Metastatik Prostat Kanserinde Nobiletinin Sitotoksik ve Apoptotik Etkisinin Belirlenmesi

Year 2018, Volume: 8 Issue: 4, 766 - 774, 30.12.2018

Gamze Güney Eskiler , Asuman Deveci Özkan , Süleyman Kaleli

https://doi.org/10.31832/smj.485666

Cited By: 4

Abstract

Amaç: Nobiletin, C₂₁H₂₂O₈
kimyasal formülü ve 402.39 kD molekül ağırlığına sahip, turunçgil kabuklarında
bulunan bir O-metillenmiş flavanoiddir. Nobiletinin sahip olduğu antikanser,
antiviral ve anti-inflamatuar etkilerden dolayı, kanser tedavisinde potansiyel terapötik
bir ajan olarak dikkat çekmektedir. Prostat kanserinde metastaza neden olan
kanser hücrelerinin invaziv özelliğinin yüksek olması, hastalığın tedavisini
zorlaştırmakta ve hastalarda kötü prognoza neden olan en önemli faktörlerden
birisidir. Bu nedenle mevcut çalışmada, nobiletinin yüksek metastatik
potansiyeli olan insan prostat kanseri (PC-3) ve insan göbek kordonu veni
endotel hücrelerinde  (HUVEC) sitotoksik
ve apoptotik etkilerinin belirlenmesi amaçlanmıştır.

Gereç ve Yöntemler: Mevcut çalışmada, PC-3 ve HUVEC hücrelerinde nobiletinin sitotoksik etkisi
WST-1 analizi ile, apoptotik etkisi ise Annexin V, akridin oranj boyaması ve
hücre siklusu analizleri ile kalitatif ve kantitatif olarak belirlenmiştir.

Bulgular: WST-1 analizi ile elde edilen bulgulara göre, 24 ve 48 saat boyunca farklı
konsantrasyonlarda nobiletin uygulanan PC-3 hücrelerinde canlılık oranının
anlamlı bir şekilde azaldığı belirlenmiştir. Annexin V ve hücre siklusu
analizleri ile elde edilen verilere göre, nobiletinin PC-3 hücrelerinde
özellikle erken apoptoza ve G0/G1 fazında artışa neden olduğu belirlenmiştir.
Ayrıca, HUVEC hücrelerinde 80 µM konsantrasyona kadar toksik etkisinin olmadığı
belirlenmiştir.

Sonuç: Kontrol
hücreleri ile karşılaştırmalı olarak nobiletinin metastatik prostat kanseri
hücrelerinde anti-proliferatif etkisinin, erken apoptoz ve G0/G1 fazında hücre
miktarında artış ile gerçekleştiği gösterilmiştir. Ancak, nobiletinin
metastatik prostat kanserinde neden olduğu apoptotik ölümün moleküler
mekanizmasının in vitro ve in vivo olarak detaylı araştırılması
gerekmektedir.

