SYNERGISTIC EFFECT OF CURCUMIN AND ATIPRIMOD AS POTENT INHIBITORS OF STAT3 AND IL-6 RECEPTOR IN CHORDOMA CELLS

Year 2024, Volume: 10 Issue: 1, 96 - 102, 30.06.2024

Esra Aydemir

https://doi.org/10.22531/muglajsci.1438575

Abstract

Chordoma, is a rare bone tumor, which is characterized by a high recurrence rate and drug resistance in addition to its potential for local invasion, and metastasis. It is a low-grade axial skeletal carcinoma derived from notochord remnants. Molecular pathways that underlie the mechanisms of chordoma pathogenesis are partially elucidated, however, the rate of success in treatment remains to be solved. Constitutively active STAT3 and partially active STAT5 suppress anti-tumor immunity, resulting in increased proliferation, survival and aggressiveness of tumor cells. Persistent activation of STAT3 mediates tumor-promoting inflammation. STAT3 upregulates pro-oncogenic inflammatory pathways, including nuclear factor-κB (NFκB), interleukin-6 (IL-6), and Janus kinase (JAK) pathways. In conclusion, IL6R and STAT3 are promising targets for rerouting inflammation for cancer therapy. In this study, curcumin and atiprimod agents were applied to chordoma cell lines in combination based on molecular docking analyses. The binding efficacy was found favorable for the treatment with two agents and synergistic anti-cancer effects of this combined application were detected on chordoma cells. Molecular docking analyses together with the in vitro results support the idea that application of IL-6R and Stat3 co-inhibition have lethal effects on chordoma cells.

Keywords

IL-6R, Atiprimod, Curcumin, Molecular Docking, Chordoma

Thanks

I would like to thank Ahmet Hakan Görkay for the technical assistance.

KORDOMA HÜCRELERİNDE STAT3 VE IL-6 RESEPTÖRÜNÜN GÜÇLÜ İNHİBİTÖRLERİ OLARAK KURKUMİN VE ATİPRİMODUN SİNERJİK ETKİSİ

Abstract

Kordoma, lokal invazyon ve metastaz potansiyelinin yanı sıra yüksek nüks oranı ve ilaç direnci ile karakterize, nadir görülen bir kemik tümörüdür. Notokord kalıntılarından kaynaklanan düşük dereceli aksiyal iskelet karsinomudur. Kordoma patogenez mekanizmalarının altında yatan moleküler yolaklar kısmen aydınlatılmış olmakla birlikte tedavideki başarı oranı henüz çözülmemiştir. Yapısal olarak aktif STAT3 ve kısmen aktif STAT5, anti-tümör bağışıklığını baskılayarak tümör hücrelerinin çoğalmasının, hayatta kalmasının ve saldırganlığının artmasına neden olur. STAT3'ün kalıcı aktivasyonu, tümörü teşvik eden inflamasyona aracılık eder. STAT3, nükleer faktör-κB (NFκB), interlökin-6 (IL-6), ve Janus kinaz (JAK) yolakları dahil olmak üzere pro-onkojenik inflamatuar yolakları düzenler. Sonuç olarak IL6R ve STAT3, kanser tedavisi için inflamasyonun yeniden yönlendirilmesi açısından umut verici bir hedeftir. Bu çalışmada, moleküler yerleştirme analizleri sonucunda kordoma hücre hatlarına kurkumin ve atiprimod ajanları kombinasyon halinde uygulanmıştır. İki ajanın tedavisi için bağlanma etkinliği olumlu, bu kombine uygulamanın sinerjistik antikanser etkilerinin olduğu bulunmuştur. Moleküler yerleştirme ve in vitro sonuçlar, IL-6R ve Stat3 ortak inhibisyonunun kordoma hücreleri üzerinde öldürücü etkileri olduğu fikrini desteklemektedir.

