Akademik Veri Yönetim Sistemi
TURKISH JOURNAL OF BIOCHEMISTRY, cilt.49, sa.3, ss.1-11, 2024 (SCI-Expanded)
Abstract
Objectives: Acute myeloid leukemia (AML) is a severe blood
cancer with less than 50 % long-term survival. Despite
advancements in treatment options, relapse is still the major
obstacle. The main reason of this problem is ineffective
targeting of leukemic stem cells (LSCs), which play an
important role in tumor development and relapse. In our
previous studies, we found that casticin, the major polyphenolic
component of Vitex trifolia’s fruit, targets both
leukemic cells and LSCs without affecting healthy tissues.
Therefore, in this study, we aimed to investigate the effect of
casticin-mediated cell death in relation to the LSCs-favored
survival pathways at gene and protein expression levels
using in vitro LSC-like and parental leukemic cell models.
Methods: We validated the LSC character of KG1a and KG1
cells (84.55 % CD34+, CD38- and 93.55 % CD34+, CD38+,
respectively) by flow cytometry. For the investigation of
casticin’s mechanism of action, we employed real time-PCR,
western blotting and bioinformatics analyses.
Results: Our results showed an increase in cleaved PARP/
β-actin ratio but no change in LC3BI/II and SQSTM/β-actin
ratios. Our gene expression, bioinformatics and immunoblotting
analyses represented significant decrease in Shh, Gli
and Wnt levels. We also elucidated a possible crosstalk
between Hedgehog and other oncogenic cascades via the Gli,
Notch, YAP, p38, Mcl-1, and Myc proteins in casticin mediated
anti-leukemic effect.
Conclusions: In conclusion, we found that casticin induces
apoptosis in both LSC-like and parental leukemia cells
mainly by suppressing Shh signaling, which is crucial for LSC
survival and AML relapse.
Keywords: acute myeloid leukemia; apoptosis; cancer stem
cells; casticin; cell signaling