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Dendrosomal Curcumin Suppresses Metastatic Breast Cancer in Mice by Changing M1/M2 Macrophage Balance in the Tumor Microenvironment

  • Shiri, Sadaf (Immunology Research Center, Tehran University of Medical Sciences) ;
  • Alizadeh, Ali Mohammad (Cancer Research Center, Tehran University of Medical Sciences) ;
  • Baradaran, Behzad (Immunology Research Center, Tehran University of Medical Sciences) ;
  • Farhanghi, Baharak (Cancer Research Center, Tehran University of Medical Sciences) ;
  • Shanehbandi, Dariush (Immunology Research Center, Tehran University of Medical Sciences) ;
  • Khodayari, Saeed (Cancer Research Center, Tehran University of Medical Sciences) ;
  • Khodayari, Hamid (Cancer Research Center, Tehran University of Medical Sciences) ;
  • Tavassoli, Abbas (Department of Pathology, Faculty of Veterinary Medicine, Tehran University)
  • Published : 2015.05.18

Abstract

Curcumin, a lipid-soluble compound extracted from the plant Curcuma Longa, has been found to exert immunomodulatory effects via macrophages. However, most studies focus on the low bioavailability issue of curcumin by nano and microparticles, and thus the role of macrophages in the anticancer mechanism of curcumin has received little attention so far. We have previously shown the potential biocompatibility, biodegradability and anti-cancer effects of dendrosomal curcumin (DNC). In this study, twenty-seven BALB/c mice were equally divided into control as well as 40 and 80 mg/kg groups of DNC to investigate the involvement of macrophages in the antitumor effects of curcumin in a typical animal model of metastatic breast cancer. At the end of intervention, the tumor volume and weight were significantly reduced in DNC groups compared to control (P<0.05). Histopathological data showed the presence of macrophages in tumor and spleen tissues. Real-time PCR results showed that DNC increased the expression of STAT4 and IL-12 genes in tumor and spleen tissues in comparison with control (P<0.05), referring to the high levels of M1 macrophages. Furthermore treatment with DNC decreased STAT3, IL-10 and arginase I gene expression (P<0.05), indicating low levels of M2 macrophage. The results confirm the role of macrophages in the protective effects of dendrosomal curcumin against metastatic breast cancer in mice.

