A novel BH3 mimetic Bcl-2 inhibitor promotes autophagic cell death and reduces in vivo Glioblastoma tumor growth

Seyma Calis, Berna Dogan, Serdar Durdagi, Asuman Celebi, Ozlem Yapicier, Turker Kilic, Eda Tahir Turanli, Timucin Avsar*

*Bu çalışma için yazışmadan sorumlu yazar

Araştırma sonucu: ???type-name???Makalebilirkişi

9 Atıf (Scopus)

Özet

Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma (GBM), the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall GBM cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in high BCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in GBM A172 cells, indicated by the upregulation of BECN1, ATG5, and MAP1LC3B expression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. Our results indicate that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex and may serve as a potential small molecule for treating GBM.

Orijinal dilİngilizce
Makale numarası433
DergiCell Death Discovery
Hacim8
Basın numarası1
DOI'lar
Yayın durumuYayınlandı - Ara 2022
Harici olarak yayınlandıEvet

Bibliyografik not

Publisher Copyright:
© 2022, The Author(s).

Finansman

This study was funded by the Scientific Research Projects Commission of Bahcesehir University. Project number: BAP.2020.02.18, and Health Institutes of Turkey (TUSEB) grant number 6836.

FinansörlerFinansör numarası
Scientific Research Projects Commission of Bahcesehir UniversityBAP.2020.02.18
TUSEB6836
Türkiye Sağlık Enstitüleri Başkanlığı

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