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Curcumin-Polyallyhydrocarbon Nanocapsules Potently Suppress 1,2-Dimethylhydrazine-Induced Colorectal Cancer in Mice by Inhibiting Wnt/β-Catenin Pathway

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Abstract

Curcumin (CUR), a natural polyphenol found in Curcuma longa (turmeric) rhizomes, has been widely studied for its anticancer activities against various types of tumors, including colorectal cancer (CRC). However, CUR’s therapeutic efficacy is limited by its low bioavailability, short half-life, limited absorption, and rapid and extensive metabolism. Recently, the use of biodegradable and non-toxic polymeric nanocapsules, such as those using polyallyhydrocarbon (PAH), has offered promising delivery systems of poorly absorbed drugs, including CUR. The aim of this study was to determine the in vivo antiproliferative efficacy of intraperitoneally injected CUR-PAH nanocapsules (100 mg/kg body weight; 5 days/week) using a mouse model of 1,2-dimethylhydrazine (DMH)-induced CRC. Histopathological analysis confirmed that the formulated nanocapsulate systems reduced the major neoplastic features of CRC. At the molecular level, CUR-PAH nanocapsules downregulated the Wnt/β-catenin pathway as determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. A statistically significant downregulation in the gene expression levels of Wnt, frizzled (Frz), β-catenin, transcription factor 4 (Tcf4), lymphoid enhancer-binding factor 1 (Lef1), c-Myc, and cyclin D1 (P < 0.01), combined with significant upregulation in the gene expression levels of glycogen synthase kinase (GSK3β) and adenomatous polyposis coli (APC) (P < 0.05), was observed upon post-treatment with CUR-PAH nanocapsules. The observed histopathological and molecular antiproliferative effects were completely absent when using free PAH polymer without CUR, confirming that the anticancer efficacy was solely exerted by the encapsulated CUR. These findings suggest the utility of CUR-PAH nanocapsules as an efficient delivery system with promising therapeutic effects against CRC.

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References

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians, 68(6), 394–424.

    Google Scholar 

  2. Polakis, P. (2012). Wnt signaling in cancer. Cold Spring Harbor Perspectives in Biology, 4(5), a008052.

    Article  Google Scholar 

  3. Novellasdemunt, L., Antas, P., & Li, V. S. (2015). Targeting Wnt signaling in colorectal cancer. A review in the theme: Cell signaling: Proteins, pathways and mechanisms. American Journal of Physiology. Cell Physiology, 309(8), C511–C521.

    Article  Google Scholar 

  4. Van der Jeught, K., Xu, H.-C., Li, Y.-J., Lu, X.-B., & Ji, G. (2018). Drug resistance and new therapies in colorectal cancer. World Journal of Gastroenterology, 24(34), 3834–3848.

    Article  Google Scholar 

  5. Rafieian-Kopaie, M., & Nasri, H. (2015). On the occasion of World Cancer Day 2015; the possibility of cancer prevention or treatment with antioxidants: the ongoing cancer prevention researches. International Journal of Preventive Medicine, 6, 108.

    Article  Google Scholar 

  6. Newman, D. J., & Cragg, G. M. (2007). Natural products as sources of new drugs over the last 25 years. Journal of Natural Products, 70(3), 461–477.

    Article  Google Scholar 

  7. Kocaadam, B., & Şanlier, N. (2017). Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Critical Reviews in Food Science and Nutrition, 57(13), 2889–2895.

    Article  Google Scholar 

  8. Gupta, S. C., Sung, B., Kim, J. H., Prasad, S., Li, S., & Aggarwal, B. B. (2013). Multitargeting by turmeric, the golden spice: From kitchen to clinic. Molecular Nutrition & Food Research, 57(9), 1510–1528.

    Article  Google Scholar 

  9. Prasad, S., Tyagi, A. K., & Aggarwal, B. B. (2014). Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Research and Treatment, 46(1), 2–18.

