The Role of Citrus Nobiletin on Oxidative Stress Levels and Superoxide Dismutase Activities in Metastatic Castration-Resistant Prostate Cancer

Yıl 2021, Cilt: 5 Sayı: 1, 84 - 89, 30.06.2021

Burcu Yüksel , Asuman Deveci Özkan

https://doi.org/10.31594/commagene.895415

Cited By: 6

Öz

Nobiletin (NOB) is a polymethoxylated flavone. It has multiple biologic activities that can modulate oxidative stress in many cancer types. However, there is no study in the literature that has examined the effects of NOB on oxidative stress levels in Metastatic Castration-Resistant Prostate Cancer (MCRPC) yet. Motivated from this gap, we investigated the impact of NOB on oxidative stress and superoxide dismutase (SOD) enzyme activities in MCRPC as a preliminary study. For this purpose, PC-3 and HUVEC cells were used to determine the effects of NOB on the amount of Malondialdehyde (MDA), hydrogen peroxide (H2O2), and proline as well as SOD enzyme activities. NOB potentially induced SOD enzyme activities but the level of MDA, H2O2, and proline decreased after incubation with NOB in PC-3 cells (p<.05 and p<.001 were considered statistically significant). Our results confirmed that NOB acted as a protective agent for cancer cells and could selectively regulate oxidant status in MCRPC cells. Consequently, these preliminary findings provide better insight into the role of citrus NOB on oxidative stress levels and antioxidant enzyme activities in MCRPC. Additionally, there is a need to elucidate the molecular mechanisms of this cytoprotective effect of NOB as a potential chemotherapeutic agent.

Anahtar Kelimeler

Antioxidant Effect;, Malondialdehyde;, Cancer;, Flavanoid;, Malondialdehyde;, Proline

Teşekkür

We would like to thank Dr. Ozlem AKSOY (Kocaeli University) for providing the lab facilities

Metastatik Kastrasyona Dirençli Prostat Kanserinde Narenciye Nobiletin'in Oksidatif Stres Düzeyleri ve Süperoksit Dismutaz Aktiviteleri Üzerindeki Rolü

Öz

Nobiletin (NOB) polimetoksile bir flavondur ve birçok kanser türünde oksidatif stresi modüle edebilen çok sayıda biyolojik aktiviteye sahiptir. Bununla birlikte, literatürde, MCRPC'de Metastatik Kastrasyona Dirençli Prostat Kanserinde (MCRPC) NOB'nin oksidatif stres seviyeleri üzerindeki etkilerine dair henüz bir çalışma bulunmamaktadır. Bu nedenle, ön çalışma olarak MCRPC'de NOB'nin oksidatif stres ve süperoksit dismutaz (SOD) enzim aktiviteleri üzerindeki etkilerini belirlemeyi amaçladık. Bu amaçla, çalışmada NOB'nin Malondialdehit (MDA), hidrojen peroksit (H2O2) ve prolin miktarı ile SOD enzim aktiviteleri üzerindeki etkilerini belirlemek için PC-3 ve HUVEC hücreleri kullanıldı. NOB’un potansiyel olarak SOD enzim aktivitelerini indüklediği, ancak PC-3 hücrelerinde NOB ile inkübasyondan sonra MDA, H2O2 ve prolin seviyesinin azaldığı tespit edildi (p<.05 ve p <.001 istatistiksel olarak anlamlı kabul edildi). Elde edilen veriler, NOB'nin kanser hücreleri için koruyucu bir ajan olarak hareket ettiğini ve MCRPC hücrelerinde oksidan durumunu seçici olarak düzenleyebildiğini doğruladı. Sonuç olarak, bu ön bulgular, MCRPC'de turunçgil NOB'nin oksidatif stres seviyeleri ve antioksidan enzim aktiviteleri üzerindeki rolü hakkında daha iyi fikir vermektedir. Ek olarak, potansiyel bir kemoterapötik ajan olarak NOB'nin bu sitoprotektif etkisinin moleküler mekanizmalarının aydınlatılmasına ihtiyaç vardır.

