Olivetol’ ün SHSY-5Y Nöroblastoma Hücrelerinin Proliferasyonu ve İnvazyonu Üzerindeki İnhibe Edici Etkileri

Amaç: Likenlerde bulunan ve fenolik yapılı doğal bir bileşik olan olivetol, antioksidan ve antikolinerjik etkisi ile bilinmektedir. Ancak olivetol’ ün kanser hücreleri üzerindeki etkinliği henüz bilinmemektedir. Biz bu çalışmada olivetol’ ün nöroblastoma hücrelerinin proliferasyonu ve invazyonu üzerindeki etkilerini inceledik. Materyal ve Metot: Bu çalışmada insan nöroblastoma SHSY-5Y hücre hattı kullanıldı. Olivetol deney gruplarına 50 ve 100µM dozlarında uygulandı. Hücre proliferasyon analizi eş zamanlı hücre sayım sistemi xCelligence ile yapıldı. Matriks metaloproteinaz (MMP2 ve MMP9) ekspresyonları RT-PCR ile analiz edildi. Olivetol’ ün invazyon üzerindeki etkisi transwell matrijel deneyi ile yapıldı. Bulgular: Olivetol’ ün insan nöroblastoma SHSY-5Y hücre proliferasyonunu inhibe ettiği tespit edildi. Olivetol’ün 100 µM’ı hücreleri 72 saat sonunda neredeyse tamamen öldürdüğü belirlendi. Olivetol’ün MMP2 ve MMP9 ekspresyonlarını doza bağlı olarak azalttığı görüldü. İnvazyon sonuçlarına bakıldığında, olivetol’ ün SHSY-5Y invazyonunu inhibe ettiği tespit edildi. Sonuç: Bu sonuçlar, olivetol’ ün nöroblastoma hücrelerinin proliferasyonunu baskıladığını göstermektedir. Olivetol, MMP2 ve MMP9 üzerindeki inhibe edici etkisinden dolayı, SHSY-5Y hücrelerinin invazyonunu önlemek için kullanılabilir. Olivetol‘ ün matriks metaloproteinaz seviyelerini baskılaması sebebiyle, nöroblastoma tedavisinde alternatif bir aday olabileceği düşünülebilir.

Anahtar Kelimeler:

Olivetol, Hücre Proliferasyonu, Nöroblastoma ve Matriks Metaloproteinaz

The Inhibitory Effects of Olivetol on Cell Proliferation and Invasion of SHSY-5Y Neuroblastoma Cells

Aim: Olivetol, is a phenolic compound found in certain species of lichen, is known with it’s anti-oxidant and anti-cholinergic effects. However, the functions of olivetol in cancer cell have not been investigated yet. We evaluated the effects of olivetol on the cell proliferation and invasion of human neuroblastoma cells. Material and Method: Human neuroblastoma SHSY-5Y cell line was used in this study. Olivetol was administered to groups at the doses of 50 and 100µM. Cell proliferation was analyzed by real time cell analyzer xCelligence. The expressions of matrix metalloproteinase (MMP2 and MMP9) were assessed by RT-PCR. Effects of olivetol on invasion were determined by transwell matrigel assays. Results: It was investigated that olivetol inhibited human neuroblastoma SHSY-5Y cell proliferation. High dose of olivetol (100µM) almost killed the total cells at the end of the 72 hours. It was also seen that olivetol decreased MMP2 and MMP9 gene expressions of neuroblastoma cells in dose dependent manner. Looking at the invasion results, it was determined that olivetol treatment inhibited the invasion of SHSY-5Y cells. Conclusion: This results showed that olivetol inhibits of neuroblastoma cell proliferations. Olivetol can be used to prevent invasion of SHSY-5Y cells, due to its inhibitory effect on MMP2 and MMP9. Olivetol can be considered as an alternative candidate in the treatment of neuroblastoma, as it suppresses matrix metalloproteinase levels.