    Article  Google Scholar 

  10. Hewlings, S. J., & Kalman, D. S. (2017). Curcumin: A review of its’ effects on human health. Foods, 6(10), 92.

    Article  Google Scholar 

  11. Rahmani, A. H., Alsahli, M. A., Aly, S. M., Khan, M. A., & Aldebasi, Y. H. (2018). Role of curcumin in disease prevention and treatment. Advanced Biomedical Research, 7, 38.

    Article  Google Scholar 

  12. Boroumand, N., Samarghandian, S., & Hashemy, S. I. (2018). Immunomodulatory, anti-inflammatory, and antioxidant effects of curcumin. Journal of Herbmed Pharmacology, 7(4), 211–219.

    Article  Google Scholar 

  13. Willenbacher, E., Khan, S. Z., Mujica, S. C. A., et al. (2019). Curcumin: New insights into an ancient ingredient against cancer. International Journal of Molecular Sciences, 20(8), 1808.

    Article  Google Scholar 

  14. Tomeh, M. A., Hadianamrei, R., & Zhao, X. (2019). A review of curcumin and its derivatives as anticancer agents. International Journal of Molecular Sciences, 20(5), 1033.

    Article  Google Scholar 

  15. Vallianou, N. G., Evangelopoulos, A., Schizas, N., & Kazazis, C. (2015). Potential anticancer properties and mechanisms of action of curcumin. Anticancer Research, 35(2), 645–651.

    Google Scholar 

  16. Schneider, C., Gordon, O. N., Edwards, R. L., & Luis, P. B. (2015). Degradation of curcumin: From mechanism to biological implications. Journal of Agricultural and Food Chemistry, 63(35), 7606–7614.

    Article  Google Scholar 

  17. Burgos-Morón, E., Calderón-Montaño, J. M., Salvador, J., Robles, A., & López-Lázaro, M. (2010). The dark side of curcumin. International Journal of Cancer, 126(7), 1771–1775.

    Google Scholar 

  18. Bansal, S. S., Goel, M., Aqil, F., Vadhanam, M. V., & Gupta, R. C. (2011). Advanced drug-delivery systems of curcumin for cancer chemoprevention. Cancer Prevention Research, 4, 1158–1171.

    Article  Google Scholar 

  19. Rizvi, S. A. A., & Saleh, A. M. (2018). Applications of nanoparticle systems in drug delivery technology. Saudi Pharmaceutical Journal, 26(1), 64–70.

    Article  Google Scholar 

  20. Slika, L., & Patra, D. (2020). A short review on chemical properties, stability and nano-technological advances for curcumin delivery. Expert Opinion on Drug Delivery, 17(1), 61–75.

  21. Mahmood, K., Zia, K. M., Zuber, M., Salman, M., & Anjum, M. N. (2015). Recent developments in curcumin and curcumin based polymeric materials for biomedical applications: a review. International Journal of Biological Macromolecules, 81, 877–890.

    Article  Google Scholar 

  22. Janeesh, P. A., Sami, H., Dhanya, C. R., Sivakumar, S., & Abraham, A. (2014). Biocompatibility and genotoxicity studies of polyallylamine hydrochloride nanocapsules in rats. RSC Advances, 4(47), 24484–24497.

    Article  Google Scholar 

  23. Li, H., Zheng, H., Tong, W., & Gao, C. (2017). Non-covalent assembly of poly(allylamine hydrochloride)/triethylamine microcapsules with ionic strength-responsiveness and auto-fluorescence. Journal of Colloid and Interface Science, 496, 228–234.

    Article  Google Scholar 

  24. Kopecek, J. (2013). Polymer-drug conjugates: origins, progress to date and future directions. Advanced Drug Delivery Reviews, 65(1), 49–59.

    Article  Google Scholar 

  25. Prabhu, R. H., Patravale, V. B., & Joshi, M. D. (2015). Polymeric nanoparticles for targeted treatment in oncology: Current insights. International Journal of Nanomedicine, 10, 1001–1018.

