image: (A) Cytotoxicity assays of four pediatric T-ALL PDX cells after treatment with 5Z7O for 48 hours (IC50s 1.6-4.0 μM). Cell viability was measured using an ATP-based assay and expressed as a percentage of the vehicle (DMSO) control. IC50 values were calculated using GraphPad Prism. (B) T-ALL PDX cells were transplanted into NSG mice (n = 5 per group) and treated in vivo with 5Z7O (15 mg/Kg daily). Flow cytometric detection of human CD45 leukemic cells after 5 and 12 days of treatment. Data is representative of two independent experiments. (C) Dose response curves of 5Z7O in combination with dexamethasone in the P12-Ichikawa cell line and with etoposide in the Molt3 cell line. (D) Plot of combination index (CI) versus fraction affected (Fa) of 5Z7O combined with dexamethasone or etoposide. CI values were determined using CompuSyn software, CI < 1.0 corresponds to synergism, CI = 1.0 to additive effect, and CI > 1.0 to antagonism. *P < 0.05 (two-tailed Student's t-test). view more
Credit: Correspondence to - H. Daniel Lacorazza - hdl@bcm.edu
Oncotarget published "Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia" which reported that mechanistically, 5Z7O-mediated apoptosis was caused by the downregulation of regulators of the G2/M checkpoint and the inhibition of survival pathways.
The anti-leukemic capacity of 5Z7O was evaluated using leukemic cells from two mouse models of T-ALL and patient-derived xenograft cells generated using lymphoblasts from pediatric T-ALL patients. Finally, a combination of 5Z7O with dexamethasone, a drug used in frontline therapy, showed synergistic induction of cytotoxicity.
Dr. H. Daniel Lacorazza from The Baylor College of Medicine said, "Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with more than 3,000 new cases diagnosed every year in the U.S."
While advances in pediatric ALL therapies through systemic and intrathecal multi-drug treatment have vastly improved 5-year event-free survival over 85%, relapsed ALL patients exhibit poor prognosis and remain the leading cause of pediatric cancer-related mortality. ALL is broadly classified based on immunophenotype into B-cell or T-cell ALL, the latter being less frequent albeit with worse prognosis and higher rate of relapse.
In response to stress signals, MAP3K activates MAP2K7 through phosphorylation at serine and threonine residues, which in turn activates JNK and downstream effectors like c-JUN and ATF2.
A loss-of-function study shows MAP2K7 mediates stress-induced JNK activation in mast cells and inhibits growth factor and antigen-driven proliferation of immune cells.
Analysis of the ATP binding pocket across the MAP2K family of proteins revealed a cysteine-218 located in the hinge region of MAP2K7 that is not present in other MAP2K proteins, offering a window of opportunity for irreversible and selective inhibition.
The Lacorazza Research Team concluded in their Oncotarget Research Output, "we provide proof-of-principle data in support of targeting the MAP2K7 pathway in pediatric T-ALL. The chemical 5Z7O shows selectivity to MAP2K7 and induces dose-dependent apoptosis and deregulation of the cell cycle in murine T-ALL models, established cell lines, and human patient-derived xenografts. The low efficacy observed in in vivo treatment suggests that more research is needed to develop small molecules with increased potency and specificity relative to MAP2K7 and evaluate their capacity to eradicate chemoresistant leukemia-initiating cells in T-ALL patients."
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DOI - https://doi.org/10.18632/oncotarget.28040
Full text - https://www.oncotarget.com/article/28040/text/
Correspondence to - H. Daniel Lacorazza - hdl@bcm.edu
Keywords - T-ALL, MAP2K7, 5z-7-oxozeaenol
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Journal
Oncotarget
Article Title
"Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia"