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Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation

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Abstract

Purpose

Colorectal tumors (CRC) with microsatellite instability (MSI) show resistance to chemotherapy with 5-fluorouracil (5-FU), the most widely used pharmacological drug for CRC treatment. The aims of this study were to test the ability of quercetin (Q) and luteolin (L) to increase the sensitivity of MSI CRC cells to 5-FU and characterize the dependence of the effects on cells’ p53 status.

Methods

Two MSI human CRC-derived cell lines were used: CO115 wild type (wt) for p53 and HCT15 that harbors a p53 mutation. Apoptosis induction in these cells by 5-FU, Q and L alone, and in combinations was evaluated by TUNEL and western blot. The dependence of the effects on p53 was confirmed by small interference RNA (siRNA) in CO115 cells and in MSI HCT116 wt and p53 knockout cells.

Results

CO115 p53-wt cells are more sensitive to 5-FU than the p53-mutated HCT15. The combination treatment of 5-FU with L and Q increased apoptosis with a significant effect for Q in CO115. Both flavonoids increased p53 expression in both cell lines, an effect particularly remarkable for Q. The significant apoptotic enhancement in CO115 incubated with Q plus 5-FU involved the activation of the apoptotic mitochondrial pathway. Importantly, knockdown of p53 by siRNA in CO115 cells and p53 knockout in HCT116 cells totally abrogated apoptosis induction, demonstrating the dependence of the effect on p53 modulation by Q.

Conclusion

This study suggests the potential applicability of these phytochemicals for enhancement 5-FU efficiency in MSI CRC therapy, especially Q in p53 wt tumors.

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References

  1. Rupnarain C, Dlamini Z, Naicker S, Bhoola K (2004) Colon cancer: genomics and apoptotic events. Biol Chem 385:449–464

    Article  PubMed  CAS  Google Scholar 

  2. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257

    Article  PubMed  CAS  Google Scholar 

  3. Bhushan S, McLeod H, Walko CM (2009) Role of pharmacogenetics as predictive biomarkers of response and/or toxicity in the treatment of colorectal cancer. Clin Colorectal Cancer 8:15–21

    Article  PubMed  CAS  Google Scholar 

  4. Mader RM, Muller M, Steger GG (1998) Resistance to 5-fluorouracil. Gen Pharmacol 31:661–666

    Article  PubMed  CAS  Google Scholar 

  5. Huerta S, Goulet EJ, Livingston EH (2006) Colon cancer and apoptosis. Am J Surg 191:517–526

    Article  PubMed  CAS  Google Scholar 

  6. Davies JM, Goldberg RM (2008) First-line therapeutic strategies in metastatic colorectal cancer. Oncology (Williston Park) 22:1470–1479

    Google Scholar 

  7. Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, Pinol V, Xicola RM, Bujanda L, Rene JM, Clofent J, Bessa X, Morillas JD, Nicolas-Perez D, Paya A, Alenda C (2006) Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55:848–855

    Article  PubMed  CAS  Google Scholar 

  8. Warusavitarne J, Schnitzler M (2007) The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis 22:739–748

    Article  PubMed  Google Scholar 

  9. Soreide K, Janssen EA, Soiland H, Korner H, Baak JP (2006) Microsatellite instability in colorectal cancer. Br J Surg 93:395–406

    Article  PubMed  CAS  Google Scholar 

  10. Sinicrope FA, Sargent DJ (2009) Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol 21:369–373

    Article  PubMed  CAS  Google Scholar 

  11. Seruca R, Velho S, Oliveira C, Leite M, Matos P, Jordan P (2009) Unmasking the role of KRAS and BRAF pathways in MSI colorectal tumors. Expert Rev Gastroenterol Hepatol 3:5–9

    Article  PubMed  Google Scholar 

  12. Benhattar J, Cerottini JP, Saraga E, Metthez G, Givel JC (1996) p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas. Int J Cancer 69:190–192

    Article  PubMed  CAS  Google Scholar 

  13. Violette S, Poulain L, Dussaulx E, Pepin D, Faussat AM, Chambaz J, Lacorte JM, Staedel C, Lesuffleur T (2002) Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int J Cancer 98:498–504

    Article  PubMed  CAS  Google Scholar 

  14. Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B (1999) Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 104:263–269

    Article  PubMed  CAS  Google Scholar 

  15. Adamsen BL, Kravik KL, Clausen OP, De Angelis PM (2007) Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol 31:1491–1500

    PubMed  CAS  Google Scholar 

  16. Mori S, Ogata Y, Shirouzu K (2004) Biological features of sporadic colorectal carcinoma with high-frequency microsatellite instability: special reference to tumor proliferation and apoptosis. Int J Clin Oncol 9:322–329

    Article  PubMed  Google Scholar 

  17. Hector S, Prehn JH (2009) Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: A review. Biochim Biophys Acta 1795:117–129

