KORDOMA HÜCRELERİNDE STAT3 VE IL-6 RESEPTÖRÜNÜN GÜÇLÜ İNHİBİTÖRLERİ OLARAK KURKUMİN VE ATİPRİMODUN SİNERJİK ETKİSİ

Abstract

Kordoma, lokal invazyon ve metastaz potansiyelinin yanı sıra yüksek nüks oranı ve ilaç direnci ile karakterize, nadir görülen bir kemik tümörüdür. Notokord kalıntılarından kaynaklanan düşük dereceli aksiyal iskelet karsinomudur. Kordoma patogenez mekanizmalarının altında yatan moleküler yolaklar kısmen aydınlatılmış olmakla birlikte tedavideki başarı oranı henüz çözülmemiştir. Yapısal olarak aktif STAT3 ve kısmen aktif STAT5, anti-tümör bağışıklığını baskılayarak tümör hücrelerinin çoğalmasının, hayatta kalmasının ve saldırganlığının artmasına neden olur. STAT3'ün kalıcı aktivasyonu, tümörü teşvik eden inflamasyona aracılık eder. STAT3, nükleer faktör-κB (NFκB), interlökin-6 (IL-6), ve Janus kinaz (JAK) yolakları dahil olmak üzere pro-onkojenik inflamatuar yolakları düzenler. Sonuç olarak IL6R ve STAT3, kanser tedavisi için inflamasyonun yeniden yönlendirilmesi açısından umut verici bir hedeftir. Bu çalışmada, moleküler yerleştirme analizleri sonucunda kordoma hücre hatlarına kurkumin ve atiprimod ajanları kombinasyon halinde uygulanmıştır. İki ajanın tedavisi için bağlanma etkinliği olumlu, bu kombine uygulamanın sinerjistik antikanser etkilerinin olduğu bulunmuştur. Moleküler yerleştirme ve in vitro sonuçlar, IL-6R ve Stat3 ortak inhibisyonunun kordoma hücreleri üzerinde öldürücü etkileri olduğu fikrini desteklemektedir.

Keywords

• IL-6R
• Atiprimod
• Kurkumin
• Moleküler Yerleştirme
• Kordoma

SYNERGISTIC EFFECT OF CURCUMIN AND ATIPRIMOD AS POTENT INHIBITORS OF STAT3 AND IL-6 RECEPTOR IN CHORDOMA CELLS

Abstract

Chordoma, is a rare bone tumor, which is characterized by a high recurrence rate and drug resistance in addition to its potential for local invasion, and metastasis. It is a low-grade axial skeletal carcinoma derived from notochord remnants. Molecular pathways that underlie the mechanisms of chordoma pathogenesis are partially elucidated, however, the rate of success in treatment remains to be solved. Constitutively active STAT3 and partially active STAT5 suppress anti-tumor immunity, resulting in increased proliferation, survival and aggressiveness of tumor cells. Persistent activation of STAT3 mediates tumor-promoting inflammation. STAT3 upregulates pro-oncogenic inflammatory pathways, including nuclear factor-κB (NFκB), interleukin-6 (IL-6), and Janus kinase (JAK) pathways. In conclusion, IL6R and STAT3 are promising targets for rerouting inflammation for cancer therapy. In this study, curcumin and atiprimod agents were applied to chordoma cell lines in combination based on molecular docking analyses. The binding efficacy was found favorable for the treatment with two agents and synergistic anti-cancer effects of this combined application were detected on chordoma cells. Molecular docking analyses together with the in vitro results support the idea that application of IL-6R and Stat3 co-inhibition have lethal effects on chordoma cells.

Keywords

• IL-6R
• Atiprimod
• Curcumin
• Molecular Docking
• Chordoma

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