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
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.
Polakis, P. (2012). Wnt signaling in cancer. Cold Spring Harbor Perspectives in Biology, 4(5), a008052.
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.
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.
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.
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.
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.
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.
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.
Hewlings, S. J., & Kalman, D. S. (2017). Curcumin: A review of its’ effects on human health. Foods, 6(10), 92.
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.
Boroumand, N., Samarghandian, S., & Hashemy, S. I. (2018). Immunomodulatory, anti-inflammatory, and antioxidant effects of curcumin. Journal of Herbmed Pharmacology, 7(4), 211–219.
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.
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.
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.
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.
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.
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.
Rizvi, S. A. A., & Saleh, A. M. (2018). Applications of nanoparticle systems in drug delivery technology. Saudi Pharmaceutical Journal, 26(1), 64–70.
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.
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.
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.
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.
Kopecek, J. (2013). Polymer-drug conjugates: origins, progress to date and future directions. Advanced Drug Delivery Reviews, 65(1), 49–59.
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.
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.
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.
Siegel, R. L., Miller, K. D., & Jemal. (2018). Cancer statistics, 2018. CA: a Cancer Journal for Clinicians, 68(1), 7–30.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Krishnamurthy, N., & Kurzrock, R. (2018). Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treatment Reviews, 62, 50–60.
Zhan, T., Rindtorff, N., & Boutros, M. (2017). Wnt signaling in cancer. Oncogene, 36(11), 1461–1473.
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.
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.
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.
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.
Song, X., Zhang, M., Dai, E., & Luo, Y. (2019). Molecular targets of curcumin in breast cancer (Review). Molecular Medicine Reports, 19(1), 23–29.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Umerska, A., Gaucher, C., Oyarzun-Ampuero, F., et al. (2018). Polymeric nanoparticles for increasing oral bioavailability of curcumin. Antioxidants, 7(4), 46.
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.
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.
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.
Udompornmongkol, P., & Chiang, B. H. (2015). Curcumin-loaded polymeric nanoparticles for enhanced anti-colorectal cancer applications. Journal of Biomaterials Applications, 30(5), 537–546.
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.
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.
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.
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.
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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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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DOI: https://doi.org/10.1007/s12668-021-00842-5