    Google Scholar 

  26. Slika, L., Moubarak, A., Borjac, J., Baydoun, E., & Patra, D. (2019). Preparation of curcumin-poly (allyl amine) hydrochloride based nanocapsules: Piperine in nanocapsules accelerates encapsulation and release of curcumin and effectiveness against colon cancer cells. Materials Science and Engineering: C, 109, 110550.

    Article  Google Scholar 

  27. El Joumaa, M., Taleb, R., Rizk, S., & Borjac, J. (2020). Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice. Journal of Complementary and Integrative Medicine, 17(3), 20190143.

    Article  Google Scholar 

  28. Siegel, R. L., Miller, K. D., & Jemal. (2018). Cancer statistics, 2018. CA: a Cancer Journal for Clinicians, 68(1), 7–30.

    Google Scholar 

  29. Gupta, S. C., Patchva, S., Koh, W., & Aggarwal, B. B. (2012). Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clinical and Experimental Pharmacology & Physiology, 39(3), 283–299.

    Article  Google Scholar 

  30. Yallapu, M. M., Nagesh, P. K. B., Jaggi, M., & Chauhan, S. C. (2015). Therapeutic applications of curcumin nanoformulations. The AAPS Journal, 17(6), 1341–1356.

    Article  Google Scholar 

  31. Martínez-Ballesta, M., Gil-Izquierdo, Á., García-Viguera, C., & Domínguez-Perles, R. (2018). Nanoparticles and controlled delivery for bioactive compounds: Outlining challenges for new "smart-foods" for health. Foods, 7(5), 72.

    Article  Google Scholar 

  32. Washington, M. K., Powell, A. E., Sullivan, R., et al. (2013). Pathology of rodent models of intestinal cancer: progress report and recommendations. Gastroenterology, 144(4), 705–717.

    Article  Google Scholar 

  33. Ismail, N. I., Othman, I., Abas, F., Lagis, N. H., & Naidu, R. (2019). Mechanism of apoptosis induced by curcumin in colorectal cancer. International Journal of Molecular Sciences, 20(10), 2454.

    Article  Google Scholar 

  34. 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-β1 and HES-1 transcripts in 1,2-dimethylhydrazine-colon carcinogenesis in mice. Toxicology, 302(2), 308–317.

    Article  Google Scholar 

  35. Youssef, K. M., Ezzo, A. M., El-Sayed, M. I., Hazzaa, A. A., El-Medany, A. H., & Arafa, M. (2015). Chemopreventive effects of curcumin analogs in DMH-induced colon cancer in albino rats model. Future Journal of Pharmaceutical Sciences, 1(2), 57–72.

    Article  Google Scholar 

  36. Murakami, A., Furukawa, I., Miyamoto, S., Tanaka, T., & Ohigashi, H. (2013). Curcumin combined with turmerones, essential oil components of turmeric, abolishes inflammation-associated mouse colon carcinogenesis. BioFactors, 39(2), 221–232.

    Article  Google Scholar 

  37. Cheng, X., Xu, X., Chen, D., Zhao, F., & Wang, W. (2019). Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer. Biomedicine & Pharmacotherapy, 110, 473–481.

    Article  Google Scholar 

  38. Krishnamurthy, N., & Kurzrock, R. (2018). Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treatment Reviews, 62, 50–60.

    Article  Google Scholar 

  39. Zhan, T., Rindtorff, N., & Boutros, M. (2017). Wnt signaling in cancer. Oncogene, 36(11), 1461–1473.

    Article  Google Scholar 

  40. Shang, S., Hua, F., & Hu, Z.-W. (2017). The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget, 8(20), 33972–33989.

    Article  Google Scholar 

  41. Dou, H., Shen, R., Tao, J., et al. (2017). Curcumin suppresses the colon cancer proliferation by inhibiting Wnt/β-catenin pathways via miR-130a. Frontiers in Pharmacology, 8, 877.

    Article  Google Scholar 

  42. Wang, M., Jiang, S., Zhou, L., et al. (2019). Potential mechanisms of action of curcumin for cancer prevention: Focus on cellular signaling pathways and miRNAs. International Journal of Biological Sciences, 15(6), 1200–1214.

