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DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate: a curcumin analog with a synergic effect in combination with paclitaxel in breast cancer treatment

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Tumor Biology

Abstract

This paper describes a new method for the preparation of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, DM-1, and 3-oxo-penta-1,4-dienyl-bis (2-methoxy-phenolate), DM-2. The aim of this work was to evaluate the antitumor effects of DM-1 in adjuvant chemotherapy for breast cancer treatment. Mice bearing mammary adenocarcinomas (Ehrlich ascites tumors) were treated with paclitaxel alone, DM-1 alone, and paclitaxel + DM-1. Tumor samples were used to perform cytological analysis by the Papanicolaou method and apoptosis analysis by annexin V and phosphorylated caspase 3. The paclitaxel + DM-1 group had decreased tumor areas and tumor volumes, and the frequency of metastasis was significantly reduced. This caused a decrease in cachexia, which is usually caused by the tumor. Furthermore, treatment with paclitaxel + DM-1 and DM-1 alone increased the occurrence of apoptosis up to 40% in tumor cells, which is 35% more than in the group treated with paclitaxel alone. This cell death was mainly caused through phosphorylated caspase 3 (11% increase in paclitaxel + DM-1 compared to the paclitaxel group), as confirmed by reduced malignancy criteria in the ascitic fluid. DM-1 emerges as a potential treatment for breast cancer and may act as an adjuvant in chemotherapy, enhancing antitumor drug activity with reduced side effects.

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References

  1. Porter PL. Global trends in breast cancer incidence and mortality. Salud Publica Mex. 2009;51 Suppl 2:s141–6.

    Article  PubMed  Google Scholar 

  2. O'Shaughnessy J. Global trends in breast cancer incidence and mortality. Oncologist. 2005;10 Suppl 3:20–9.

    Article  PubMed  Google Scholar 

  3. Foster TS, Miller JD, Boye ME, Blieden MB, Gidwani R, Russell MW. The economic burden of metastatic breast cancer: a systematic review of literature from developed countries. Cancer Treat Rev. 2011;37:405–15.

    PubMed  Google Scholar 

  4. Mareel M, Oliveira MJ, Madani I. Cancer invasion and metastasis: interacting ecosystems. Virchows Arch. 2009;454:599–622.

    Article  PubMed  CAS  Google Scholar 

  5. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15:117–34.

    Article  PubMed  Google Scholar 

  6. Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev. 2003;83:337–76.

    PubMed  CAS  Google Scholar 

  7. Ehrlich P. Experimentelle carcinomstudien an Mäusen. Arb Inst Exp Ther. 1906;1:78–80.

    Google Scholar 

  8. von Minckwitz G. Evidence-based treatment of metastatic breast cancer—2006 recommendations by the AGO Breast Commission. Eur J Cancer. 2006;42:2897–908.

    Article  Google Scholar 

  9. Seyhan AA, Varadarajan U, Choe S, Liu Y, McGraw J, Woods M, et al. A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments. Mol Biosyst. 2011;7:1974–89.

    Article  PubMed  CAS  Google Scholar 

  10. Rivera E, Gomez H. Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res. 2010;12(2):S2.

    PubMed  Google Scholar 

  11. Burstein HJ, Calrson RW, Kiel KD (2007) NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. http://www.nccn.org. Accessed on 07 Oct 2011.

  12. Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist. 2007;12:271–80.

    Article  PubMed  CAS  Google Scholar 

  13. Smith I. Goals of treatment for patients with metastatic breast cancer. Semin Oncol. 2006;33:S2–5.

    Article  PubMed  Google Scholar 

  14. Discher DE, Eisenberg A. Polymer vesicles. Science. 2002;297:967–73.

    Article  PubMed  CAS  Google Scholar 

  15. Torchilin VP. PEG-based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev. 2002;54:235–52.

    Article  PubMed  CAS  Google Scholar 

  16. Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S. Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res. 2010;70:3594–605.

    Article  PubMed  CAS  Google Scholar 

  17. Henning SM, Seeram NP, Zhang Y, Li L, Gao K, Lee RP, et al. Strawberry consumption is associated with increased antioxidant capacity in serum. J Med Food. 2010;13:116–22.

    Article  PubMed  CAS  Google Scholar 

  18. Ray RB, Raychoudhuri A, Steele R, Nerurkar P. Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Cancer Res. 2010;70:1925–31.

    Article  PubMed  CAS  Google Scholar 

  19. Aggarwal S, Ndinguri MW, Solipuram R, Wakamatsu N, Hammer RP, Ingram D, et al. [DLys(6) ]-LHRH-curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo. Int J Cancer. 2011;129:1611–23.

    Article  PubMed  CAS  Google Scholar 

  20. Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor kappa B signaling. Int J Cancer. 2004;111:679–92.

    Article  PubMed  CAS  Google Scholar 

  21. Huang MT, Lou YR, Xie JG, Ma W, Lu YP, Yen P, et al. Effect of dietary curcumin and dibenzoylmethane on formation of 7,12-dimethylbenz[a]anthracene-induced mammary tumors and lymphomas/leukemias in Sencar mice. Carcinogenesis. 1998;19:1697–700.

    Article  PubMed  CAS  Google Scholar 

  22. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol. 2006;69:195–206.

    PubMed  CAS  Google Scholar 

  23. Carvalho FR, Vassão RC, Nicoletti MA, Maria DA. Effect of Curcuma zedoaria crude extract against tumor progression and immunomodulation. J Venom Anim Toxins Incl Trop Dis. 2010;16:324–41.

    Article  Google Scholar 

  24. Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B, et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 2008;76:1590–611.

    Article  PubMed  CAS  Google Scholar 

  25. Schaaf C, Shan B, Buchfelder M, Losa M, Kreutzer J, Rachinger W, et al. Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivo. Endocr Relat Cancer. 2009;16:1339–50.

    Article  PubMed  CAS  Google Scholar 

  26. Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int J Cancer. 2008;122:1966–71.

    Article  PubMed  CAS  Google Scholar 

  27. Rivera-Espinoza Y, Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int. 2009;29:1457–66.

    Article  PubMed  CAS  Google Scholar 

  28. Bisht S, Maitra A. Systemic delivery of curcumin: 21st century solutions for an ancient conundrum. Curr Drug Discov Technol. 2009;6:192–9.

    Article  PubMed  CAS  Google Scholar 

  29. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64:353–6.

    Article  PubMed  CAS  Google Scholar 

  30. Safavy A, Raisch KP, Mantena S, Sanford LL, Sham SW, Krishna NR, et al. Design and development of water-soluble curcumin conjugates as potential anticancer agents. J Med Chem. 2007;50:6284–8.

    Article  PubMed  CAS  Google Scholar 

  31. Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21:2895–900.

    PubMed  CAS  Google Scholar 

  32. Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, Camalier RF, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg Med Chem. 2004;12:3871–83.

    Article  PubMed  CAS  Google Scholar 

  33. Fuchs JR, Pandit B, Bhasin D, Etter JP, Regan N, Abdelhamid D, et al. Structure-activity relationship studies of curcumin analogues. Bioorg Med Chem Lett. 2009;19:2065–9.

    Article  PubMed  CAS  Google Scholar 

  34. Liang G, Shao L, Wang Y, Zhao C, Chu Y, Xiao J, et al. Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents. Bioorg Med Chem. 2009;17:2623–31.

    Article  PubMed  CAS  Google Scholar 

  35. Hour TC, Chen J, Huang CY, Guan JY, Lu SH, Pu YS. Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation. Prostate. 2002;51:211–8.

    Article  PubMed  CAS  Google Scholar 

  36. Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2005;280:6301–8.

    Article  PubMed  CAS  Google Scholar 

  37. Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11:7490–8.

    Article  PubMed  CAS  Google Scholar 

  38. Quincoces Suarez J, Rando DG, Santos RP, Gonçalves CP, Ferreira E, Carvalho J, et al. New antitumoral agents I: In vitro anticancer activity and in vivo acute toxicity of synthetic 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives. Bioorg Med Chem. 2010;18:6275–81.

    Article  PubMed  Google Scholar 

  39. Quincoces Suarez J, Rando DG, Maria DA, Pardi P, Martins C, De Souza P. Brazilian Patent PI 0602640-0 (06.07.2006); PCT/BR2007/000175 (06.07.2007); WO 2008/003155.

  40. Ji Z. Targeting DNA damage and repair by curcumin. Breast Cancer (Auckl). 2010;4:1–3.

    CAS  Google Scholar 

  41. Li J, Wang Y, Yang C, Wang P, Oelschlager DK, Zheng Y, et al. Polyethylene glycosylated curcumin conjugate inhibits pancreatic cancer cell growth through inactivation of Jab1. Mol Pharmacol. 2009;76:81–90.

    Article  PubMed  CAS  Google Scholar 

  42. Mosmann TJ. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  PubMed  CAS  Google Scholar 

  43. Montgomery CA. Oncological and toxicological research: alleviation and control of pain and distress in laboratory animals. Cancer Bull. 1990;42:230–7.

    Google Scholar 

  44. Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Expression analysis of maspin in invasive ductal carcinoma of breast and modulation of its expression by curcumin in breast cancer cell lines. Chem Biol Interact. 2010;183:455–61.

    Article  PubMed  CAS  Google Scholar 

  45. Chatterjee SJ, Pandey S. Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy. Cancer Biol Ther. 2011;11:216–28.

    Article  PubMed  CAS  Google Scholar 

  46. Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett. 2008;267:133–64.

    Article  PubMed  CAS  Google Scholar 

  47. Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.

    Article  PubMed  CAS  Google Scholar 

  48. Gururaj AE, Belakavadi M, Venkatesh DA, Marmé D, Salimath BP. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun. 2002;297:934–42.

    Article  PubMed  CAS  Google Scholar 

  49. Ozcan Arican G, Ozalpan A. Evaluation of the effect of paclitaxel, epirubicin and tamoxifen by cell kinetics parameters in estrogen-receptor-positive ehrlich ascites tumor (eat) cells growing in vitro. Acta Biol Hung. 2007;58:49–59.

