IRE1α İNHİBİTÖRÜ GSK2850163’ÜN NÜKLEOZİT METABOLİK İNHİBİTÖRÜ KAPESİTABİN ÜZERİNDEKİ GÜÇLENDİRİCİ ROLÜNÜN KOLON KANSERİ HÜCRELERİNDE DEĞERLENDİRİLMESİ

Öz

Amaç: Kapesitabin kolon kanseri tedavisine yönelik yaygın olarak kullanılan etkili ajanlardan birisidir. Ancak sistemik yan etkiler ve direnç gelişimi gibi olumsuz durumlar tedavi etkinliğini sınırlandırabilmektedir. Çalışmamızın amacı, UPR sinyal yolunun IRE1α/XBP-1 dalının seçici inhibitör olan GSK2850163 aracılı inhibe edilmesinin kolon kanseri hücrelerinde kapesitabine olan duyarlılığa olan etkilerinin araştırılmasıdır. Gereç ve Yöntem: Çalışmalarımızda insan kolon kanseri hücreleri olan Caco-2 ve HT-29 hücreleri kullanılmıştır. Kapesitabin ve GSK2850163'ün hücre canlılığı üzerine olan etkileri WST-1 testi ile incelendi. Takiben belirlenen etkin konsantrasyonlarda kombinasyon çalışmaları ile canlılık analizlerine devam edildi. GSK2850163’ün IRE1α/XBP-1 yolu üzerindeki inhibe edici etkisi immünoblotlama çalışmaları ile doğrulandı. Kapesitabin ve GSK2850163 eş uygulama tedavisinin hücrelerin migrasyon ve invazyon yeteneği üzerine olan etkileri yara iyileşme ve matrijel-kaplı Boyden-chamber invazyon testi ile değerlendirildi. Sonuç ve Tartışma: Çalışmamızda IRE1α/XBP-1’in GSK2850163 aracılı inhibisyonunun kolon kanseri hücrelerinin canlılığını, migrasyon ve invazyon kapasitesini önemli ölçüde sınırladığı belirlendi. Kapesitabin ve GSK2850163’ün eş uygulama tedavisinin yalnız başına kapesitabin veya GSK2850163 uygulamalarına kıyasla kolon kanseri hücreleri üzerinde daha etkili olduğunu gözlemlendi. Araştırma bulgularımız, kolon kanserine yönelik IRE1α/XBP-1 sinyal yolunun farmakolojik olarak hedeflenmesinin etkili tedavi yaklaşımları sunabileceğini önermektedir.

Anahtar Kelimeler

• GSK2850163
• IRE1α
• kapesitabin
• kolon kanseri
• UPR

Destekleyen Kurum

Süleyman Demirel Üniversitesi

Proje Numarası

TSG-2021-8302, TAB-2020-8253

Etik Beyan

Yazarlar bu çalışma için etik komite onayının gerekli olmadığını beyan etmektedir.

Teşekkür

Bu çalışmanın hayata geçirilmesinde Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri birimi tarafından daha önce desteklenen projelerimizin (TSG-2021-8302, TAB-2020-8253) bütçesinden faydalanılmıştır.

EVALUATION OF THE BOOSTER ROLE OF IRE1α INHIBITOR GSK2850163 ON NUCLEOSIDE METABOLIC INHIBITOR CAPECITABINE IN COLON CANCER CELLS

Öz

Objective: Capecitabine is one of the widely used potent agents for the treatment of colon cancer. However, adverse events, such as systemic side effects and resistance development, may limit the effectiveness of the treatment. Our study aimed to investigate the impact of GSK2850163-mediated selective inhibition of the IRE1α/XBP-1 branch of the UPR signaling pathway on the sensitivity of colon cancer cells to capecitabine. Material and Method: Human colon cancer cells Caco-2 and HT-29 were used in our studies. The effects of capecitabine and GSK2850163 on cell viability were examined by WST-1 test. Viability analyses were continued with combination studies to determine effective concentrations. The inhibitory effect of GSK2850163 on the IRE1α/XBP-1 pathway was confirmed by immunoblotting studies. The impact of capecitabine and GSK2850163 co-administration treatment on the migration and invasion ability of cells was evaluated by wound healing and matrigel-coated Boyden-chamber invasion test. Result and Discussion: Our study determined that GSK2850163-mediated inhibition of IRE1α/XBP-1 significantly limited the viability, migration and invasion capacity of colon cancer cells. We observed that co-administration of capecitabine and GSK2850163 was more effective on colon cancer cells compared to capecitabine or GSK2850163 alone. Our research findings suggest that pharmacological targeting of the IRE1α/XBP-1 signaling pathway for colon cancer may offer effective treatment approaches.

Anahtar Kelimeler

• Capecitabine
• colon cancer
• GSK2850163
• IRE1α
• UPR

Destekleyen Kurum

Suleyman Demirel University

Proje Numarası

TSG-2021-8302, TAB-2020-8253

Etik Beyan

The authors declare that ethics committee approval was not required for this study.

Teşekkür

To actualize of this study, the budget of our previously supported projects (TSG-2021-8302, TAB-2020-8253) by the Scientific Research Projects unit of Süleyman Demirel University was used.

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