Anahtar Kelimeler

Antioksidan Etki;, Flavanoid;, Kanser;, Malondialdehyde;, Proline

Kaynakça

• Acharya, A., Das, I., Chandhok, D., & Saha, T. (2010). Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxidative medicine and cellular longevity, 3(1), 23-34. https://doi.org/10.4161/oxim.3.1.10095
• Amaral, T.M.S., Macedo, D., Fernandes, I., & Costa, L. (2012). Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate cancer, 2012, 1-11. https://doi.org/10.1155/2012/327253
• Ananieva, E.A., Alexieva, V.S., & Popova, L.P. (2002). Treatment with salicylic acid decreases the effects of paraquat on photosynthesis. Journal of Plant Physiology, 159(7), 685-693. https://doi.org/10.1078/0176-1617-0706
• Beauchamp, C., & Fridovich, I. (1971). Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Analytical Biochemistry, 44(1), 276-287. https://doi.org/10.1016/0003-2697(71)90370-8
• Bernini, R., Crisante, F., & Ginnasi, M.C. (2011). A convenient and safe O-methylation of flavonoids with dimethyl carbonate (DMC). Molecules, 16(2), 1418-1425. https://doi.org/10.3390/molecules16021418
• Cho, H. W., Jung, S. Y., Lee, G. H., Cho, J. H., & Choi, I. Y. (2015). Neuroprotective effect of Citrus unshiu immature peel and nobiletin inhibiting hydrogen peroxide-induced oxidative stress in HT22 murine hippocampal neuronal cells. Pharmacognosy Magazine, 11(2), 284. https://dx.doi.org/10.4103%2F0973-1296.166047
• Cooke, M.S., Evans, M.D., Dizdaroglu, M., & Lunec, J. (2003). Oxidative DNA damage: mechanisms, mutation, and disease. The FASEB Journal, 17(10), 1195-1214. https://doi.org/10.1096/fj.02-0752rev
• Cooke, M.S., Evans, M.D., Herbert, K.E., & Lunec, J. (2000). Urinary 8-oxo-2′-deoxyguanosine—source, significance and supplements. Free radical research, 32(5), 381-397.7. https://doi.org/10.1080/10715760000300391
• Deveci Ozkan, A., Kaleli, S., Onen, H.I., Sarihan, M., Guney Eskiler, G., Kalayci Yigin, A., & Akdogan, M. (2020). Anti-inflammatory effects of nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in prostate cancer cells. Immunopharmacology and immunotoxicology, 42(2), 93-100. https://doi.org/10.1080/08923973.2020.1725040
• DeWeese, T.L., Hruszkewycz, A.M., & Marnett, L.J. (2001). Oxidative stress in chemoprevention trials. Urology, 57(4), 137-140. https://doi.org/10.1016/S0090-4295(00)00959-6
• Dusabimana, T., Kim, S.R., Kim, H.J., Park, S.W., & Kim, H. (2019). Nobiletin ameliorates hepatic ischemia and reperfusion injury through the activation of SIRT-1/FOXO3a-mediated autophagy and mitochondrial biogenesis. Experimental & molecular medicine, 51(4), 1-16. https://doi.org/10.1038/s12276-019-0245-z
• Gates, M.A., Vitonis, A.F., Tworoger, S.S., Rosner, B., Titus‐Ernstoff, L., & Hankinson, S.E. (2009). Flavonoid intake and ovarian cancer risk in a population‐based case‐control study. International journal of cancer, 124(8), 1918-1925. https://doi.org/10.1002/ijc.24151
• Goh, J. X. H., Tan, L. T. H., Goh, J. K., Chan, K. G., Pusparajah, P., Lee, L. H., & Goh, B. H. (2019). Nobiletin and derivatives: Functional compounds from citrus fruit peel for colon cancer chemoprevention. Cancers, 11(6), 867. https://doi.org/10.3390/cancers11060867