    Article  Google Scholar 

  43. Zhang, Z., Chen, H., Xu, C., et al. (2016). Curcumin inhibits tumor epithelialmesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. Oncology Reports, 35(5), 2615–2623.

    Article  Google Scholar 

  44. Song, X., Zhang, M., Dai, E., & Luo, Y. (2019). Molecular targets of curcumin in breast cancer (Review). Molecular Medicine Reports, 19(1), 23–29.

    Google Scholar 

  45. Li, X., Wang, X., Xie, C., et al. (2018). Sonic hedgehog and Wnt/beta-catenin pathways mediate curcumin inhibition of breast cancer stem cells. Anti-Cancer Drugs, 29(3), 208–215.

    Article  Google Scholar 

  46. Choi, H. Y., Lim, J. E., & Hong, J. H. (2010). Curcumin interrupts the interaction between the androgen receptor and Wnt/beta-catenin signaling pathway in LNCaP prostate cancer cells. Prostate Cancer and Prostatic Diseases, 13(4), 343–349.

    Article  Google Scholar 

  47. Hu, P., Ke, C., Guo, X., et al. (2019). Both glypican-3/Wnt/beta-catenin signaling pathway and autophagy contributed to the inhibitory effect of curcumin on hepatocellular carcinoma. Digestive and Liver Disease, 51(1), 120–126.

    Article  Google Scholar 

  48. Wang, J. Y., Wang, X., Wang, X. J., et al. (2018). Curcumin inhibits the growth via Wnt/beta-catenin pathway in non-small-cell lung cancer cells. European Review for Medical and Pharmacological Sciences, 22(21), 7492–7499.

    Google Scholar 

  49. Zhu, J. Y., Yang, X., Chen, Y., et al. (2017). Curcumin suppresses lung cancer stem cells via inhibiting Wnt/beta-catenin and sonic hedgehog pathways. Phytotherapy Research, 31(4), 680–688.

    Article  Google Scholar 

  50. Lu, Y., Wei, C., & Xi, Z. (2014). Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/beta-catenin pathway. In Vitro Cellular & Developmental Biology. Animal, 50(9), 840–850.

    Article  Google Scholar 

  51. Feng, W., Yang, C. X., Zhang, L., Fang, Y., & Yan, M. (2014). Curcumin promotes the apoptosis of human endometrial carcinoma cells by downregulating the expression of androgen receptor through Wnt signal pathway. European Journal of Gynaecological Oncology, 35(6), 718–723.

    Google Scholar 

  52. Zheng, R., Deng, Q., Liu, Y., & Zhao, P. (2017). Curcumin inhibits gastric carcinoma cell growth and induces apoptosis by suppressing the Wnt/beta-catenin signaling pathway. Medical Science Monitor, 23, 163–171.

    Article  Google Scholar 

  53. Srivastava, N. S., & Srivastava, R. A. K. (2019). Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/beta-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine, 52, 117–128.

    Article  Google Scholar 

  54. Wong, K. E., Ngai, S. C., Chan, K.-G., Lee, L.-H., Goh, B.-H., & Chuah, L.-H. (2019). Curcumin nanoformulations for colorectal cancer: A review. Frontiers in Pharmacology, 10, 152.

    Article  Google Scholar 

  55. Lee, W. H., Loo, C. Y., Young, P. M., Traini, D., Mason, R. S., & Rohanizadeh, R. (2014). Recent advances in curcumin nanoformulation for cancer therapy. Expert Opinion on Drug Delivery, 11(8), 1183–1201.

    Article  Google Scholar 

  56. Li, L., Ahmed, B., Mehta, K., & Kurzrock, R. (2007). Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Molecular Cancer Therapeutics, 6(4), 1276–1282.

    Article  Google Scholar 

  57. Tefas, L. R., Sylvester, B., Tomuta, I., et al. (2017). Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach. Drug Design, Development and Therapy, 11, 1605–1621.