Keywords

IL-6R, Atiprimod, Kurkumin, Moleküler Yerleştirme, Kordoma

References

• Walcott, B. P., Nahed, B. V, Mohyeldin, A., Coumans, J.-V., Kahle, K. T., and Ferreira, M. J., “Chordoma: current concepts, management, and future directions,” Lancet Oncology., 13,2, 69-76, 2012.
• Fourney, D. R., Rhines, L. D., Hentschel, S. J., Skibber, J. M., Wolinsky, J. P., Weber, K. L., Suki, D., Gallia, G. L., Garonzik, I., & Gokaslan, Z. L., “En bloc resection of primary sacral tumors: classification of surgical approaches and outcome.,” Journal of. Neurosurgery. Spine, vol. 3, no. 2, pp. 111–22, Aug. 2005
• Zanin, N., Viaris de Lesegno, C., Podkalicka, J., Meyer, T., Gonzalez Troncoso, P., Bun, P., Danglot, L., Chmiest, D., Urbé, S., Piehler, J., Blouin, C. M., & Lamaze, C, “STAM and Hrs interact sequentially with IFN-α Receptor to control spatiotemporal JAK–STAT endosomal activation,” Nature cell biology, 2023
• Hanlon, M. M., Rakovich, T., Cunningham, C. C., Ansboro, S., Veale, D. J., Fearon, U., & McGarry, T, “STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function.,” Frontiers in immunology., vol. 10, p. 2056, 2019
• J. S. Rawlings, K. M. Rosler, and D. A. Harrison, “The JAK/STAT signaling pathway,” Journal of Cell Science., vol. 117, no. 8, pp. 1281–1283, Mar. 2004
• D. E. Johnson, R. A. O’Keefe, and J. R. Grandis, “Targeting the IL-6/JAK/STAT3 signalling axis in cancer.,” Nature Reviews Clinical Oncology, vol. 15, no. 4, pp. 234–248, Apr. 2018
• Ishibashi, K., Koguchi, T., Matsuoka, K., Onagi, A., Tanji, R., Takinami-Honda, R., Hoshi, S., Onoda, M., Kurimura, Y., Hata, J., Sato, Y., Kataoka, M., Ogawsa, S., Haga, N., & Kojima, Y., “Interleukin-6 induces drug resistance in renal cell carcinoma.,” Fukushima journal of medical science, vol. 64, no. 3, pp. 103–110, Dec. 2018
• Bromberg, J. F., Wrzeszczynska, M. H., Devgan, G., Zhao, Y., Pestell, R. G., Albanese, C., & Darnell, J. E., Jr., “Stat3 as an oncogene.,” Cell, vol. 98, no. 3, pp. 295–303, Aug. 1999
• Priego, N., Zhu, L., Monteiro, C., Mulders, M., Wasilewski, D., Bindeman, W., Doglio, L., Martínez, L., Martínez-Saez, E., Ramón Y Cajal, S., Megías, D., Hernández-Encinas, E., Blanco-Aparicio, C., Martínez, L., Zarzuela, E., Muñoz, J., Fustero-Torre, C., Piñeiro-Yáñez, E., Hernández-Laín, A., Bertero, L., … Valiente, M. ,“STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.,” Nature medicine,, vol. 24, no. 7, pp. 1024–1035, Jul. 2018
• Wang, T., Fahrmann, J. F., Lee, H., Li, Y. J., Tripathi, S. C., Yue, C., Zhang, C., Lifshitz, V., Song, J., Yuan, Y., Somlo, G., Jandial, R., Ann, D., Hanash, S., Jove, R., & Yu, H., “JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.,” Cell metabolism., vol. 27, no. 1, pp. 136-150.e5, Jan. 2018
• J. Wang, W. Hu, X. Du, Y. Sun, S. Han, and G. Tu, “Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling,” Bioscience Reports., vol. 40, no. 2, p. BSR20200221, Feb. 2020
• F. N. Novikov and G. G. Chilov, “Molecular docking: theoretical background, practical applications and perspectives,” Mendeleev Communications., vol. 19, no. 5, pp. 237–242, 2009
• S. F. Sousa, P. A. Fernandes, and M. J. Ramos, “Protein-ligand docking: current status and future challenges.,” Proteins, vol. 65, no. 1, pp. 15–26, Oct. 2006
• H. M. Geysen, F. Schoenen, D. Wagner, and R. Wagner, “Combinatorial compound libraries for drug discovery: an ongoing challenge.,” Nature Reviews Drug Discovery., vol. 2, no. 3, pp. 222–230, Mar. 2003
• Scior, T., Bender, A., Tresadern, G., Medina-Franco, J. L., Martínez-Mayorga, K., Langer, T., Cuanalo-Contreras, K., & Agrafiotis, D. K.., “Recognizing pitfalls in virtual screening: a critical review.,” Journal of chemical information and modeling, vol. 52, no. 4, pp. 867–881, Apr. 2012
