Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib

Year 2020, Volume: 10 Issue: 2, 427 - 440, 30.12.2020

Ramazan Gundogdu

https://doi.org/10.37094/adyujsci.737262

Abstract

Colorectal cancer is one of the main reasons for cancer-related mortality around the world and conventional chemotherapy approaches lead the clinical management of colorectal cancer treatment. Although many chemotherapeutics including paclitaxel have been effectively used to treat colorectal cancer patients, some tumour cells acquire drug resistance by increasing the regulation of various cellular mechanisms, primarily becoming addictive to some DNA repair activities. Preclinical evaluation of small-molecule inhibitors targeting various DNA damage response components is currently an active area of cancer research. This study aimed to assess the cytotoxic effect of paclitaxel combined with small-molecule PARP inhibitor olaparib in HCT116 colorectal cancer cells. We conducted clonogenic assays, showing that the paclitaxel and olaparib combination significantly inhibits the survival of colorectal cancer cells compared to paclitaxel or olaparib alone. By performing two distinct immunological methodology, Western blotting and immunofluorescence, we further demonstrated that olaparib intensifies the DNA damage accumulation induced by paclitaxel treatment. In conclusion, our preclinical study with HCT116 colorectal cancer cells suggests that olaparib may potentially serve as a combination partner to paclitaxel for effective colorectal cancer treatment.

Keywords

Colorectal cancer, Paclitaxel treatment, PARP inhibitors

Thanks

The author thanks Dr. M.K. Erdogan and S. Acikgoz for critical reading of the manuscript. The author further acknowledges the funding supports of the Scientific and Technological Research Council of Turkey (TUBITAK 119S007) and the Scientific Research Projects Coordination Unit of Bingol University (BAP-SHMYO.2019.00.002).

HCT116 Kolorektal Kanser Hücre Sağ-kalımının Paklitaksel ve Olaparib Kombinasyon Tedavisiyle Engellenmesi

Abstract

Kolorektal kanser, dünya genelinde kansere bağlı ölümün temel sebeplerinden biridir ve konvansiyonel kemoterapi yaklaşımları kolorektal kanser tedavisinin klinik yönetimine öncülük etmektedir. Paklitaksel dahil olmak üzere çoğu kemoterapötik, kolorektal kanser hastalarını tedavi etmede etkili bir şekilde kullanılmasına rağmen, bazı tümör hücreleri özellikle çeşitli DNA tamir aktivitelerine bağımlılık kazanmak suretiyle çok sayıda hücresel mekanizmaların düzenlenmesini arttırarak ilaç direnci kazanırlar. Çeşitli DNA hasar yanıtı bileşenlerini hedefleyen küçük-moleküllü inhibitörlerin klinik öncesi değerlendirmesi günümüzde kanser araştırmalarının aktif bir alanını oluşturmaktadır. Bu çalışma, HCT116 kolorektal kanser hücrelerinde paklitaksel ile kombine edilen küçük-moleküllü PARP inhibitörü olaparibin sitotoksik etkisini değerlendirmeyi amaçlamıştır. Gerçekleştirdiğimiz koloni sağ-kalım analizleri paklitaksel ve olaparib kombinasyonunun sadece paklitaksel ya da olaparib tedavisi ile kıyas edildiğinde kolorektal kanser hücrelerinin sağ kalımını önemli derecede inhibe ettiğini gösterdi. Western blot ve immünofloresan olmak üzere iki farklı immünolojik yöntem gerçekleştirilerek, olaparibin paklitaksel tedavisinin oluşturduğu DNA hasarı birikimini yoğunlaştırdığı tespit edildi. Sonuç olarak, HCT116 kolorektal kanser hücreleriyle gerçekleştirdiğimiz klinik öncesi çalışmamız, olaparib ve paklitaksel kombinasyonunun kolorektal kanser tedavisi için potansiyel bir tedavi yaklaşımı sunabileceğini göstermektedir.

Keywords

Kolorektal kanser, Paklitaksel tedavisi, PARP inhibitörleri

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