Therapeutic Potential of Amcasertib in a Xenograft Model of Ovarian Cancer

Öz

Ovarian cancer is one of the leading causes of mortality among women and is an aggressive disease that is usually diagnosed in advanced stages. Treatment options are usually limited due to late diagnosis. Although chemotherapy plays an important role in the treatment of ovarian cancer, since the chemotherapeutic agents used in clinical treatment do not produce the desired response in all patients, new agents are being sought. Amcasertib (BBI503), the first cancer stemness kinase inhibitor, inhibits NANOG and other cancer stem cell pathways by targeting kinases with anti-cancer activity. In this study, it was aimed to investigate the therapeutic effects of Amcasertib, which we previously thought that it could be used as a new therapeutic agent in ovarian cancer and cancer stem cell models by in vitro methods, in ovarian cancer xenograft model for the first time. Firstly, the highest tolerable MTD dose of Amcasertib was determined for the first time by performing acute cytotoxicity analysis and then a xenograft model was established using ovarian cancer stem cells (OCSC). Amcasertib treatment was administered to mice with complete tumour development and the effects of Amcasertib on tumour growth were evaluated. The MTD dose of Amcasertib was determined to be 10 mg/kg by acute cytotoxicity analysis and it was determined that Amcasertib was ineffective on tumour treatment by comparative analyses performed on tumour tissues sacrificed as a result of Amcasertib treatment in xenograft ovarian cancer models established using OCSC cells. It is predicted that Amcasertib, which is determined to have anti-invasive, anti-metastatic and increased apoptotic effects in line with the findings obtained as a result of in-vitro studies, can be used as a therapeutic agent with some molecular modifications to be made in its chemical structure. Additional studies are needed to determine the molecular mechanisms underlying the failure of Amcasertib to show anti-cancer activity in ovarian cancer treatment in-vivo.

Anahtar Kelimeler

• Ovarian cancer
• Cancer stem cell
• Amcasertib
• kinase inhibitor

Ksenograft Over Kanseri Modelinde Amcasertib’in Terapötik Potansiyeli

Öz

Over kanseri; kadınlar arasında önde gelen mortalite nedenlerinden biri olup çoğunlukla ileri evrelerde tanı konulan agresif bir hastalıktır. Geç teşhisten dolayı tedavi seçenekleri genellikle sınırlı kalmaktadır. Over kanseri tedavisinde kemoterapi önemli bir yer tutmakta ancak klinik tedavide kullanılan kemoterapötiklerin her hastada istenilen yanıtı verememesi nedeniyle, kemoterapide yeni ajan arayışlarına gidilmektedir. Amcasertib (BBI503), kanser köklülük kinaz inhibitörlerinin ilki olup antikanser aktivitesiyle kinazları hedefleyerek NANOG ve diğer kanser kök hücre yolaklarını inhibe etmektedir. Bu çalışmada daha önce over kanser ve kanser kök hücre modellerinde in vitro yöntemlerle yeni terapötik ajan olarak kullanılabileceğini düşündüğümüz Amcasertib’in ilk kez over kanseri ksenograft modelindeki terapötik etkilerinin araştırılması amaçlanmıştır. Öncelikle akut sitotoksisite analizi yapılarak Amcasertib’in tolere edilebilir en yüksek MTD dozu ilk kez belirlenmiş ve ardından over kanser kök hücreleri (OCSC) kullanılarak ksenograft model oluşturulmuştur. Tümör gelişimi tamamlanan farelerde Amcasertib tedavisi uygulanmış ve Amcasertib’in tümör büyümesi üzerine etkileri değerlendirilmiştir. Akut sitotoksisite analizi ile Amcasertib’in MTD dozunun 10 mg/kg olduğu belirlenmiş ve OCSC hücreleri kullanılarak oluşturulmuş ksenograft over kanseri modellerinde Amcasertib tedavisi sonucunda sakriye edilen tümör dokularında yapılan karşılaştırmalı analizler ile Amcasertib’in tümör tedavisi üzerine etkisiz kaldığı belirlenmiştir. İn-vitro çalışmalar sonucunda elde ettiğimiz bulgular doğrultusunda anti-invaziv, anti-metastatik ve artmış apoptotik etkilere sahip olduğu belirlenen Amcasertib’in kimyasal yapısında yapılacak bazı moleküler modifikasyonlarla tedavide kullanılabilir bir ajan olarak yer alabileceği öngörülmektedir. Amcasertib’in in-vivo over kanseri tedavisinde anti-kanser aktivite gösterememesinin altında yatan moleküler mekanizmaların belirlenebilmesi için ek çalışmalara ihtiyaç duyulmaktadır.

Anahtar Kelimeler

• Over kanseri
• Kanser kök hücresi
• Amcasertib
• kinaz inhibitörü

Kaynakça

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