• K. Onodera, K. Satou, and H. Hirota, “Evaluations of molecular docking programs for virtual screening.,” Journal of chemical information and modeling., vol. 47, no. 4, pp. 1609–1618, 2007
• Cross, J. B., Thompson, D. C., Rai, B. K., Baber, J. C., Fan, K. Y., Hu, Y., & Humblet, C., “Comparison of several molecular docking programs: pose prediction and virtual screening accuracy.,” Journal of chemical information and modeling., vol. 49, no. 6, pp. 1455–1474, Jun. 2009
• J. S. Shim and J. O. Liu, “Recent advances in drug repositioning for the discovery of new anticancer drugs.,” International Journal of Biological Sciences, vol. 10, no. 7, pp. 654–663, 2014
• M. Hendlich, “Databases for protein-ligand complexes.,” Acta Crystallographica Section D, vol. 54, no. Pt 6 Pt 1, pp. 1178–1182, Nov. 1998
• J. J. Irwin and B. K. Shoichet, “ZINC--a free database of commercially available compounds for virtual screening.,” Journal of Chemical Information and Modeling, vol. 45, no. 1, pp. 177–182, 2005
• Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., & Bourne, P. E., “The Protein Data Bank.,” Nucleic acids research, vol. 28, no. 1, pp. 235–242, Jan. 2000
• J. Yang and Y. Zhang, “I-TASSER server: new development for protein structure and function predictions.,” Nucleic acids research., vol. 43, no. W1, pp. W174-81, Jul. 2015
• D. Xu and Y. Zhang, “Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization.,” Biophysical Journal, vol. 101, no. 10, pp. 2525–2534, Nov. 2011
• Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E, “UCSF Chimera—A visualization system for exploratory research and analysis,” Journal of computational chemistry, vol. 25, no. 13, pp. 1605–1612, 2004
• Y. Liu, X. Yang, J. Gan, S. Chen, Z.-X. Xiao, and Y. Cao, “CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting.,” Nucleic acids research, vol. 50, no. W1, pp. W159–W164, Jul. 2022
• D. Hanahan, “Rethinking the war on cancer.,” Lancet (London, England), vol. 383, no. 9916, pp. 558–563, Feb. 2014
• Aggarwal, B. B., Sethi, G., Ahn, K. S., Sandur, S. K., Pandey, M. K., Kunnumakkara, A. B., Sung, B., & Ichikawa, H., “Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution.,” Annals of the New York Academy of Sciences., vol. 1091, pp. 151–169, Dec. 2006
• Pandey, A., Vishnoi, K., Mahata, S., Tripathi, S. C., Misra, S. P., Misra, V., Mehrotra, R., Dwivedi, M., & Bharti, A. C, “Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil.,” Nutrition and cancer, vol. 67, no. 8, pp. 1293–1304, 2015
• Fetoni, A. R., Paciello, F., Mezzogori, D., Rolesi, R., Eramo, S. L., Paludetti, G., & Troiani, D.., “Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling.,” British journal of cancer, vol. 113, no. 10, pp. 1434–1444, Nov. 2015
• L. Wu, L. Guo, Y. Liang, X. Liu, L. Jiang, and L. Wang, “Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the JAK2/STAT3 signaling pathway.,” Oncology Reports., vol. 34, no. 6, pp. 3311–3317, Dec. 2015
• Roy, N. K., Bordoloi, D., Monisha, J., Padmavathi, G., Kotoky, J., Golla, R., & Kunnumakkara, A. B., “Specific Targeting of Akt Kinase Isoforms: Taking the Precise Path for Prevention and Treatment of Cancer.,” Current drug targets, vol. 18, no. 4, pp. 421–435, 2017
• F. Guan, Y. Ding, Y. Zhang, Y. Zhou, M. Li, and C. Wang, “Curcumin Suppresses Proliferation and Migration of MDA-MB-231 Breast Cancer Cells through Autophagy-Dependent Akt Degradation.,” PLoS One, vol. 11, no. 1, p. e0146553, 2016