    Article  Google Scholar 

  58. Chuah, L. H., Roberts, C. J., Billa, N., Abdullah, S., & Rosli, R. (2014). Cellular uptake and anticancer effects of mucoadhesive curcumin-containing chitosan nanoparticles. Colloids and Surfaces. B, Biointerfaces, 116, 228–236.

    Article  Google Scholar 

  59. Li, L., Xiang, D., Shigdar, S., et al. (2014). Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells. International Journal of Nanomedicine, 9, 1083–1096.

    Google Scholar 

  60. Xiao, B., Si, X., Han, M. K., Viennois, E., Zhang, M., & Merlin, D. (2015). Co-delivery of camptothecin and curcumin by cationic polymeric nanoparticles for synergistic colon cancer combination chemotherapy. Journal of Materials Chemistry B, 3(39), 7724–7733.

    Article  Google Scholar 

  61. Umerska, A., Gaucher, C., Oyarzun-Ampuero, F., et al. (2018). Polymeric nanoparticles for increasing oral bioavailability of curcumin. Antioxidants, 7(4), 46.

    Article  Google Scholar 

  62. Klippstein, R., Wang, J. T.-W., El-Gogary, R. I., et al. (2015). Passively targeted curcumin-loaded PEGylated PLGA nanocapsules for colon cancer therapy in vivo. Small, 11(36), 4704–4722.

    Article  Google Scholar 

  63. Le, T. T., & Kim, D. (2019). Folate-PEG/Hyd-curcumin/C18-g-PSI micelles for site specific delivery of curcumin to colon cancer cells via Wnt/beta-catenin signaling pathway. Materials Science & Engineering C-Materials, 101, 464–471.

    Article  Google Scholar 

  64. Lotfi-Attari, J., Pilehvar-Soltanahmadi, Y., Dadashpour, M., et al. (2017). Co-delivery of curcumin and chrysin by polymeric nanoparticles inhibit synergistically growth and hTERT gene expression in human colorectal cancer cells. Nutrition and Cancer, 69(8), 1290–1299.

    Article  Google Scholar 

  65. Udompornmongkol, P., & Chiang, B. H. (2015). Curcumin-loaded polymeric nanoparticles for enhanced anti-colorectal cancer applications. Journal of Biomaterials Applications, 30(5), 537–546.

    Article  Google Scholar 

  66. Yang, X., Li, Z., Wang, N., et al. (2015). Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo. Scientific Reports, 5, 10322.

    Article  Google Scholar 

  67. Gou, M., Men, K., Shi, H., et al. (2011). Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. Nanoscale, 3(4), 1558–1567.

    Article  Google Scholar 

  68. Alizadeh, A. M., Khaniki, M., Azizian, S., Mohaghgheghi, M. A., Sadeghizadeh, M., & Najafi, F. (2012). Chemoprevention of azoxymethane-initiated colon cancer in rat by using a novel polymeric nanocarrier--curcumin. European Journal of Pharmacology, 689(1-3), 226–232.

    Article  Google Scholar 

  69. Chaurasia, S., Chaubey, P., Patel, R. R., Kumar, N., & Mishra, B. (2016). Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies. Drug Development and Industrial Pharmacy, 42(5), 694–700.

    Article  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Dr. Ruzanna Petrosyan at the Faculty of Medicine at Beirut Arab University for her kind assistance in the histopathological analysis.

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This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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  1. Department of Biological Sciences, Beirut Arab University, Debbieh, Lebanon

    Alaa Al Moubarak, Manal El Joumaa & Jamilah Borjac

  2. Department of Chemistry, American University of Beirut, Beirut, Lebanon

    Layal Slika & Digambara Patra

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  1. Alaa Al Moubarak
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Al Moubarak, A., El Joumaa, M., Slika, L. et al. Curcumin-Polyallyhydrocarbon Nanocapsules Potently Suppress 1,2-Dimethylhydrazine-Induced Colorectal Cancer in Mice by Inhibiting Wnt/β-Catenin Pathway. BioNanoSci. 11, 518–525 (2021). https://doi.org/10.1007/s12668-021-00842-5

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