OKSİDATİF STRESE KARŞI 3,4-DHPEA'NIN KORUYUCU ETKİSİNİN MODÜLASYONUNDA PTEN'İN ROLÜ

Phosphate tensin homolog (PTEN) gen mutasyonuna sahip prostat kanseri (PCa) agresif hale gelebilir. Bu çalışmada, PCa hücre hatlarındaki PTEN mutasyonel durumunun, 3,4-dihydroxyphenyl ethanolün (3,4- DHPEA) kemopreventif etkisini değiştirebileceği ve böylece hücrelerin N,N,N′ ,N′ -Tetrakis(2- pyridylmethyl)ethylenediamine (TPEN) tarafından oluşturulan oksidatif stresi yönetme yeteneğini belirlediği hipotezi ileri sürülmüştür. Farklı PTEN statüsüne sahip DU-145 (PTEN +/−), 22Rv1 (PTEN +/+) ve PC3 (PTEN −/−) insan PCa hücre hatları 24 saat boyunca 100 µM'a kadar 3,4-DHPEA ve/veya 6,5 µM'a kadar TPEN ile muamele edildi. Muameleden sonra hücre canlılıkları Cell Titer-Glo Luminescent Assay ile ölçüldü ve varyans analizi testi ile analiz edildi. 50 μM kadar yüksek 3,4- DHPEA uygulaması 22Rv1 üzerinde en fazla sitotoksik etki gösterdi ve bunu DU-145 ve PC3 izledi. Benzer bir genel eğilim TPEN muamelesi ile de gözlemlendi. TPEN uygulamasnda IC50 değerleri 22Rv1 için 4.718 µM, DU145 için 4.963 μM ve PC3 için 5.245 μM idi. Hücrelerin IC50 dozunda TPEN ile birlikte 3,4-DHPEA ile muamelesi 3,4-DHPEA’nın yalnız uygulaması ile aynı şekilde sitotoksisite göstermiştir. 3,4-DHPEA'ya bağlı herhangi bir kemopreventif koruma etkisi gözlemlenmemiştir. Sonuçlar oksidatif stres oluşturan ajanların PTEN statüsüne bağlı oldukları hipotezi ile örtüşmektedir. Bu, wild tip PTEN içeren 22Rv1’in 3,4-DHPEA'ya karşı en büyük duyarlılığı göstermesi ile tutarlıdır.

ROLE OF PTEN IN MODULATING PREVENTIVE EFFECT OF 3,4-DHPEA AGAINST OXIDATIVE STRESS

Prostate cancer (PCa) with a Phosphate tensin homolog(PTEN) gene mutation can become aggressive. In thisstudy, it was hypothesized that the PTEN mutationalstatus in PCa cell lines might modify the chemopreventiveeffect of 3,4-dihydroxyphenyl ethanol (3,4-DHPEA),thus, determining the cells’ ability to manage oxidativestress created by N,N,N′ ,N′ -Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). The humanPCa cell lines with varying PTEN status, DU-145 (PTEN+/−), 22Rv1 (PTEN +/+), and PC3 (PTEN −/−), weretreated with up to 100 µM of 3,4-DHPEA and/or up to6.5 µM of TPEN for 24 hours. The viability of cells aftertreatment was measured with Cell Titer-Glo LuminescentAssay and analyzed with the analysis of variancetest. 3,4-DHPEA treatment as high as 50 µM had thegreatest cytotoxic effect on 22Rv1 followed by DU-145and PC3. Similar overall trend was also observed withTPEN treatment. When the cells were treated withTPEN at IC50 doses, 3,4-DHPEA co-treatment stillshowed cytotoxicity in the same order as 3,4-DHPEAtreatment alone. No chemoprotective effect due to 3,4-DHPEA was observed. The data is still consistent withthe hypothesis that oxidative stress inducing agents aredependent on the PTEN status. This is consistent with22Rv1 with wild type PTEN showing the greatest susceptibilityto 3,4-DHPEA.

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Cuzick J, Yang ZH, Fisher G. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer 2013; 108:2582-2589.
Schmitz M, Grignard G, Margue C. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer 2007; 120:1284-1292.
Carver BS, Chapinski C, Wongvipat J. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011; 19:575-586.
Selvaggini R, Servili M, Urbani S, et al. Evaluation of phenolic compounds in virgin olive oil by direct injection in high-performance liquid chromatography with fluorometric detection. J Agric Food Chem 2006; 54:2832–2838.
Cooke MS, Evans MD, Dizdaroglu M, et al. Oxidative DNA damage: mechanisms, mutation, and disease. Lancet J 2003; 17:1195–1214.
Facchini A, Cetrullo S, D’Adamo S, et al. Hydroxytyrosol Prevents Increase of Osteoarthritis Markers in Human Chondrocytes Treated with Hydrogen Peroxide or Growth-Related Oncogene. PLoS One, 2014; 9:e109724.
Warleta F, Quesada CS, Campos M, et al. Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients 2011; 3:839- 857.
Quiles JL, Farquharson AJ, Simpson DK, et al. Olive oil phenolics: effects on DNA oxidation and redox enzyme mRNA in prostate cells. Br J Nutr 2002; 28:225–234.
Young J, Wahle KWJ, Boyle SP. Cytoprotective effects of phenolic antioxidants and essential fatty acids in human blood monocyte and neuroblastoma cell lines: Surrogates for neurological damage in vivo, Prostaglandins, Leukotrienes. Essent Fatty Acids 2008; 78:45–59.
Adler M, Shafer H, Hamilton T, et al. Cytotoxic actions of the heavy metal chelator TPEN on NG108- 15 neuroblastoma-glioma cells. Neuro Toxicology 1999; 20:571-582.
Gmeiner WH, Boyacioglu O, Stuart CH, et al. The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn2+-chelation and inhibiting the serine protease Omi/HtrA2. Prostate 2014; 75:360-369.
Hashemi M, Ghavami S, Eshraghi M, et al. Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells. Eur J Pharmacol 2007; 557:9–19.
Makhov P, Golovine K, Uzzo RG, et al. Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Cell Death Differ 2008; 15:1745–1751.
Corniola RS, Tassabehji NM, Hare J, et al. Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Research C 2008; 1237:52–61.
Ra H, Kim HL, Lee HW, et al. Essential role of p53 in TPEN-induced neuronal apoptosis. FEBS Letters 2009; 583:1516–1520.
Kao GD, Jiang Z, Fernandes AM, et al. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 2007; 282:21206- 21212.
Rosignoli P, Fuccelli R, Sepporta MV, et al. In vitro chemo-preventive activities of hydroxytyrosol: the main phenolic compound present in extra-virgin olive oil. Food Funct 2016; 7:301-307.
Servili M, Esposto S, Fabiani R, et al. Phenolic compounds in olive oil: antioxidant, health and organoleptic activities according to their chemical structure. Inflammopharmacology 2009; 17:76– 84.
Niture SK, Velu CS, Smith QR, et al. Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemo-preventive natural products in human lymphocytes and tumor cell lines. Carcinogenesis 2007; 28:378–389.
Casaburi F, Puoci A, Chimento R, et al. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies, Mol Nutr Food Res 2013; 57:71–83.
Fabiani R, Fuccelli R, Pieravanti F, et al. Production of hydrogen peroxide is responsible for then induction of apoptosis on HL60 cells. Mol Nutr Food Res 2009; 53:887–896