Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Inhibition of Cancer Stem-Like Phenotype by Curcumin and Deguelin in CAL-62 Anaplastic Thyroid Cancer Cells

Author(s): Mehmet A. Kocdor*, Hakan Cengiz, Halil Ates and Hilal Kocdor

Volume 19 , Issue 15 , 2019

Page: [1887 - 1898] Pages: 12

DOI: 10.2174/1871520619666191004144025

Price: $65


Background: Anaplastic Thyroid Cancer (ATC) is one of the most lethal and aggressive human malignancies. Studies have shown that Cancer Stem-Cell (CSC) phenotype is mainly responsible for ATC aggressiveness. Cytostatic compounds are mostly ineffective because of multidrug resistance mechanisms driven by the CSC phenotype. Taxanes have limited efficacy. Recently, CSC inhibition using plant-derived, less toxic compounds, which have anti-cancer efficacy, has become a novel treatment modality. The aim of the study was to evaluate the anti-cancer activity of two natural compounds (curcumin and deguelin) on ATC cells and their CSC properties. In addition, the efficacies of these compounds were compared with that of docetaxel.

Methods: Besides control, five treatment groups were formed. ATC cells (CAL-62) were treated with curcumin, deguelin, docetaxel, and their combinations (curcumin+docetaxel, deguelin+docetaxel) at previously determined IC50 doses. Stemness was analyzed by quantitative estimation of sphere formation in matrigel, expression of several cell surface markers (CD133, CD90, Nanog, and OCT3/4) using flow cytometry, and quantification of the hypoxic status [Oxidative Stress Index (OSI) and Superoxide Dismutase (SOD) activity]. The anti-cancer efficacies of these compounds and their combinations were evaluated by determining the alterations in the cell cycle, apoptosis, and tumoral cell migration.

Results: Both the natural compounds (particularly curcumin) significantly suppressed the spheroid formation and cellular motility in matrigel as well as suppressed the accumulation of cells in the G0/1 phase, in which the maximum CSC activity is observed. The compounds did not suppress the expression of CSC markers, but twothirds of the cells expressed CD90. Deguelin was found to be particularly effective in inducing apoptosis similar to docetaxel at IC50 concentrations. Curcumin reduced the OSI and deguelin enhanced the SOD activity, even in docetaxel pre-treated cells.

Conclusion: A large proportion of anaplastic tumors might consist of heterogeneous CSC population. Curcumin and deguelin have anti-cancer and several anti-stem cell activities against ATC cells. These natural compounds are capable of altering the aggressive behavior of ATC cells through the inhibition of the CSC phenotype. As a novel therapeutic target, CD90 should be investigated in other ATC cell lines and in vivo models.

Keywords: Anaplastic thyroid cancer, deguelin, curcumin, docetaxel, cancer stem cell, CSC phenotype.