Keywords:

Olivetol, Cell Proliferation, Neuroblastoma and Matrix Metalloproteinase,

PDF

___

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63(1):11-30.
2. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet 2007;369(9579):2106-2120.
3. Lee S, Qiao J, Paul P, Chung DH. Integrin beta1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion. Surgery 2013;154(2):369-75.
4. Beierle EA, Ma X, Stewart J, Nyberg C, Trujillo A, Cance WG et al. Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma. Cell Cycle 2010;9(5):1005-15.
5. Hayashi M, Okabe K, Kato K, Okumura M, Fukui R, Fukushima N et al. Differential function of lysophosphatidic acid receptors in cell proliferation and migration of neuroblastoma cells. Cancer Lett 2012;316(1):91-6.
6. Solarova Z, Liskova A, Samec M, Kubatka P, Busselberg D, Solar P. Anticancer Potential of Lichens' Secondary Metabolites. Biomolecules 2020;10(1).
7. Muller AG, Sarker SD, Saleem IY, Hutcheon GA. Delivery of natural phenolic compounds for the potential treatment of lung cancer. Daru 2019;27(1):433-49.
8. Oettl SK, Gerstmeier J, Khan SY, Wiechmann K, Bauer J, Atanasov AG et al. Imbricaric acid and perlatolic acid: multi-targeting anti-inflammatory depsides from Cetrelia monachorum. PLoS One 2013;8(10):e76929.
9. Attygalle AB, Siegel B, Vostrowsky O, Bestmann HJ, Maschwitz U. Chemical composition and function of metapleural gland secretion of the ant,Crematogaster deformis smith (hymenoptera: Myrmicinae). J Chem Ecol 1989;15(1):317-28.
10. Taura F, Tanaka S, Taguchi C, Fukamizu T, Tanaka H, Shoyama Y et al. Characterization of olivetol synthase, a polyketide synthase putatively involved in cannabinoid biosynthetic pathway. FEBS Lett 2009;583(12):2061-6.
11. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag 2008;4(1):245-59.
12. Keating GM. Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex((R))): A Review in Multiple Sclerosis-Related Spasticity. Drugs 2017;77(5):563-74.
13. Velasco G, Sanchez C, Guzman M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 2012;12(6):436-44.
14. Abrams DIGuzman M. Can Cannabis Cure Cancer? JAMA Oncol 2020.
15. Livak KJSchmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25(4): 402-8.
16. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3(3):203-16.
17. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 1999;341(16):1165-73.
18. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 2009;27(2):298-303.
19. Steeg PSTheodorescu D. Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 2008;5(4):206-19.
20. Wittekind CNeid M. Cancer invasion and metastasis. Oncology 2005;69Suppl 1:14-6.
21. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141(1):52-67.
22. Calabriso N, Massaro M, Scoditti E, Pellegrino M, Ingrosso I, Giovinazzo G et al. Red Grape Skin Polyphenols Blunt Matrix Metalloproteinase-2 and -9 Activity and Expression in Cell Models of Vascular Inflammation: Protective Role in Degenerative and Inflammatory Diseases. Molecules 2016;21(9).
23. Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis. Int J Mol Sci 2016;17(6).
24. Tonn JC, Kerkau S, Hanke A, Bouterfa H, Mueller JG, Wagner S et al. Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer 1999;80(5):764-72.
25. Radisky ES, Raeeszadeh-Sarmazdeh M, Radisky DC. Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer. J Cell Biochem 2017;118(11):3531-48.
26. Winer A, Adams S, Mignatti P. Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol Cancer Ther 2018;17(6):1147-55.
27. Amawi H, Ashby CR, Samuel T, Peraman R, Tiwari AK. Polyphenolic Nutrients in Cancer Chemoprevention and Metastasis: Role of the Epithelial-to-Mesenchymal (EMT) Pathway. Nutrients 2017;9(8).
28. Tsao SM, Hsia TC, Yin MC. Protocatechuic acid inhibits lung cancer cells by modulating FAK, MAPK, and NF-kappaB pathways. Nutr Cancer 2014; 66(8):1331-41.
29. Yang GW, Jiang JS, Lu WQ. Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis. Int J Mol Sci 2015;16(10):24011-31.
30. Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 1995;22(4):375-83.
31. Taslimi P, Gülçin I. Antioxidant and anticholinergic properties of olivetol. Journal of Food Biochemistry 2018;42(3):e12516.
32. Anantharaju PG, Gowda PC, Vimalambike MG, Madhunapantula SV. An overview on the role of dietary phenolics for the treatment of cancers. Nutr J 2016;15(1):99.
33. Duthie GG, Duthie SJ, Kyle JA. Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants. Nutr Res Rev 2000;13(1):79-106.
34. de Oliveira CB, Comunello LN, Maciel ES, Giubel SR, Bruno AN, Chiela EC et al. The inhibitory effects of phenolic and terpenoid compounds from Baccharis trimera in Siha cells: differences in their activity and mechanism of action. Molecules 2013;18(9):11022-32.
35. Lee YJ, Liao PH, Chen WK, Yang CY. Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells. Cancer Lett 2000; 153(1-2):51-6.