Keywords

Dendrosomal curcumin;macrophage;breast cancer;BALB/c mice

References

  1. Aggarwal BB, Sundaram C, Malani N, Ichikawa H (2007). Curcumin: the Indian solid gold. In The molecular targets and therapeutic uses of curcumin in health and disease (Springer), pp. 1-75.
  2. Aggarwal BB, Sung B (2009). Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci, 30, 85-94. https://doi.org/10.1016/j.tips.2008.11.002
  3. Alexandrow MG, Song LJ, Altiok S, et al (2012). Curcumin: a novel stat 3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev, 21, 407. https://doi.org/10.1097/CEJ.0b013e32834ef194
  4. Alizadeh AM, Khaniki M, Azizian S, et al (2012). Chemoprevention of azoxymethane-initiated colon cancer in rat by using a novel polymeric nanocarrier-curcumin. European J Pharmacol, 689, 226-32. https://doi.org/10.1016/j.ejphar.2012.06.016
  5. Alizadeh AM, Shiri S, Farsinejad S (2014). Metastasis review: from bench to bedside. Tumor Biol, 35, 8483-523. https://doi.org/10.1007/s13277-014-2421-z
  6. Antony S, Kuttan R, Kuttan G (1999). Immunomodulatory activity of curcumin. Immunol Invest, 28, 291-303. https://doi.org/10.3109/08820139909062263
  7. Babaei E, Sadeghizadeh M, Hassan ZM, et al (2012). Dendrosomal curcumin significantly suppresses cancer cell proliferation< i> in vitro and< i> in vivo. Int Immunopharmacol, 12, 226-34. https://doi.org/10.1016/j.intimp.2011.11.015
  8. Bhattacharyya S, Hossain DMS, Mohanty S, et al (2010). Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cellular Mol Immunol, 7, 306-15. https://doi.org/10.1038/cmi.2010.11
  9. Biswas SK, Chittezhath M, Shalova IN, Lim J-Y (2012). Macrophage polarization and plasticity in health and disease. Immunol Res, 53, 11-24. https://doi.org/10.1007/s12026-012-8291-9
  10. Bounaama A, Djerdjouri B, Laroche-Clary A, Le Morvan V, Robert J (2012). Short curcumin treatment modulates oxidative stress, arginase activity, aberrant crypt foci, and TGF-${\beta}$1 and HES-1 transcripts in 1, 2-dimethylhydrazine-colon carcinogenesis in mice. Toxicol, 302, 308-17. https://doi.org/10.1016/j.tox.2012.08.014
  11. Colombo MP, Trinchieri G (2002). Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev, 13, 155-68. https://doi.org/10.1016/S1359-6101(01)00032-6
  12. Cui Y-L, Li H-K, Zhou H-Y, Zhang T, Li Q (2013). Correlations of tumor-associated macrophage subtypes with liver metastases of colorectal cancer. Asian Pac J Cancer Prev, 14, 1003-7. https://doi.org/10.7314/APJCP.2013.14.2.1003
  13. Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S (2014). Nanotechnology-applied curcumin for different diseases therapy. Bio Med Res Int, 2014, 394264
  14. Hao N-B, Lu M-H, Fan Y-H, et al (2012). Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol, 2012, 948098.
  15. Heusinkveld M, van der Burg SH (2011). Identification and manipulation of tumor associated macrophages in human cancers. J Translat Med, 9, 216. https://doi.org/10.1186/1479-5876-9-216
  16. Huang Y, Lei Y, Zhang H, Zhang M, Dayton A (2011). Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells. J Leukocyte Biol, 90, 87-97. https://doi.org/10.1189/jlb.1210674
  17. Jagetia GC, Aggarwal BB (2007). "Spicing up" of the immune system by curcumin. J Clin Immunol, 27, 19-35. https://doi.org/10.1007/s10875-006-9066-7
  18. Kamran MZ, Patil P, Gude RP (2013). Role of STAT3 in cancer metastasis and translational advances. Bio Med Res Int, 2013, 421821.
  19. Kelloff GJ, Crowell JA, Steele VE, et al (2000). Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr, 130, 467-71.
  20. Khaniki M, Azizian S, Alizadeh AM, et al (2013). The antiproliferative and anticancerogenic effects of nanocurcumin in rat colon cancer. Tehran Univers Med J, 71, 277-284.
  21. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2-${\Delta}{\Delta}$CT method. Methods, 25, 402-8. https://doi.org/10.1006/meth.2001.1262
  22. Martinez FO, Sica A, Mantovani A, Locati M (2007). Macrophage activation and polarization. Frontiers in Bioscience: J Virtual Library, 13, 453-61.
  23. Medrek C, Ponten F, Jirstrom K, Leandersson K (2012). The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer, 12, 306. https://doi.org/10.1186/1471-2407-12-306
  24. Mohsenikia M, Alizadeh AM, Khodayari S, et al (2013). The protective and therapeutic effects of alpha-solanine on mice breast cancer. Eur J Pharmacol, 718, 1-9. https://doi.org/10.1016/j.ejphar.2013.09.015
