Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway.

Refractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.

Adverse events in lymphoma patients treated with phosphoinositide 3 kinase Inhibitor in clinical trials: a meta-analysis.

BACKGROUND: Malignant lymphomas are one of the most common cancers worldwide and with high biologic heterogeneity, while the phosphoinositide 3 kinase (PI3K)/mTOR pathway is crucial in maintaining cell growth and survival both in physiological and in pathological conditions (i.e., lymphoma). PI3K inhibitors have been proven to be effective in several subtypes of lymphomas. However, the high incidence of treatment-related adverse events as well as the special safety profile in PI3K inhibitors draws great attention. Thus, this meta-analysis was conducted to compare adverse events in PI3K inhibitors to conventional regimens in lymphoma patients. METHODS: Articles were retrieved from PubMed, Cochrane, and Embase to identify randomized controlled trials and phase III clinical trials that used PI3K inhibitors comparing with non-PI3K inhibitors in lymphoma patients. To achieve the appropriate results, we calculated the risk ratio and 95% confidence intervals. RESULTS: Four trials with 1399 patients that met our criteria were included. The PI3K inhibitors group significantly increased the risk of all-grade adverse events (AEs) (RR 0.95, 95% CI: 0.92-0.98) and high-grade AEs (RR 0.63, 95% CI: 0.57-0.70), compared with the non-PI3K inhibitors group. Besides, the incidence of neutropenia (RR 0.81, 95% CI: 0.74-0.90), pneumonia (RR 0.62, 95% CI: 0.46-0.83), and diarrhea (RR 0.40, 95% CI: 0.32-0.49) were significantly high in the PI3Ki group, while the incidence of anemia (RR 0.78, 95% CI: 0.50-1.20) and thrombocytopenia (RR 0.85, 95% CI: 0.51-1.42) had no statistic significant. CONCLUSION: PI3K inhibitors increased the risk of certain AEs in lymphoma patients.

Preclinical Studies of Chiauranib Show It Inhibits Transformed Follicular Lymphoma through the VEGFR2/ERK/STAT3 Signaling Pathway.

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.