• Güney Eskiler, G., Özkan, A.D., & Kaleli, S. (2018). Metastatik prostat kanserinde nobiletinin sitotoksik ve apoptotik etkisinin belirlenmesi. Sakarya Tıp Dergisi, 8(4), 766-774. https://doi.org/10.31832/smj.485666
• He, W. T., Wan, H., Hu, L., Chen, P., Wang, X., Huang, Z., & Han, J. (2015). Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell research, 25(12), 1285-1298. https://doi.org/10.1038/cr.2015.139
• Huang, H., Li, L., Shi, W., Liu, H., Yang, J., Yuan, X., & Wu, L. (2016). The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evidence-Based Complementary and Alternative Medicine, 2016. https://doi.org/10.1155/2016/2918796
• Huynh, T.Y.L., Zareba, I., Baszanowska, W., Lewoniewska, S., & Palka, J. (2020). Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy. Molecular and cellular biochemistry, 466(1), 35-44. https://doi.org/10.1007/s11010-020-03685-y
• Jana, S., & Choudhuri, M.A. (1981). Glycolate metabolism of three submersed aquatic angiosperms: effect of heavy metals. Aquatic Botany, 11, 67-77. https://doi.org/10.1016/0304-3770(81)90047-4
• Kawabata, K., Murakami, A., & Ohigashi, H. (2005). Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells. Bioscience, biotechnology, and biochemistry, 69(2), 307-314. https://doi.org/10.1271/bbb.69.307
• Kunimasa, K., Ikekita, M., Sato, M., Ohta, T., Yamori, Y., Ikeda, M., & Oikawa, T. (2010). Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis‐related endothelial cell functions and angiogenesis in vivo. Cancer science, 101(11), 2462-2469. https://doi.org/10.1111/j.1349-7006.2010.01668.x
• Lee, Y.S., Cha, B.Y., Choi, S.S., Choi, B.K., Yonezawa, T., Teruya, T., & Woo, J.T. (2013). Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. The Journal of nutritional biochemistry, 24(1), 156-162. https://doi.org/10.1016/j.jnutbio.2012.03.014
• Liu, F., Zhang, H., Li, Y., & Lu, X. (2019). Nobiletin suppresses oxidative stress and apoptosis in H9c2 cardiomyocytes following hypoxia/reoxygenation injury. European journal of pharmacology, 854, 48-53. https://doi.org/10.1016/j.ejphar.2019.03.056
• Lu, Y.H., Su, M.Y., Huang, H.Y., & Yuan, C.G. (2010). Protective effects of the citrus flavanones to PC12 cells against cytotoxicity induced by hydrogen peroxide. Neuroscience Letters, 484(1), 6-11. https://doi.org/10.1016/j.neulet.2010.07.078
• Luo, G., Guan, X., & Zhou, L. (2008). Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer biology & therapy, 7(6), 966-973. https://doi.org/10.4161/cbt.7.6.5967
• Ma, Q. (2010). Transcriptional responses to oxidative stress: pathological and toxicological implications. Pharmacology & therapeutics, 125(3), 376-393. https://doi.org/10.1016/j.pharmthera.2009.11.004
• Malik, S., Bhatia, J., Suchal, K., Gamad, N., Dinda, A. K., Gupta, Y. K., & Arya, D. S. (2015). Nobiletin ameliorates cisplatin-induced acute kidney injury due to its antioxidant, anti-inflammatory and anti-apoptotic effects. Experimental and Toxicologic Pathology, 67(7-8), 427-433. https://doi.org/10.1016/j.etp.2015.04.008
• Meng, H.Z., Ni, X.F., Yu, H.N., Wang, S.S., & Shen, S.R. (2017). Effects of astaxanthin on oxidative stress induced by Cu 2+ in prostate cells. Journal of Zhejiang University-SCIENCE B, 18(2), 161-171. https://doi.org/10.1631/jzus.B1500296