    Article  PubMed  CAS  Google Scholar 

  50. Oliveira MJ, Van Damme J, Lauwaet T, De Corte V, De Bruyne G, Verschraegen G, et al. β-casein-derived peptides, produced by bacteria, stimulate cancer cell invasion and motility. EMBO J. 2003;22:6161–73.

    Article  PubMed  CAS  Google Scholar 

  51. Leask A, Abraham DJ. TGF-β signaling and the fibrotic response. FASEB J. 2004;18:816–27.

    Article  PubMed  CAS  Google Scholar 

  52. Togni V, Ota CC, Folador A, Junior OT, Aikawa J, Yamazaki RK, et al. Cancer cachexia and tumor growth reduction in walker 256 tumor-bearing rats supplemented with N-3 polyunsaturated fatty acids for one generation. Nutr Cancer. 2003;46:52–8.

    Article  PubMed  CAS  Google Scholar 

  53. Huang MT, Newmark HL, Frenkel KJ. Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem Suppl. 1997;27:26–34.

    Article  PubMed  CAS  Google Scholar 

  54. Faião-Flores F, Pardi PC, Santos RP, Rando DG, Quincoces Suarez JAP, Maria DA. Antiproliferative and antimetastatic activity of DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, in B16F10 melanoma. Applied Cancer Res. 2008;28:72–9.

    Google Scholar 

  55. Fischer AH, Zhao C, Li QK, Gustafson KS, Eltoum IE, Tambouret R, et al. The cytologic criteria of malignancy. J Cell Biochem. 2010;110:795–811.

    Article  PubMed  CAS  Google Scholar 

  56. Schulte EK, Fink DK. Hematoxylin staining in quantitative DNA cytometry: an image analysis study. Anal Cell Pathol. 1995;9:257–68.

    PubMed  CAS  Google Scholar 

  57. Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast cancer cells: modulation of Wnt/-catenin signaling. Chem Biol Interact. 2009;181:263–71.

    Article  PubMed  CAS  Google Scholar 

  58. Fecher LA, Amaravadi RK, Schuchter LM, Flaherty KT. Drug targeting of oncogenic pathways in melanoma. Hematol Oncol Clin North Am. 2009;23:599–618.

    Article  PubMed  Google Scholar 

  59. Philchenkov AJ. Caspases: potential targets for regulating cell death. J Cell Mol Med. 2004;8:432–44.

    Article  PubMed  CAS  Google Scholar 

  60. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67:3853–61.

    Article  PubMed  CAS  Google Scholar 

  61. Chauhan DP. Chemotherapeutic potential of curcumin for colorectal cancer. Curr Pharm Des. 2002;8:1695–706.

    Article  PubMed  CAS  Google Scholar 

  62. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res. 2010;70:3606–17.

    Article  PubMed  CAS  Google Scholar 

  63. Subramaniam D, May R, Sureban SM, Lee KB, George R, Kuppusamy P, et al. Diphenyl difluoroketone: a curcumin derivative with potent in vivo anticancer activity. Cancer Res. 2008;68:1962–9.

    Article  PubMed  CAS  Google Scholar 

  64. Yadav B, Taurin S, Rosengren RJ, Schumacher M, Diederich M, Somers-Edgar TJ, et al. Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin. Bioorg Med Chem. 2010;18:6701–7.

    Article  PubMed  CAS  Google Scholar 

  65. Tang H, Murphy CJ, Zhang B, Shen Y, Van Kirk EA, Murdoch WJ, et al. Curcumin polymers as anticancer conjugates. Biomaterials. 2010;31:7139–49.

    Article  PubMed  CAS  Google Scholar 

  66. Friedman L, Lin L, Ball S, Bekaii-Saab T, Fuchs J, Li PK, et al. Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells. Anticancer Drugs. 2009;20:444–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to the São Paulo Research Foundation, FAPESP (2006/59450-1 and 2004/11351-0) for financial support.

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Authors and Affiliations

  1. Laboratory of Biochemistry and Biophysics, Butantan Institute, São Paulo, Brazil

    Fernanda Faião-Flores & Durvanei Augusto Maria

  2. Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    Fernanda Faião-Flores

  3. Laboratory of Organic Synthesis, Bandeirante University of São Paulo, São Paulo, Brazil

    José Agustín Quincoces Suarez

  4. Laboratory of Experimental Pathology, Bandeirante University of São Paulo, São Paulo, Brazil

    Paulo Celso Pardi

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  1. Fernanda Faião-Flores
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  2. José Agustín Quincoces Suarez
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Correspondence to Fernanda Faião-Flores or Durvanei Augusto Maria.

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Faião-Flores, F., Suarez, J.A.Q., Pardi, P.C. et al. DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate: a curcumin analog with a synergic effect in combination with paclitaxel in breast cancer treatment. Tumor Biol. 33, 775–785 (2012). https://doi.org/10.1007/s13277-011-0293-z

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