  25. Murray PJ, Wynn TA (2011). Protective and pathogenic functions of macrophage subsets. Nature Rev Immunol, 11, 723-37. https://doi.org/10.1038/nri3073
  26. Niu G, Wright KL, Ma Y, et al (2005). Role of Stat3 in regulating p53 expression and function. Mol Cell Bio, 25, 7432-40. https://doi.org/10.1128/MCB.25.17.7432-7440.2005
  27. Olefsky JM, Glass CK (2010). Macrophages, inflammation, and insulin resistance. Ann Rev Phys, 72, 219-46. https://doi.org/10.1146/annurev-physiol-021909-135846
  28. Sadeghizadeh M, Ranjbar B, Damaghi M, et al (2008). Dendrosomes as novel gene porters-III. J Chem Technol Biotechnol, 83, 912-20. https://doi.org/10.1002/jctb.1891
  29. Sarbolouki MN, Sadeghizadeh M, Yaghoobi MM, et al (2000). Dendrosomes: a novel family of vehicles for transfection and therapy. J Chem Technol Biotechnol, 75, 919-22. https://doi.org/10.1002/1097-4660(200010)75:10<919::AID-JCTB308>3.0.CO;2-S
  30. Schindler H, Lutz MB, Rollinghoff M, Bogdan C (2001). The production of IFN-${\gamma}$ by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. J Immunol, 166, 3075-82. https://doi.org/10.4049/jimmunol.166.5.3075
  31. Sica A, Mantovani A (2012). Macrophage plasticity and polarization: in vivo veritas. J Clin Invest, 122, 787-95. https://doi.org/10.1172/JCI59643
  32. Sica A, Schioppa T, Mantovani A, Allavena P (2006). Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer, 42, 717-27. https://doi.org/10.1016/j.ejca.2006.01.003
  33. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S (2007). Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol, 179, 977-83. https://doi.org/10.4049/jimmunol.179.2.977
  34. Siveen KS, Sikka S, Surana R, et al (2014). Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta, 1845, 136-54.
  35. Solinas G, Germano G, Mantovani A, Allavena P (2009). Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukocyte Biol, 86, 1065-73. https://doi.org/10.1189/jlb.0609385
  36. Srivastava RM, Singh S, Dubey SK, Misra K, Khar A (2011). Immunomodulatory and therapeutic activity of curcumin. Intern Immunopharmacol, 11, 331-41. https://doi.org/10.1016/j.intimp.2010.08.014
  37. Tu SP, Jin H, Shi JD, et al (2012). Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev Res, 5, 205-15. https://doi.org/10.1158/1940-6207.CAPR-11-0247
  38. Uddin S, Hussain AR, Manogaran PS, et al (2005). Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma. Oncogene, 24, 7022-30. https://doi.org/10.1038/sj.onc.1208864
  39. Varalakshmi C, Ali AM, Pardhasaradhi B, et al (2008). Immunomodulatory effects of curcumin: In-vivo. Intern Immunopharmacol, 8, 688-700. https://doi.org/10.1016/j.intimp.2008.01.008
  40. Vasquez-Dunddel D, Pan F, Zeng Q, et al (2013). STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest, 123, 1580-9. https://doi.org/10.1172/JCI60083
  41. Vishvakarma NK, Singh SM (2010). Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: implication in antitumor activation of tumor-associated macrophages. Immunol Letters, 134, 83-92. https://doi.org/10.1016/j.imlet.2010.09.002
  42. Wang W, Wang J, Dong S-f, et al (2010). Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response. Acta Pharmacologica Sinica, 31, 191-201. https://doi.org/10.1038/aps.2009.205
  43. Weiss JM, Ridnour LA, Back T, et al (2010). Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med, 207, 2455-67. https://doi.org/10.1084/jem.20100670
  44. Xu M, Mizoguchi I, Morishima N, et al (2010). Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. J Immunol Res, 2010, 832454.
  45. Yang C-L, Liu Y-Y, Ma Y-G, et al (2012). Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through Janus kinase-STAT3 signalling pathway. PLoS One, 7, 37960. https://doi.org/10.1371/journal.pone.0037960
  46. Yu H, Jove R (2004). The STATs of cancer-new molecular targets come of age. Nature Rev Cancer, 4, 97-105. https://doi.org/10.1038/nrc1275
  47. Yu H, Pardoll D, Jove R (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Rev Cancer, 9, 798-809. https://doi.org/10.1038/nrc2734
  48. Zhang X, Tian W, Cai X, et al (2013a). Hydrazinocurcumin encapsuled nanoparticles "re-educate" tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression. PloS One, 8, 65896. https://doi.org/10.1371/journal.pone.0065896
  49. Zhang Y, Cheng S, Zhang M, et al (2013b). High-infiltration of tumor-associated macrophages predicts unfavorable clinical outcome for node-negative breast cancer. PloS One, 8, 76147. https://doi.org/10.1371/journal.pone.0076147

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