Publication: Bortezomib ve carfilzomib’in glioblastoma hücrelerine anti-tümör etkisi ve tümör mikro çevresindeki sağlıklı beyin hücrelerinde stres cevabı ve iskelet hasar tayini
Abstract
Amaç: Çalışmamızda amaç glioblastomanın (GB) rutin tedavisi iyonize radyasyon (IR) ve temozolomid (TMZ) ile birlikte proteazom inhibitörleri bortezomib (BTZ) ve carfilzomib (CFZ) kullanılarak GB’de anti-tümör etkisi ve tümör mikro çevresindeki sağlıklı beyin hücrelerinde stres cevabı ve iskelet hasarının incelenmesidir.Gereç ve Yöntem: GB ile astrosit veya mikroglia hücreleri ile insertler yardımıyla ko-kültür ortamında kültür edildi ve uygulamalar için sekiz grup oluşturuldu. Gruplara uygulanmak üzere BTZ, CFZ, TMZ ve IR için dozlar seçildi. Uygulamalar sonrası; proteazom aktivitesi, apoptoz tayini, iskelet hasarı ve stres cevabı için proteinlere bakıldı. Bulgular: GB ile astrosit ve mikroglia ko-kültüründe ilaç ve IR uygulamalarından sonra GB tümör hücrelerinin mikroglia ve astrosit hücrelerine göre canlılığı düştü. Uygulamalardan sonra astrosit hücrelerinde iskelet hasarı için; β-aktin protein ekspresyonu kombine gruplarında kontrole göre azalma gösterdi. Hem mikroglia hem astrosit hücrelerinde; ARP-2 ve Transgelin 2 proteininde; inhibitör ve kombinasyon gruplarında kontrole göre azalma görüldü. Sonuçlar: Çalışmamızdan elde edilen verilerin kemoterapi sırasında gelişen dirence karşı yeni tedavi önerisi olarak proteazom inhibitörlerinin klinikte kullanımının geliştirilmesine katkı sağlanması beklenmektedir.
Objective: The aim of our study was to use the proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) together with ionizing radiation (IR) and temozolomide (TMZ) for routine treatment of glioblastoma (GB), investigation of anti-tumor effect in GB and stress response and skeletal damage in tumor microenvironment healthy brain cells.Materials and Methods: GB and astrocyte, GB and microglia cells were cultured in co-culture enviroment with the help of inserts. Eight groups were created for the applications. Doses for BTZ, CFZ, TMZ, and IR were selected to be administered to the groups. After drugs application; Proteins were examined for proteasome activity, determination of apoptosis, skeletal damage and stress response.Results: In GB and astrocyte, GB and microglia co-culture; the viability of GB tumor cells decreased compared to microglia and astrocyte cells after drug and IR applications. For skeletal damage in astrocyte cells after applications; β-actin protein expression decreased in the combined groups compared to the control. In both microglia and astrocyte cells; ARP-2 and Transgelin 2 proteins were decreased in inhibitor and combination groups compared to controlConclusions: It is expected that the data obtained from our study will contribute to the development of clinical use of proteasome inhibitors as a new treatment proposal against resistance developed during chemotherapy.
Objective: The aim of our study was to use the proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) together with ionizing radiation (IR) and temozolomide (TMZ) for routine treatment of glioblastoma (GB), investigation of anti-tumor effect in GB and stress response and skeletal damage in tumor microenvironment healthy brain cells.Materials and Methods: GB and astrocyte, GB and microglia cells were cultured in co-culture enviroment with the help of inserts. Eight groups were created for the applications. Doses for BTZ, CFZ, TMZ, and IR were selected to be administered to the groups. After drugs application; Proteins were examined for proteasome activity, determination of apoptosis, skeletal damage and stress response.Results: In GB and astrocyte, GB and microglia co-culture; the viability of GB tumor cells decreased compared to microglia and astrocyte cells after drug and IR applications. For skeletal damage in astrocyte cells after applications; β-actin protein expression decreased in the combined groups compared to the control. In both microglia and astrocyte cells; ARP-2 and Transgelin 2 proteins were decreased in inhibitor and combination groups compared to controlConclusions: It is expected that the data obtained from our study will contribute to the development of clinical use of proteasome inhibitors as a new treatment proposal against resistance developed during chemotherapy.