    PubMed  CAS  Google Scholar 

  18. Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421

    Article  PubMed  CAS  Google Scholar 

  19. Ramos S (2008) Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Mol Nutr Food Res 52:507–526

    Article  PubMed  CAS  Google Scholar 

  20. Subapriya Rajamanickam RA (2008) Natural products and colon cancer: current status and future prospects. Drug Dev Res 69:460–471

    Article  PubMed  Google Scholar 

  21. Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9:537–549

    Article  PubMed  CAS  Google Scholar 

  22. Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15:36–42

    Article  PubMed  Google Scholar 

  23. Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA (2009) p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med 15:369–379

    Article  PubMed  CAS  Google Scholar 

  24. Xavier CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M, Pereira-Wilson C (2009) Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett 281:162–170

    Article  PubMed  CAS  Google Scholar 

  25. Gayet J, Zhou XP, Duval A, Rolland S, Hoang JM, Cottu P, Hamelin R (2001) Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines. Oncogene 20:5025–5032

    Article  PubMed  CAS  Google Scholar 

  26. Barbour KW, Berger FG (2008) Cell death in response to antimetabolites directed at thymidylate synthase. Cancer Chemother Pharmacol 61:189–201

    Article  PubMed  CAS  Google Scholar 

  27. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501

    Article  PubMed  CAS  Google Scholar 

  28. Preto A, Figueiredo J, Velho S, Ribeiro A, Soares P, Oliveira C, Seruca R (2008) BRAF provides proliferation and survival signals in MSI colorectal carcinoma cells displaying BRAF(V600E) but not KRAS mutations. J Pathol 214:320–327

    Article  PubMed  CAS  Google Scholar 

  29. Itoh N, Semba S, Ito M, Takeda H, Kawata S, Yamakawa M (2002) Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 94:3127–3134

    Article  PubMed  CAS  Google Scholar 

  30. Osaki M, Oshimura M, Ito H (2004) PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9:667–676

    Article  PubMed  CAS  Google Scholar 

  31. Rychahou PG, Jackson LN, Silva SR, Rajaraman S, Evers BM (2006) Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma. Ann Surg 243:833–842 discussion 843–844

    Article  PubMed  Google Scholar 

  32. Thompson N, Lyons J (2005) Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. Curr Opin Pharmacol 5:350–356

    Article  PubMed  CAS  Google Scholar 

  33. McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279

    Article  PubMed  CAS  Google Scholar 

  34. Tang XY, Zhu YQ, Tao WH, Wei B, Lin XL (2007) Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinoma. Postgrad Med J 83:338–343

    Article  PubMed  CAS  Google Scholar 

  35. Zhang YQ, Tang XQ, Sun L, Dong L, Qin Y, Liu HQ, Xia H, Cao JG (2007) Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor gamma. World J Gastroenterol 13:1534–1540

    Article  PubMed  CAS  Google Scholar 

  36. Wang CZ, Luo X, Zhang B, Song WX, Ni M, Mehendale S, Xie JT, Aung HH, He TC, Yuan CS (2007) Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells. Cancer Chemother Pharmacol 60:69–79

    Article  PubMed  Google Scholar 

  37. Shi R, Huang Q, Zhu X, Ong YB, Zhao B, Lu J, Ong CN, Shen HM (2007) Luteolin sensitizes the anticancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Mol Cancer Ther 6:1338–1347

    Article  PubMed  CAS  Google Scholar 

  38. Hou Q (2008) Effect of staurosporine induced apoptosis of MCF7/GFP-Bax stable cell line on Bax translocation from cytosol into mitochondria. Yao Xue Xue Bao 43:378–382

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

CPRX was supported by the Foundation for Science and Technology (FCT), Portugal, through the grant SFRH/BD/27524/2006, and the work was supported by the FCT research grant PTDC/AGR-AAM/70418/2006.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. CBMA—Centre of Molecular and Environmental Biology, Department of Biology, School of Sciences, University of Minho, 4710-057, Braga, Portugal

    Cristina P. R. Xavier & Cristina Pereira-Wilson

  2. CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Department of Biology, School of Sciences, University of Minho, 4710-057, Braga, Portugal

    Cristovao F. Lima

  3. Apoptosis Department, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Mikkel Rohde

Authors
  1. Cristina P. R. Xavier
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  2. Cristovao F. Lima
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  3. Mikkel Rohde
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  4. Cristina Pereira-Wilson
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Correspondence to Cristina Pereira-Wilson.

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Xavier, C.P.R., Lima, C.F., Rohde, M. et al. Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation. Cancer Chemother Pharmacol 68, 1449–1457 (2011). https://doi.org/10.1007/s00280-011-1641-9

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  • DOI: https://doi.org/10.1007/s00280-011-1641-9

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