach A, Bender-Sigel J, Schrenk D, Flugel D, Kietzmann K (2010) The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF. Antioxid Redox Signal 13:437–448PubMedCrossRef
12.
go back to reference Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S (2009) Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res 29:4629–4632PubMed Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S (2009) Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res 29:4629–4632PubMed
13.
go back to reference Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FM, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600PubMedCrossRef Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FM, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600PubMedCrossRef
14.
go back to reference Hsieh TC, Wu JM (2009) Targeting CWR22Rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res 29:4025–4032PubMed Hsieh TC, Wu JM (2009) Targeting CWR22Rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res 29:4025–4032PubMed
15.
go back to reference Ferraresi R, Troiano L, Roat E, Lugli E, Nemes E, Nasi M, Pinti M, Fernandez MI, Cooper EL, Cossarizza A (2005) Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin. Free Radic Res 39:1249–1258PubMedCrossRef Ferraresi R, Troiano L, Roat E, Lugli E, Nemes E, Nasi M, Pinti M, Fernandez MI, Cooper EL, Cossarizza A (2005) Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin. Free Radic Res 39:1249–1258PubMedCrossRef
16.
go back to reference Lo HW, Ali-Osman F (2007) Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance. Curr.Opin. Pharmacol. 7:367–374PubMedCrossRef Lo HW, Ali-Osman F (2007) Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance. Curr.Opin. Pharmacol. 7:367–374PubMedCrossRef
17.
go back to reference Tsuchida S, Sato K (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27:337–384PubMedCrossRef Tsuchida S, Sato K (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27:337–384PubMedCrossRef
18.
go back to reference Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Ann Rev Pharmacol Toxicol 45:51–88CrossRef Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Ann Rev Pharmacol Toxicol 45:51–88CrossRef
19.
go back to reference Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D (2000) The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues. Cancer Lett 158:7–16PubMedCrossRef Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D (2000) The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues. Cancer Lett 158:7–16PubMedCrossRef
20.
go back to reference Akbas SH, Timur M, Ozben T (2005) The effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB 231 human breast cancer cells. J Surg Res 125(125):49–55PubMedCrossRef Akbas SH, Timur M, Ozben T (2005) The effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB 231 human breast cancer cells. J Surg Res 125(125):49–55PubMedCrossRef
21.
go back to reference Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, Dharmawardhane SF (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1:19–27PubMed Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, Dharmawardhane SF (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1:19–27PubMed
22.
go back to reference Du G, Lin H, Wang M, Zhang S, Wu X, Lu L, Ji L, Yu L (2010) Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1alpha in tumor and normal cells. Cancer Chemother Pharmacol 65:277–287PubMedCrossRef Du G, Lin H, Wang M, Zhang S, Wu X, Lu L, Ji L, Yu L (2010) Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1alpha in tumor and normal cells. Cancer Chemother Pharmacol 65:277–287PubMedCrossRef
23.
go back to reference Du G, Lin H, Yang Y, Zhang S, Wu X, Wang M, Ji L, Lu L, Yu L, Han G (2010) Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice. Int Immunopharmacol 10:819–826PubMedCrossRef Du G, Lin H, Yang Y, Zhang S, Wu X, Wang M, Ji L, Lu L, Yu L, Han G (2010) Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice. Int Immunopharmacol 10:819–826PubMedCrossRef
24.
go back to reference Vaclavikova R, Kondrova E, Ehrlichova M, Boumendjel A, Kovar J, Stopka P, Soucek P, Gut I (2008) The effect of flavonoid derivatives on doxorubicin transport and metabolism. Bioorg Med Chem 16:2034–2042PubMedCrossRef Vaclavikova R, Kondrova E, Ehrlichova M, Boumendjel A, Kovar J, Stopka P, Soucek P, Gut I (2008) The effect of flavonoid derivatives on doxorubicin transport and metabolism. Bioorg Med Chem 16:2034–2042PubMedCrossRef
25.
go back to reference Juillerat-Jeanneret L, Chapuis Bernasconi C, Bricod C, Gros S, Trepey S, Benhattar J, Janzer RC (2008) Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine methyl transferase. Cancer Invest 26:597–608PubMedCrossRef Juillerat-Jeanneret L, Chapuis Bernasconi C, Bricod C, Gros S, Trepey S, Benhattar J, Janzer RC (2008) Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine methyl transferase. Cancer Invest 26:597–608PubMedCrossRef
26.
go back to reference Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261PubMedCrossRef Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261PubMedCrossRef
27.