• Morley, K.L., Ferguson, P.J., & Koropatnick, J. (2007). Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer letters, 251(1), 168-178. https://doi.org/10.1016/j.canlet.2006.11.016
• Myara, I., Charpentier, C., & Lemonnier, A. (1982). Optimal conditions for prolidase assay by proline colorimetric determination: application to iminodipeptiduria. Clinica Chimica Acta, 125(2), 193-205. https://doi.org/10.1016/0009-8981(82)90196-6
• Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical biochemistry, 95(2), 351-358. https://doi.org/10.1016/0003-2697(79)90738-3
• Park, M. H., & Hong, J. T. (2016). Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells, 5(2), 15. https://doi.org/10.3390/cells5020015
• Phang, J.M., & Liu, W. (2012). Proline metabolism and cancer. Frontiers in bioscience (Landmark edition), 17, 1835-1845. https://dx.doi.org/10.2741/4022
• Phang, J.M., Liu, W., Hancock, C.N., & Fischer, J.W. (2015). Proline metabolism and cancer: emerging links to glutamine and collagen. Current opinion in clinical nutrition and metabolic care, 18(1), 71-77. https://dx.doi.org/10.1097%2FMCO.0000000000000121
• Phang, J.M. (2019). Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses. Antioxidants & redox signaling, 30(4), 635-649. https://doi.org/10.1089/ars.2017.7350
• Shen, M.M., & Abate-Shen, C. (2010). Molecular genetics of prostate cancer: new prospects for old challenges. Genes & development, 24(18), 1967-2000. https://doi.org/10.1101/gad.1965810
• Surichan, S., Arroo, R.R., Ruparelia, K., Tsatsakis, A.M., & Androutsopoulos, V.P. (2018). Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes. Food and Chemical Toxicology, 113, 228-235. https://doi.org/10.1016/j.fct.2018.01.047
• Wagner, B.A., Evig, C.B., Reszka, K.J., Buettner, G.R., & Burns, C.P. (2005). Doxorubicin increases intracellular hydrogen peroxide in PC3 prostate cancer cells. Archives of biochemistry and biophysics, 440(2), 181-190. https://doi.org/10.1016/j.abb.2005.06.015
• Xiao, J., Capanoglu, E., Jassbi, A.R., & Miron, A. (2016). Advance on the flavonoid C-glycosides and health benefits. Critical Reviews in Food Science and Nutrition, 56(sup1), S29-S45. https://doi.org/10.1080/10408398.2015.1067595
• Xiong, Y., Chen, D., Yu, C., Lv, B., Peng, J., Wang, J., & Lin, Y. (2015). Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function. Molecular nutrition & food research, 59(5), 829-842. https://doi.org/10.1002/mnfr.201400614
• Zhang, R., Chen, J., Mao, L., Guo, Y., Hao, Y., Deng, Y., & Yuan, M. (2020). Nobiletin triggers reactive oxygen species-mediated pyroptosis through regulating autophagy in ovarian cancer cells. Journal of agricultural and food chemistry, 68(5), 1326-1336. https://doi.org/10.1021/acs.jafc.9b07908
• Zheng, G.D., Hu, P.J., Chao, Y.X., Zhou, Y., Yang, X.J., Chen, B.Z., & Cai, Y. (2019). Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666‐1 cells through regulating PARP‐2/SIRT 1/AMPK signaling pathway. Food science & nutrition, 7(3), 1104-1112. https://doi.org/10.1002/fsn3.953
• Zhou, J.F., Xiao, W.Q., Zheng, Y.C., Dong, J., & Zhang, S.M. (2006). Increased oxidative stress and oxidative damage associated with chronic bacterial prostatitis. Asian journal of andrology, 8(3), 317-323. https://doi.org/10.1111/j.1745-7262.2006.00144.x