Asuman DEVECİ ÖZKAN, Ayten HACIEFENDİ, Fatih ÖZKAN, Gamze Güney ESKİLER, Süleyman KALELİ, Ecir Ali ÇAKMAK, Özge TURNA

Traf2 ve Nck Etkileşimli Protein Kinaz (TNIK) Inhibitörünün Metastatik Köpek Meme Tümör Hücrelerinde Apoptotik Etkisinin Belirlenmesi

ÖZAmaç: Köpek meme tümörleri (KMT) dişi köpeklerde en sık görülen tümörlerdir ve kullanılan başlıca tedavi seçeneği olarak cerrahi ciddi komplikasyonlara neden olmaktadır. Bu nedenle KMT için yeni tedavi seçeneklerine ihtiyaç duyulmaktadır. Traf2 ve Nck ile etkileşime giren serin protein kinaz (TNIK) WNT hedef genlerinin transkripsiyonel bir düzenleyicisidir ve meme kanseri gelişiminde yüksek oranda eksprese edilmektedir. TNIK'in inhibisyonu, anormal WNT sinyali olan kanserlerde yeni bir terapötik hedef olabilir. Bu nedenle, bu çalışmada NCB-0846'nın metastatik sarkom KMT alt tipi üzerindeki potansiyel terapötik etkisini ilk kez araştırılması amaçlanmıştır. Materyal ve Metot: NCB-0846'nın KMT hücreleri üzerindeki sitotoksik ve apoptotik etkileri, WST‑1, Annexin V, hücre döngüsü, akridin oranj (AO) ve DAPI boyama ile analiz edilmiştir. Bulgular: Elde edilen verilere göre NCB-0846, doza ve zamana bağlı anlamlı bir şekilde KMT hücre canlılığını azaltmış ve nükleer hasara sebep olmuştur. Ayrıca, NCB-0846, G0/G1 fazında hücrelerin birikmesi yoluyla apoptotik hücre ölümünü indüklemiştir. Sonuç: Sonuç olarak elde ettiğimiz bulgular, NCB-0846'nın potansiyel olarak KMT için yeni bir terapötik anti-kanser ajan olabileceğini göstermektedir. Bununla birlikte KMT hücreleri üzerinde NCB-0846’nın TNIK ve Wnt sinyalinin inhibe edici aktivitesinin aydınlatılmasına yönelik daha ileri araştırmalara ihtiyaç duyulmaktadır.

Anahtar Kelimeler:

Köpek meme tümörleri, apoptoz, TNIK inhibitörü

Determination of the Apoptotic Effect of Raf2 and Nck-Interacting Protein Kinase Inhibitor on Metastatic Canine Mammary Gland Tumor Cells

Objective: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs and the main treatment options used in CMGTs are surgery caused some complications. Therefore, new treatment options are needed for the CMGTs. Traf2 and Nck-interacting serine protein kinase (TNIK) as a transcriptional coregulator of Wnt targeted genes is highly expressed in breast cancer development. The inhibition of TNIK may be a new therapeutic target in cancers with abnormal WNT signaling. Therefore we aimed to investigate the potential therapeutic effect of NCB-0846 on metastatic sarcoma CMGTs subtype, for the first time. Materials and Methods: The cytotoxic and apoptotic effects of NCB-0846 on CMGT cells were analyzed by WST‑1, Annexin V, cell cycle, acridine orange (AO) and DAPI staining. Results: NCB-0846 significantly inhibited cell viability in a dose and time dependent manner (p<0.05) and induced nuclear damage in CMGT cells. Furthermore, NCB-0846 caused apoptotic cell death through the accumulation of cells in the G0/G1 phase. Conclusion: Our findings demonstrated that NCB-0846 could be potentially a new therapeutic anti-cancer agent in the treatment of CMGTs. However, further investigations need to be performed in order to elucidate the inhibitory activity of TNIK and Wnt signaling by NCB-0846 on CMGT cells.

Keywords:

Canine mammary gland tumor cells, apoptosis, TNIK inhibitor,

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