Graphical Abstract
Keutgen, X.M.; Sadowski, S.M.; Kebebew, E. Management of anaplastic thyroid cancer. Gland Surg., 2015, 4(1), 44-51.
Perrier, N.D.; Brierley, J.D.; Tuttle, R.M. Differentiated and anaplastic thyroid carcinoma: Major changes in the american joint committee on cancer eighth edition cancer staging manual. CA Cancer J. Clin., 2017, 68, 55-63.
Sugitani, I.; Miyauchi, A.; Sugino, K.; Okamoto, T.; Yoshida, A.; Suzuki, S. Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J. Surg., 2012, 36(6), 1247-1254.
Liu, X.; Fan, D. The epithelial-mesenchymal transition and cancer stem cells: Functional and mechanistic links. Curr. Pharm. Des., 2015, 21(10), 1279-1291.
Smallridge, R.C.; Ain, K.B.; Asa, S.L.; Bible, K.C.; Brierley, J.D.; Burman, K.D.; Kebebew, E.; Lee, N.Y.; Nikiforov, Y.E.; Rosenthal, M.S.; Shah, M.H.; Shaha, A.R.; Tuttle, R.M. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid, 2012, 22(11), 1104-1139.
Are, C.; Shaha, A.R. Anaplastic thyroid carcinoma: Biology, pathogenesis, prognostic factors, and treatment approaches. Ann. Surg. Oncol., 2006, 13(4), 453-464.
Haghpanah, V.; Fallah, P.; Naderi, M.; Tavakoli, R.; Soleimani, M.; Larijani, B. Cancer stem-like cell behavior in anaplastic thyroid cancer: A challenging dilemma. Life Sci., 2016, 146, 34-39.
Vicari, L.; Colarossi, C.; Giuffrida, D.; De Maria, R.; Memeo, L. Cancer stem cells as a potential therapeutic target in thyroid carcinoma. Oncol. Lett., 2016, 12(4), 2254-2260.
Borovski, T.; De Sousa, E.; Melo, F.; Vermeulen, L.; Medema, J.P. Cancer stem cell niche: The place to be. Cancer Res., 2011, 71(3), 634-639.
Jung, C.W.; Han, K.H.; Seol, H.; Park, S.; Koh, J.S.; Lee, S.S.; Kim, M.J.; Choi, I.J.; Myung, J.K. Expression of cancer stem cell markers and epithelial-mesenchymal transition-related factors in anaplastic thyroid carcinoma. Int. J. Clin. Exp. Pathol., 2015, 8(1), 560-568.
Ahmad, A.; Gadgeel, S.M. Lung cancer and personalized medicine: novel therapies and clinical management. Adv. Exp. Med. Biol., 2016, 890, v-vi.
Montemayor-Garcia, C.; Hardin, H.; Guo, Z.; Larrain, C.; Buehler, D.; Asioli, S.; Chen, H.; Lloyd, R.V. The role of epithelial mesenchymal transition markers in thyroid carcinoma progression. Endocr. Pathol., 2013, 24(4), 206-212.
Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; Campbell, L.L.; Polyak, K.; Brisken, C.; Yang, J.; Weinberg, R.A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, 133(4), 704-715.
Peitzsch, C.; Tyutyunnykova, A.; Pantel, K.; Dubrovska, A. Cancer stem cells: The root of tumor recurrence and metastases. Semin. Cancer Biol., 2017, 44, 10-24.
García-Rubiño, M.E.; Lozano-López, C.; Campos, J.M. Inhibitors of cancer stem cells. Anticancer. Agents Med. Chem., 2016, 16(10), 1230-1239.
Hamamura, K.; Furukawa, K. Glycosylation is involved in malignant properties of cancer cells. Cancer Transl. Med., 2017, 3, 209-213.
Rassouli, F.B.; Matin, M.M.; Saeinasab, M. Cancer stem cells in human digestive tract malignancies. Tumour Biol., 2016, 37(1), 7-21.
Larzabal, L.; El-Nikhely, N.; Redrado, M.; Seeger, W.; Savai, R.; Calvo, A. Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis. PLoS One, 2013, 8(11)e79798
Nath, S.; Devi, G.R. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol. Ther., 2016, 163, 94-108.
Cammareri, P.; Lombardo, Y.; Francipane, M.G.; Bonventre, S.; Todaro, M.; Stassi, G. Isolation and culture of colon cancer stem cells. Methods Cell Biol., 2008, 86(08), 311-324.
Slater, C.; De La Mare, J.A.; Edkins, A.L. In vitro analysis of putative cancer stem cell populations and chemosensitivity in the SW480 and SW620 colon cancer metastasis model. Oncol. Lett., 2018, 15(6), 8516-8526.
Buczacki, S. Cancer stem cells. Encycl. Cell Biol., 2015, 3(12), 807-812.
Fang, N.; Casida, J.E. Cubé resin insecticide: Identification and biological activity of 29 rotenoid constituents. J. Agric. Food Chem., 1999, 47(5), 2130-2136.
Wang, Y.; Ma, W.; Zheng, W. Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention. Mol. Clin. Oncol., 2013, 1(2), 215-219.
Zhao, D.; Han, W.; Liu, X.; Cui, D.; Chen, Y. Deguelin inhibits epithelial-to-mesenchymal transition and metastasis of human non-small cell lung cancer cells by regulating NIMA-related kinase 2. Thorac. Cancer, 2017, 8(4), 320-327.
Zheng, W.; Lu, S.; Cai, H.; Kang, M.; Qin, W.; Li, C.; Wu, Y. Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway. Oncol. Lett., 2016, 12(4), 2761-2765.
Deng, Y.I.; Verron, E.; Rohanizadeh, R. Molecular mechanisms of anti-metastatic activity of curcumin. Anticancer Res., 2016, 36(11), 5639-5647.
