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01-08-2010 | Preclinical Study

Targeting breast stem cells with the cancer preventive compounds curcumin and piperine

Authors: Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu, Max S. Wicha

Published in: Breast Cancer Research and Treatment | Issue 3/2010

Abstract

The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 μM and completely at 10 μM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 μM and completely at 10 μM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

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Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47CrossRefPubMed

Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270CrossRefPubMed

Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15:907–913CrossRefPubMed

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567CrossRefPubMed

Liu S, Ginestier C, Charafe-Jauffret E, Foco H, Kleer CG, Merajver SD, Dontu G, Wicha MS (2008) BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci USA 105:1680–1685CrossRefPubMed

Cella D, Land SR, Chang CH, Day R, Costantino JP, Wolmark N, Ganz PA (2008) Symptom measurement in the Breast Cancer Prevention Trial (BCPT) (P-1): psychometric properties of a new measure of symptoms for midlife women. Breast Cancer Res Treat 109:515–526CrossRefPubMed

Gennari L, Merlotti D, Paola VD, Nuti R (2008) Raloxifene in breast cancer prevention. Expert Opin Drug Saf 7:259–270CrossRefPubMed

Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y, Skaar TC, Gomez B, O’Brien K, Wang Y, Hilakivi-Clarke LA (2003) Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene 22:7316–7339CrossRefPubMed

Howell A (2008) The endocrine prevention of breast cancer. Best Pract Res Clin Endocrinol Metab 22:615–623CrossRefPubMed

10.

Powles TJ (2008) Prevention of breast cancer using SERMs. Adv Exp Med Biol 630:232–236CrossRefPubMed

11.

Lindvall C, Bu W, Williams BO, Li Y (2007) Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 3:157–168CrossRefPubMed

12.

Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95CrossRefPubMed

13.

Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY (2008) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68:4287–4295CrossRefPubMed

14.

Park CH, Hahm ER, Park S, Kim HK, Yang CH (2005) The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett 579:2965–2971CrossRefPubMed

15.

Bachmeier B, Nerlich AG, Iancu CM, Cilli M, Schleicher E, Vene R, Dell’Eva R, Jochum M, Albini A, Pfeffer U (2007) The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell Physiol Biochem 19:137–152CrossRefPubMed

16.

Bachmeier BE, Mohrenz IV, Mirisola V, Schleicher E, Romeo F, Hohneke C, Jochum M, Nerlich AG, Pfeffer U (2008) Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis 29:779–789CrossRefPubMed

17.

Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY, Cheng AL (2000) Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis 21:331–335CrossRefPubMed

18.

Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH (1994) Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res 54:5841–5847PubMed

19.

Huang MT, Newmark HL, Frenkel K (1997) Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem Suppl 27:26–34CrossRefPubMed

20.

Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 302:645–650CrossRefPubMed

21.

Pradeep CR, Kuttan G (2004) Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Int Immunopharmacol 4:1795–1803CrossRefPubMed

22.

Pradeep CR, Kuttan G (2002) Effect of piperine on the inhibition of lung metastasis induced B16F-10 melanoma cells in mice. Clin Exp Metastasis 19:703–708CrossRefPubMed

23.

Selvendiran K, Banu SM, Sakthisekaran D (2004) Protective effect of piperine on benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Clin Chim Acta 350:73–78CrossRefPubMed

24.

Selvendiran K, Prince Vijeya Singh J, Sakthisekaran D (2006) In vivo effect of piperine on serum and tissue glycoprotein levels in benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Pulm Pharmacol Ther 19:107–111CrossRefPubMed

25.

Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64:353–356CrossRefPubMed

26.

Huang MZ, Zhang FC, Zhang YY (2008) Influence factors on the formation of mammospheres from breast cancer stem cells. Beijing Da Xue Xue Bao 40:500–504PubMed

27.

Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS (2009) Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol 7:e1000121CrossRefPubMed

28.

Cho RW, Wang X, Diehn M, Shedden K, Chen GY, Sherlock G, Gurney A, Lewicki J, Clarke MF (2008) Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26:364–371CrossRefPubMed

29.

Katoh M (2007) Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev 3:30–38CrossRefPubMed

30.

Kwan H, Pecenka V, Tsukamoto A, Parslow TG, Guzman R, Lin TP, Muller WJ, Lee FS, Leder P, Varmus HE (1992) Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice. Mol Cell Biol 12:147–154PubMed

31.

Turashvili G, Bouchal J, Burkadze G, Kolar Z (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223CrossRefPubMed

32.

Ugolini F, Charafe-Jauffret E, Bardou VJ, Geneix J, Adelaide J, Labat-Moleur F, Penault-Llorca F, Longy M, Jacquemier J, Birnbaum D, Pebusque MJ (2001) WNT pathway and mammary carcinogenesis: loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type. Oncogene 20:5810–5817CrossRefPubMed

33.

Jaiswal AS, Marlow BP, Gupta N, Narayan S (2002) Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21:8414–8427CrossRefPubMed

34.

Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, Park BS, Oh S (2008) Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 377:1304–1308

35.

Moen MD, Keating GM (2008) Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs 68:2059–2083CrossRefPubMed

36.

Lao CD, Ruffin MTt, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE (2006) Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 6:10CrossRefPubMed

37.

Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G (2007) Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. Biochem Pharmacol 73:1024–1032CrossRefPubMed

38.

Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMed

39.

Anuchapreeda S, Leechanachai P, Smith MM, Ambudkar SV, Limtrakul PN (2002) Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol 64:573–582CrossRefPubMed

40.

Aravindan N, Madhusoodhanan R, Ahmad S, Johnson D, Herman TS (2008) Curcumin inhibits NFkappaB mediated radioprotection and modulate apoptosis related genes in human neuroblastoma cells. Cancer Biol Ther 7:569–576CrossRefPubMed

41.

Binion DG, Otterson MF, Rafiee P (2008) Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut 57:1509–1517CrossRefPubMed

42.

Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH (2006) Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106:2503–2513CrossRefPubMed

43.

Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R (2009) Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 181:263–271CrossRefPubMed

44.

45.

Chearwae W, Anuchapreeda S, Nandigama K, Ambudkar SV, Limtrakul P (2004) Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochem Pharmacol 68:2043–2052CrossRefPubMed

46.

Limtrakul P, Chearwae W, Shukla S, Phisalphong C, Ambudkar SV (2007) Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. Mol Cell Biochem 296:85–95CrossRefPubMed

47.

Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818CrossRefPubMed

48.

Singh S, Khar A (2006) Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem 6:259–270CrossRefPubMed

Title: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine
Authors: Madhuri Kakarala
Dean E. Brenner
Hasan Korkaya
Connie Cheng
Karim Tazi
Christophe Ginestier
Suling Liu
Gabriela Dontu
Max S. Wicha
Publication date: 01-08-2010
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-009-0612-x

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