go back to reference Nagaraja GM, Othman M, Fox BP, Alsaber R, Pellegraino CM, Zeng Y, Khanna R, Tamburini P, Swaroop A, Kandpal RP (2006) Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene 25:2328–2338PubMedCrossRef Nagaraja GM, Othman M, Fox BP, Alsaber R, Pellegraino CM, Zeng Y, Khanna R, Tamburini P, Swaroop A, Kandpal RP (2006) Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene 25:2328–2338PubMedCrossRef
28.
go back to reference Wang K, Ramji S, Bhathena A, Lee C, Riddick DS (1999) Glutathione S-transferase in wild-type and doxorubicin-resistant MCF-7 human breast cancer cell lines. Xenobiotica 29:155–170PubMedCrossRef Wang K, Ramji S, Bhathena A, Lee C, Riddick DS (1999) Glutathione S-transferase in wild-type and doxorubicin-resistant MCF-7 human breast cancer cell lines. Xenobiotica 29:155–170PubMedCrossRef
29.
go back to reference Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRef Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRef
30.
31.
go back to reference Momparler RM, Karon M, Siegel SE, Avila F (1976) Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 36:2891–2895PubMed Momparler RM, Karon M, Siegel SE, Avila F (1976) Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 36:2891–2895PubMed
32.
go back to reference Diaz Bessone MI, Berardi DE, Campodonico PB, Todaro LB, Lothstein L, Bal de Kier Joffe ED, Urtreger AJ (2010) Involvement of PKC delta (PKCdelta) in the resistance against different doxorubicin analogs. Breast Cancer Res Treat (in press) Diaz Bessone MI, Berardi DE, Campodonico PB, Todaro LB, Lothstein L, Bal de Kier Joffe ED, Urtreger AJ (2010) Involvement of PKC delta (PKCdelta) in the resistance against different doxorubicin analogs. Breast Cancer Res Treat (in press)
33.
go back to reference Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC (2007) Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93–100PubMedCrossRef Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC (2007) Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93–100PubMedCrossRef
34.
go back to reference van Zanden JJ, Ben Hamman O, van Iersel ML, Boeren S, Cnubben NH, Lo Bello M, Vervoort J, van Bladeren PJ, Rietjens IM (2003) Inhibition of human glutathione S-transferase P1–1 by the flavonoid quercetin. Chem Biol Interact 145:139–148PubMedCrossRef van Zanden JJ, Ben Hamman O, van Iersel ML, Boeren S, Cnubben NH, Lo Bello M, Vervoort J, van Bladeren PJ, Rietjens IM (2003) Inhibition of human glutathione S-transferase P1–1 by the flavonoid quercetin. Chem Biol Interact 145:139–148PubMedCrossRef
35.
go back to reference Gutzeit HO, Henker Y, Kind B, Franz A (2004) Specific interactions of quercetin and other flavonoids with target proteins are revealed by elicited fluorescence. Biochem Biophys Res Commun 318:490–495PubMedCrossRef Gutzeit HO, Henker Y, Kind B, Franz A (2004) Specific interactions of quercetin and other flavonoids with target proteins are revealed by elicited fluorescence. Biochem Biophys Res Commun 318:490–495PubMedCrossRef
36.
go back to reference Murakami A, Ashida H, Terao J (2008) Multitargeted cancer prevention by quercetin. Cancer Lett 269:315–325PubMedCrossRef Murakami A, Ashida H, Terao J (2008) Multitargeted cancer prevention by quercetin. Cancer Lett 269:315–325PubMedCrossRef
37.
go back to reference Cai Q, Rahn RO, Zhang R (1997) Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett 119:99–107PubMedCrossRef Cai Q, Rahn RO, Zhang R (1997) Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett 119:99–107PubMedCrossRef
38.
go back to reference Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ (2000) Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2:203–210PubMedCrossRef Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ (2000) Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2:203–210PubMedCrossRef
39.
go back to reference Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z (2008) Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res 68:946–955PubMedCrossRef Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z (2008) Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res 68:946–955PubMedCrossRef
40.
go back to reference Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedCrossRef Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedCrossRef
41.
go back to reference Singhal RL, Yeh YA, Praja N, Olah E, Sledge GW, Weber G (1995) Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem Biophys Res Commun 208:425–431PubMedCrossRef Singhal RL, Yeh YA, Praja N, Olah E, Sledge GW, Weber G (1995) Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem Biophys Res Commun 208:425–431PubMedCrossRef
42.
go back to reference Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, Chen YC (2008) Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 29:1807–1815PubMedCrossRef Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, Chen YC (2008) Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 29:1807–1815PubMedCrossRef
Metadata
Title
Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells
Authors
Davide Staedler
Elita Idrizi
Blanka Halamoda Kenzaoui
Lucienne Juillerat-Jeanneret
Publication date
01-11-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1596-x

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