Keywords

Prostat kanseri, Flavonoidler, Nobiletin, Apoptoz

References

• 1. Siegel R, Ma J, Zou Z., Jemal A. Cancer. Statistics, 2014. CA: CA Cancer J Clin. 2014;64(1):9–29.
• 2. Williamson SC, Hartley AE, Heer R. A review of tasquinimod in the treatment of advanced prostate cancer. Drug Des Dev Ther 2013;7:167–174.
• 3. Amaral TMS, Macedo D. Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate cancer 2012;2012:11.
• 4. Hori S, Butler E, McLoughlin J. Prostate cancer and diet: food for thought? BJU Int 2011;107(9):1348-1359.
• 5. Meiyanto E, Hermawan A, Anindyajati. Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev 2012;13:427–436.
• 6. Yang C, Wang X, Lu G, Picinich S. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 2009;9:429–439.
• 7. McCann S, Freudenheim J, Marshall J, Saxon G. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nut 2003;133:1937–1942.
• 8. Wu X, Song M, Qiu P, Rakariyatham K, Li F, Gao Z, Cai X, Wang M, Xu F, Zheng J, Xiao H. Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis. Carcinogenesis 2017;38(4):455-464.
• 9. Gates M, Vitonis A, Tworoger S, Rosner B, Titus-Ernstoff L, Hankinson S, Cramer H. Flavonoid intake and ovarian cancer risk in a population based case-control study. Int J Cancer 2009;124:1918–1925.
• 10. Bernini R, Crisante F, Ginnasi MC. A convenient and safe O-methylation offlavonoids with dimethyl carbonate (DMC). Molecules 2011;16:1418–1425.
• 11. Knekt P, Järvinen R, Seppänen R, Heliövaara M, Teppo L, Pukkala E, Aromaa A. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol 1997;146:223–230.
• 12. Li S, Yu H, Ho CT. Nobiletin: efficient and large quantity isolation from orange peel extract. Biomed Chromatogr 2006;20:133–138.
• 13. Kunimasa K, Ikekita M, Sato M, Ohta T, Yamori Y, Ikeda M, Kuranuki S, Oikawa T. Nobiletin, a citrus polymethoxy flavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo. Cancer Sci 2010;101:2462–2469.
• 14. Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K, Kuwahara S, Takahashi Y, Ogawa K, Yano M, Tokuda H, Nishino H, Mimaki Y, Sashida Y, Kitanaka S, Ohigashi H. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 2000;60:5059–5066.
• 15. Kim SJ, Uehara H, Yazici S, Langley RR, He J, Tsan R, Fan D, Killion JJ, Fidler IJ. Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice. Cancer Res 2004;64:4201–4208.
• 16. Kim SJ, Johnson M, Koterba K, Herynk MH, Uehara H, Gallick GE. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin Cancer Res 2003;9:5161–5170.
• 17. Pulukuri SM, Gondi CS, Lakka SS, Jutla A, Estes N, Gujrati M, Rao JS. RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo. J Bio Chem 2005;280:36529–36540.
• 18. Sp N, Kang DY, Joung YH, Park JH, Kim WS, Lee HK, Song KD, Park YM, Yang YM. Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells. Int J Mol Sci 2017;18(5):E935.
• 19. Jiang YP, Guo H, Wang XB. Nobiletin (NOB) suppresses autophagic degradation via over-expressing AKT pathway and enhances apoptosis in multidrug-resistant SKOV3/TAX ovarian cancer cells. Biomed Pharmacother 2018;103:29-37.
• 20. Silva I, Estrada MF, V Pereira C, Silva AB, Bronze MR, Alves PM, Duarte CMM, Brito C, Serra AT. Polymethoxylated Flavones from Orange Peels Inhibit Cell Proliferation in a 3D Cell Model of Human Colorectal Cancer. Nutr Cancer 2018;70(2):257-266.
• 21. Manthey JA, Guthrie N, Grohman K. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem 2001;8(2):135-153.
• 22. Chen C, Ono M, Takeshima M, Nakano S. Antiproliferative and apoptosis-inducing activity of nobiletin against three subtypes of human breast cancer cell lines. Anticancer Res 2014;34(4):1785-1792.
• 23. Chen J, Chen AY, Huang H, Ye X, Rollyson WD, Perry HE, Chen YC. The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway. Int J Oncol 2015;46(6):2629-2638.
• 24. Yoshimizu N, Otani Y, Saikawa Y, Kubota T, Yoshida M, Furukawa T, Sato T. Anti‐tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol Ther 2004;20:95-101.
• 25. Huang H, Li L, Shi W, Liu H, Yang J, Yuan X, Wu L. The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. J Evid Based Complementary Altern Med 2016.
• 26. Niu FW, Zhang YJ, Li K, Zhang MS. Nobiletin acts as a potential anticancer agent against osteosarcoma by regulating ERK and AKT signaling pathways. Bangladesh J Pharmacol 2014;9(3):406-412.
• 27. Shi MD, Liao YC, Shih YW, Tsai LY. Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF treated liver cancer HepG2 cells. Phytomedicine 2013; 20: 743-52.
• 28. Chen J, Creed A, Chen AY, Huang H, Li, Z, Rankin GO, Chen YC. Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells. BMC Pharmacol Toxicol 2014;15(1): 59.
• 29. Tang M, Ogawa K, Asamoto M, Hokaiwado N, Seeni A, Suzuki S, Shirai T. Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer SCI 2007;98(4): 471-477.
• 30. Kastan MB, Artek, J. Cell-cycle checkpoints and cancer. Nature 2004;432(7015): 316.
• 31. Funk JO. Cell cycle checkpoint genes and cancer. e LS, 2011.