• Jia, T., Zhang, L., Duan, Y., Zhang, M., Wang, G., Zhang, J., & Zhao, Z., “The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway.,” Cancer cell international., vol. 14, no. 1, p. 126, 2014
• M. Starok, P. Preira, M. Vayssade, K. Haupt, L. Salomé, and C. Rossi, “EGFR Inhibition by Curcumin in Cancer Cells: A Dual Mode of Action.,” Biomacromolecules, vol. 16, no. 5, pp. 1634–1642, May 2015
• Panyam, J., Dali, M. M., Sahoo, S. K., Ma, W., Chakravarthi, S. S., Amidon, G. L., Levy, R. J., & Labhasetwar, V, “Polymer degradation and in vitro release of a model protein from poly(D,L-lactide-co-glycolide) nano- and microparticles.,” Journal of controlled release : official journal of the Controlled Release Society, vol. 92, no. 1–2, pp. 173–187, Sep. 2003
• X.-D. Sun, X.-E. Liu, and D.-S. Huang, “Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression.,” Molecular Medicine Reports, vol. 6, no. 6, pp. 1267–1270, Dec. 2012
• T. J. Somers-Edgar, M. J. Scandlyn, E. C. Stuart, M. J. Le Nedelec, S. P. Valentine, and R. J. Rosengren, “The combination of epigallocatechin gallate and curcumin suppresses ERα-breast cancer cell growth in vitro and in vivo,” International Journal of Cancer, vol. 122, no. 9, pp. 1966–1971, 2008
• Zhang, B. Y., Shi, Y. Q., Chen, X., Dai, J., Jiang, Z. F., Li, N., & Zhang, Z. B, “Protective effect of curcumin against formaldehyde-induced genotoxicity in A549 Cell Lines.,” Journal of applied toxicology, vol. 33, no. 12, pp. 1468–1473, Dec. 2013
• H. Jin, F. Qiao, Y. Wang, Y. Xu, and Y. Shang, “Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathway,” Oncology Reports, vol. 34, no. 5, pp. 2782–2789, 2015
• Li, S., Fang, C., Zhang, J., Liu, B., Wei, Z., Fan, X., Sui, Z., & Tan, Q, “Catanionic lipid nanosystems improve pharmacokinetics and anti-lung cancer activity of curcumin.,” Nanomedicine, vol. 12, no. 6, pp. 1567–1579, Aug. 2016
• Y. Lu, C. Wei, and Z. Xi, “Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway,” In Vitro Cellular & Developmental Biology - Animal, vol. 50, no. 9, pp. 840–850, 2014
• Dance-Barnes, S. T., Kock, N. D., Moore, J. E., Lin, E. Y., Mosley, L. J., D'Agostino, R. B., Jr, McCoy, T. P., Townsend, A. J., & Miller, M. S, “Lung tumor promotion by curcumin,” Carcinogenesis, vol. 30, no. 6, pp. 1016–1023, 2009
• Q. Yao Jie and W. Xuejian, “Study on the mechanism of curcumin on the apoptosis and radiosensitivity of human chordoma cell line CM-319,” Chinese Journal of Orthopedics., vol. 41, no. 01, pp. 33–42, 2021
• F. Al-Ejeh, R. Kumar, A. Wiegmans, S. R. Lakhani, M. P. Brown, and K. K. Khanna, “Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes,” Oncogene, vol. 29, no. 46, pp. 6085–6098, 2010
• Barone, D., Cito, L., Tommonaro, G., Abate, A. A., Penon, D., De Prisco, R., Penon, A., Forte, I. M., Benedetti, E., Cimini, A., Indovina, P., Nicolaus, B., Pentimalli, F., & Giordano, A., “Antitumoral potential, antioxidant activity and carotenoid content of two Southern Italy tomato cultivars extracts: San Marzano and Corbarino.,” Journal of cellular physiology, vol. 233, no. 2, pp. 1266–1277, Feb. 2018
• S. Faderl, A. Ferrajoli, D. Harris, Q. Van, H. M. Kantarjian, and Z. Estrov, “Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cellsLeukemia Research, vol. 31, no. 1, pp. 91–95, 2007.
• M. Catanzaro, E. Corsini, M. Rosini, M. Racchi, and C. Lanni, “Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea.,” Molecules, vol. 23, no. 11, Oct. 2018
• K. Spiekermann, M. Pau, R. Schwab, K. Schmieja, S. Franzrahe, and W. Hiddemann, “Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells,” Experimental Hematology, vol. 30, no. 3, pp. 262–271, 2002