RÉSUMÉ
Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.
Sujet(s)
Récepteur PPAR alpha , Phosphatidylinositol 3-kinases , Humains , Animaux , Souris , Modèles animaux de maladie humaine , Cellules souchesRÉSUMÉ
Treatment of acute myeloid leukemia (AML) with chemotherapeutic agents fails to eliminate leukemia stem cells (LSC)ï¼and thus patients remain at high risk for relapse. Therefore, the identification of agents that target LSC is an important consideration for the development of new therapies. Enhanced glycolysis in LSC contributes to the aggressiveness of AML, which is difficult to be targeted. In this study, we showed that targeting peroxisome-proliferator-activated receptor α (PPARα), a ligand-activated transcription factor by chiglitazar provided a promising therapeutic approach. We first identified that chiglitazar reduced cell viability and proliferation of the leukemia stem-like cells population in AML. Treatment with chiglitazar blocked the ubiquitination of PPARα and increased its expression, resulting in the inhibition of glucose metabolism and apoptosis of AML cells. Consistent with its anti-leukemia stem-like cells activity in vitro, chiglitazar treatment in vivo resulted in the significant killing of leukemia stem-like cells as demonstrated in AML patient-derived xenograft (PDX) models. Mechanistically, PPARα overexpression inhibited the expression and promoter activity of PGK1 through blocking HIF1-α interaction on the PGK1 promoter. Thus, we concluded that targeting PPARα may serve as a novel approach for enhancing stem and progenitor cells elimination in AML.
Sujet(s)
Leucémie aigüe myéloïde , Récepteur PPAR alpha , Humains , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/métabolisme , Cellules souches tumorales/métabolisme , Phosphoglycerate kinase/métabolisme , Récepteur PPAR alpha/génétique , Récepteur PPAR alpha/métabolisme , Récepteur PPAR alpha/usage thérapeutique , Transduction du signalRÉSUMÉ
It remains challenging to capture and investigate the drift dynamics of primary hot carriers because of their ultrashort lifetime (â¼200 fs). Here we report a new mechanism for secondary hot carrier (â¼25 ps) generation in monolayer transition metal dichalcogenides such as WS2 and WSe2, triggered by the Auger recombination of trions and biexcitons. Using ultrafast photocurrent spectroscopy, we measured and characterized the photocurrent stemming from the Auger recombination of trions and biexcitons in WS2 and WSe2. A mobility of 0.24 cm2 V-1 s-1 and a drift length of â¼3.8 nm were found for the secondary hot carriers in WS2. By leveraging interactions between exciton complexes, we envision a new mechanism for generating and controlling hot carriers, which could lead to efficient devices in photophysics, photochemistry, and photosynthesis.
RÉSUMÉ
Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway.