Publication: İlaç yeniden konumlandırma ile belirlenen aday ilaçların akut myeloid lösemi hücrelerinde proteazom inhibitörü ile kombinasyon tedavisinin incelenmesi
Abstract
Amaç: Akut myeloid lösemi (AML) tedavisi için ilaç yeniden konumlandırma ile belirlenen aday ilaçların proteazomal aktivite tayini ardından Desipramine (DSP), Risedronate (RSD) ve Leucovorin (LEU) ilaçlarının proteazom inhibitörü Ixazomib (IXA) ile kombine ilaç tedavisinin AML hücreleri üzerinde anti-tümör etkilerinin incelenmesi. Gereç ve Yöntem: İlaç yeniden konumlandırma ile belirlenen aday ilaçların florometrik proteazomal aktivite tayini ardından aday ilaçlardan DSP, RSD, LEU ve IXA için WST-1 canlılık testlerinin yapılması ile AML hücrelerine 24 saatlik kombine ilaç maruziyeti sonrasında proteazomal aktivite, apoptoz ve hücre döngüsü tayini yapıldı. Western blot yöntemi ile apoptoz belirteci PARP proteini seviyesine bakıldı. Bulgular: Çalışmamızın sonuçlarına göre, ilaç yeniden konumlandırma ile belirlenen aday ilaçların AML hücrelerinde proteazom inhibisyon etkisi gösterilmiştir. DSP+IXA ilaç kombinasyon tedavisinin AML hücrelerinde kontrol ve IXA ilaç grubuna göre canlılığı azalttığı, proteazomal aktiviteyi inhibe ettiği, apoptozu indüklediği gösterilmiştir. DSP’nin canlılık testlerinde sitotoksik etki göstermesi ile beraber apoptozu indüklemediği ama hücre döngüsünü yavaşlattığı bulunmuştur. Sonuçlar: Çalışmamızdan elde ettiğimiz sonuçlar ışığında ilaç yeniden konumlandırma ile belirlenen antidepresan DSP ilacının, proteazom inhibitörü IXA’in kombine tedavisi sonucu IXA ilacının kanser hücreleri üzerindeki etkinliğinin artması sonucu her iki ilacında klinikte kullanımının geliştirilmesi için yapılan çalışmalara katkı sağlaması beklenmektedir.
Objective: To investigate the anti-tumor effects of combined drug treatment of the Desipramine (DSP), Risedronate (RSD) and Leucovorin (LEU) with the Ixazomib (IXA) on AML cells, followed by determination of proteasomal activity of candidate drugs identified by drug repositioning for acute myeloid leukemia (AML) treatment. Materials and Methods: After fluorometric determination of proteasomal activity of the drug candidates, viability assays were performed for the drug candidates DSP, RSD, LEU and IXA and proteasomal activity, apoptosis and cell cycle were determined after 24 hours of combined drug exposure to AML cells. Results:According to the results of our study, the proteasome inhibitory effect of the candidate drugs, determined by drug repositioning, was demonstrated in AML cells. The combination therapy (DSP+IXA) was shown to reduce viability, inhibit proteasomal activity and induce apoptosis in AML cells compared to the control and IXA groups. It was found that DSP with its cytotoxic effect did not induce apoptosis, but slowed the cell cycle. Conclusion:Considering the results of our study, it is expected that the antidepressant DSP, determined by the repositioning of the drug, will contribute to the studies conducted to improve the clinical use of both drugs as a result of the combined treatment with the IXA, by increasing the efficacy of the IXA on cancer cells.
Objective: To investigate the anti-tumor effects of combined drug treatment of the Desipramine (DSP), Risedronate (RSD) and Leucovorin (LEU) with the Ixazomib (IXA) on AML cells, followed by determination of proteasomal activity of candidate drugs identified by drug repositioning for acute myeloid leukemia (AML) treatment. Materials and Methods: After fluorometric determination of proteasomal activity of the drug candidates, viability assays were performed for the drug candidates DSP, RSD, LEU and IXA and proteasomal activity, apoptosis and cell cycle were determined after 24 hours of combined drug exposure to AML cells. Results:According to the results of our study, the proteasome inhibitory effect of the candidate drugs, determined by drug repositioning, was demonstrated in AML cells. The combination therapy (DSP+IXA) was shown to reduce viability, inhibit proteasomal activity and induce apoptosis in AML cells compared to the control and IXA groups. It was found that DSP with its cytotoxic effect did not induce apoptosis, but slowed the cell cycle. Conclusion:Considering the results of our study, it is expected that the antidepressant DSP, determined by the repositioning of the drug, will contribute to the studies conducted to improve the clinical use of both drugs as a result of the combined treatment with the IXA, by increasing the efficacy of the IXA on cancer cells.