Chiablaem, K.; Lirdprapamongkol, K.; Keeratichamroen, S.; Surarit, R.; Svasti, J. Curcumin suppresses vasculogenic mimicry capacity of hepatocellular carcinoma cells through STAT3 and PI3K/AKT inhibition. Anticancer Res., 2014, 34(4), 1857-1864.
Panda, A.K.; Chakraborty, D.; Sarkar, I.; Khan, T.; Sa, G. New insights into therapeutic activity and anticancer properties of curcumin. J. Exp. Pharmacol., 2017, 9, 31-45.
Li, Y.; Zhang, T. Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett., 2014, 346(2), 197-205.
Suresh, R.; Ali, S.; Ahmad, A.; Philip, P.A.; Sarkar, F.H. The role of cancer stem cells in recurrent and drug-resistant lung cancer. Adv. Exp. Med. Biol., 2016, 890, 57-74.
Erel, O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin. Biochem., 2004, 37(4), 277-285.
Erel, O. A new automated colorimetric method for measuring total oxidant status. Clin. Biochem., 2005, 38(12), 1103-1111.
Grotenhuis, B.A.; Wijnhoven, B.P.L.; van Lanschot, J.J.B. Cancer stem cells and their potential implications for the treatment of solid tumors. J. Surg. Oncol., 2012, 106(2), 209-215.
Fulawka, L.; Donizy, P.; Halon, A. Cancer stem cells--the current status of an old concept: Literature review and clinical approaches. Biol. Res., 2014, 47(1), 66.
Li, W.; Reeb, A.N.; Sewell, W.A.; Elhomsy, G.; Lin, R.Y. Phenotypic characterization of metastatic anaplastic thyroid cancer stem cells. PLoS One, 2013, 8(5)e65095
Kumar, A.; Bhanja, A.; Bhattacharyya, J.; Jaganathan, B.G. Multiple roles of CD90 in cancer. Tumour Biol., 2016, 37(9), 11611-11622.
He, J.; Zhu, T.; Liu, Y.; Vescovi, A.L.; Muraszko, K.M.; Zhu, J.; Lubman, D.M.; Fan, X.; DiMeco, F.; Heth, J.A. CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays. Mol. Cell. Proteomics, 2011, 11(6), M111.010744.
Tang, K.H.; Dai, Y.D.; Tong, M.; Chan, Y.P.; Kwan, P.S.; Fu, L.; Qin, Y.R.; Tsao, S.W.; Lung, H.L.; Lung, M.L.; Tong, D.K.; Law, S.; Chan, K.W.; Ma, S.; Guan, X.Y.A. CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res., 2013, 73(7), 2322-2332.
Kakarala, M.; Brenner, D.E.; Korkaya, H.; Cheng, C.; Tazi, K.; Ginestier, C.; Liu, S.; Dontu, G.; Wicha, M.S. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res. Treat., 2010, 122(3), 777-785.
Almanaa, T.N.; Geusz, M.E.; Jamasbi, R.J. Effects of curcumin on stem-like cells in human esophageal squamous carcinoma cell lines. BMC Complement. Altern. Med., 2012, 12, 195.
Allegri, L.; Rosignolo, F.; Mio, C.; Filetti, S.; Baldan, F.; Damante, G. Effects of nutraceuticals on anaplastic thyroid cancer cells. J. Cancer Res. Clin. Oncol., 2018, 144(2), 285-294.
Schwertheim, S.; Wein, F.; Lennartz, K.; Worm, K.; Schmid, K.W.; Sheu-Grabellus, S.Y. Curcumin induces G2/M arrest, apoptosis, NF-KB inhibition, and expression of differentiation genes in thyroid carcinoma cells. J. Cancer Res. Clin. Oncol., 2017, 143(7), 1-12.
Wei, Y.; Pu, X.; Zhao, L. Preclinical studies for the combination of paclitaxel and curcumin in cancer therapy (Review). Oncol. Rep., 2017, 37(6), 3159-3166.
Park, C.H.; Han, S.E.; Nam-Goong, I.S.; Kim, Y.I.; Kim, E.S. Combined effects of baicalein and docetaxel on apoptosis in 8505c anaplastic thyroid cancer cells via downregulation of the ERK and Akt/mTOR pathways. Endocrinol. Metab. (Seoul), 2018, 33(1), 121-132.
Henry, C.M.; Hollville, E.; Martin, S.J. Measuring apoptosis by microscopy and flow cytometry. Methods, 2013, 61(2), 90-97.
Plesca, D.; Mazumder, S.; Almasan, A. DNA damage response and apoptosis. Methods Enzymol., 2008, 446, 107-122.
Pinto, A.E.; Silva, G.; Banito, A.; Leite, V.; Soares, J. Anaeploidy and high S-phase as biomarkers of poor clinical outcome in poorly differentiated and anaplastic thyroid cancer. Oncol. Rep., 2008, 20, 913-919.
Lamb, R.; Lisanti, M.P.; Clarke, R.B.; Landberg, G. Co-ordination of cell cycle, migration and stem cell-like activity in breast cancer. Oncotarget, 2014, 5(17), 7833-7842.
Mahkamova, K.; Latar, N.; Aspinall, S.; Meeson, A. Hypoxia increases thyroid cancer stem cell-enriched side population. World J. Surg., 2018, 42(2), 350-357.
Shi, X.; Zhang, Y.; Zheng, J.; Pan, J. Reactive oxygen species in cancer stem cells. Antioxid. Redox Signal., 2012, 16(11), 1215-1228.
Shimamura, M.; Yamamoto, K.; Kurashige, T.; Nagayama, Y. Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines. Exp. Cell Res., 2018, 370(2), 699-707.
Xu, B.; Ghossein, R. Genomic landscape of poorly differentiated and anaplastic thyroid carcinoma. Endocr. Pathol., 2016, 27(3), 205-212.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy