Kolorektal Kanserde İrinotekan Sitotoksisitesini Arttırmak için TGF-Β Sinyalizasyonunun Modülasyonu

Abstract

Amaç: Bozulmuş  Transforme edici büyüme faktörü beta (Transforming Growth Factor Beta, TGF-β) sinyalizasyonu kolorektal kanser (CRC) ilerlemesine katkıda bulunur. TGF-β reseptörlerini (TGFβR) bilinen kemoterapilerle birlikte hedeflemek tedavi etkinliğini artırabilir. Amacımız insan kolorektal kanser hücre hattı HCT-116'da TGFβR-I/II inhibitörü (LY2109761) ile irinotekanın sitotoksik aktivitesine olan etkilerinin belirlenmesidir.

Materyal ve metod: HCT-116 hücrelerinde TGFβR-I/II'yi farmakolojik olarak inhibe etmek için LY2109761 inhibitörü kullanıldı. MTT analizleri, irinotekan, LY2109761 ve bunların kombinasyonu ile tedaviden sonraki hücre canlılığı değerlendirildi. Kantitatif Real Time PCR (RT-qPCR) ile, hücre ölümü, hücre döngüsü ve TGF-β sinyalizasyonu ile ilişkili genlerin mRNA düzeyleri değerlendirildi.

Bulgular: LY2109761 ve irinotekanın kombinasyon tedavisi, HCT-116 hücrelerinde hücre canlılığını doza ve zamana bağlı bir şekilde önemli ölçüde azalttı. Hücre döngüsü inhibitörü P21'in artan ekspresyonu ve apoptoz ve otofaji belirteçlerinin arttığı gözlemlendi.

Sonuç: LY2109761 ve irinotekanın kombinasyonu, irinotekanın tek başına kullanımına kıyasla artan sitotoksisite sonucu CRC için umut verici bir tedavi stratejisi olduğunu göstermektedir. Anahtar Kelimeler: Kolorektal kanser, TGFβR-I/II, İrinotekan, LY2109761, Sitotoksisite

Keywords

• Kolorektal kanser
• TGFβR-I/II
• İrinotekan
• LY2109761
• Sitotoksisite

Modulation of TGF-Β Signaling to Enhance Irinotecan Cytotoxicity in Colorectal Cancer

Abstract

Background: Impaired Transforming Growth Factor Beta (TGF-β) signaling contributes to colorectal cancer (CRC) progression. Targeting TGF-β receptors (TGFβR) in combination with established chemotherapies may enhance treatment efficacy. This study investigates the effects of a TGFβR-I/II inhibitor (LY2109761) on the cytotoxic activity of irinotecan in the human colorectal cancer cell line HCT-116.

Materials and Methods: LY2109761 was used to pharmacologically inhibit TGFβR-I/II in HCT-116 cells. Cell viability following treatment with irinotecan, LY2109761, or their combination was assessed using the MTT assay. Real-time quantitative polymerase chain reaction (RT-qPCR) quantified mRNA levels of genes associated with cell death, cell cycle, and TGF-β signaling.

Results: Combination therapy of LY2109761 and irinotecan significantly reduced cell viability in HCT-116 cells in a dose- and time-dependent manner. Enhanced expression of cell cycle inhibitor P21 and increased markers of apoptosis and autophagy were observed.

Conclusions:  The combination of LY2109761 and irinotecan exhibited enhanced cytotoxicity compared to irinotecan alone, suggesting this approach as a promising therapeutic strategy for CRC.

 

Keywords

• Colorectal cancer
• TGFβR-I/II
• Irinotecan
• LY2109761
• Cytotoxicity

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