PSMB8 as a Novel Target for AML Therapy: Uncovering Synergistic Potential with PI3K Inhibitors

Öz

Acute myeloid leukemia (AML) is a bone marrow condition that arises from abnormalities in hematopoietic stem cells due to genetic mutations in progenitor blood cells. These mutations lead to the uncontrolled proliferation of malignant clonal myeloid stem cells. Although extramedullary symptoms such as myeloid sarcomas and leukemia cutis can arise, the main issue continues to be the disturbances in hematologic cell production. Despite the high complete remission rate in elderly patients, a notable number of patients experience relapse within three years. To address this issue, new objectives must be identified. In a previous study, PSMB8 drew our attention due to its elevated expression levels in AML patients exhibiting lower survival rates compared to those with reduced expression levels. PSMB8 was used for drug repurposing studies by performing in silico drug screening, an ADMET analysis which is followed by Molecular Dynamics (MD) simulations. Three ligand molecules were identified as potential treatment options for AML which were Adozelesin, Fiduxosin and Omipalisib. Omipalisib is known as a PI3K/mTOR inhibitor which was taken our attention for cytotoxic analysis due to overexpression of PI3K/mTOR pathway proteins in AML development. In the subsequent phase, we assessed the cytotoxicity of Omipalisib in comparison to ONX-0914, an inhibitor of PSMB8, in the HL60 cell lines. This research indicated that PSMB8 could be a possible target for Acute Myeloid Leukemia and that a potential medication can be utilized for targeted treatment.

Anahtar Kelimeler

• Omipalisib
• ONX-0914
• AML
• PI3K/mTOR
• PSMB8
• Proteasome

AML Tedavisinde Yeni Bir Hedef Olarak PSMB8 ve PI3K İnhibitörleri ile Sinerjik Potansiyelin Belirlenmesi

Öz

Akut miyeloid lösemi (AML), progenitör kan hücrelerindeki genetik mutasyonlar nedeniyle hematopoetik kök hücrelerde meydana gelen düzensizliklerden kaynaklanan bir kemik iliği hastalığıdır. Bu mutasyonlar, malign klonal miyeloid kök hücrelerin kontrolsüz çoğalmasına yol açar. Miyeloid sarkomlar ve lösemi kutisi gibi ekstramedüller belirtiler ortaya çıkabilse de, temel sorun hematolojik hücre üretimindeki bozulmalardır. Yaşlı hastalarda tam remisyon oranı yüksek olmasına rağmen, önemli sayıda hasta üç yıl içinde nüks yaşamaktadır. Bu sorunun üstesinden gelmek için yeni hedeflerin belirlenmesi gerekmektedir. Önceki çalışmamızda, AML hastalarında PSMB8’in yüksek ekspresyon seviyeleri göstermesi ve düşük ekspresyon seviyelerine sahip hastalara kıyasla daha düşük sağkalım oranları ile ilişkilendirilmesi dikkatimizi çekmiştir. Daha önceki çalışmamızda, PSMB8 hedef alınarak sanal ilaç taramaları, ADMET analizi ve ardından Moleküler Dinamik (MD) simülasyonları gerçekleştirilmiştir. Bu çalışmalar sonucunda AML tedavisi için üç potansiyel ilaç adayı belirlenmiştir: Adozelesin, Fiduxosin ve Omipalisib. PI3K/mTOR inhibitörü olarak bilinen Omipalisib, AML gelişiminde PI3K/mTOR yolak proteinlerinin aşırı ekspresyon göstermesi nedeniyle sitotoksisite analizi için dikkatimizi çekmiştir. Sonraki aşamada, HL60 hücre hattında Omipalisib’in sitotoksisitesi, PSMB8 inhibitörü olan ONX-0914 ile karşılaştırılmıştır. Bu araştırma, PSMB8'in Akut Myeloid Lösemi için olası bir hedef olabileceğini ve potansiyel bir ilacın hedefli tedavi için kullanılabileceğini gösterdi.

Anahtar Kelimeler

• Omipalisib
• ONX-0914
• AML PI3K/mTOR
• PSMB8
• Proteazom

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