Using defined cell line models, and primary leukemia patient as w

Using defined cell line models, and primary leukemia patient as well as donor samples we studied the distinct effects of NVP BGT226 on cellular proliferation, cell cycle progression and induction of apoptosis. Thereby we com pared NVP BGT226 to a second dual inhibitor, NVP BEZ235, which is currently under investigation selleck screening library in a phase I study for relapsedrefractory ALL or AML. Our cell models included cell lines with defined geno mic alterations rendering the AKT signaling pathway autoactivated, i. e. a PTEN deficient acute T lymphoblastic leukemia cell line, patient derived leukemia cell lines with well described TK mutations, engineered BaF3 cell lines transfected with mutant tyrosine kinases expressed in an otherwise isogenic cellular background and native ex vivo acute leukemia cells, with or without a defined TK mutation, derived from consented patients with newly diagnosed acute leukemia.

In addition, we comparatively studied native physiologic mononuclear cells derived from bone marrow donors. In PTEN deficient Jurkat cells, NVP BGT226 proved to potently inhibit cellular proliferation in the low nanomolar range. Inhibitors,Modulators,Libraries The sensitivity profile is thereby in the same range compared to the additionally tested dual PI3KMTOR inhibitor, NVP BEZ235. It was previously noted, that the predominant antitumor effect of inhibitors of PI3KAKTMTOR signaling cascades is mediated via inhibition of cellular proliferation rather than induction of apoptosis. Surprisingly how ever, NVP BGT226 proved to have genuine proapoptotic efficacy whilst the proapoptotic effect achieved by NVP BEZ235 was, as expected by previous reports, at most moderate.

To Inhibitors,Modulators,Libraries model the effects of NVP BGT226 and NVP BEZ235 on mutant TK triggered AKT activation, we chose two well established acute leukemia cell lines harboring a FLT3 ITD mutation or a BCR Inhibitors,Modulators,Libraries ABL1 mutation. Similar to the findings for Jurkat cells, both inhibitors, proved to be highly potent in inhibiting cellular proli feration. However again, NVP BEZ235 only moderately induced a meaningful proapoptotic effect, whereas NVP BGT226 was a strong inducer of the programmed cell death machinery. Inhibitors,Modulators,Libraries As the AKT pathway controls cell cycle checkpoints, we speculated that the discrepancy may be due to differential activity on the cell cycle compartment. And indeed, a strong and sustained G0G1 arrest was observed for NVP BEZ235 preventing cells to undergo apoptosis. On the protein level, where both agents were similarly targeting downstream proteins controlling cell cycle pro gression or ULK1 induced autophagy, only NVP BGT226 was capable to override cell protective mechanisms to potently Inhibitors,Modulators,Libraries www.selleckchem.com/products/BI6727-Volasertib.html induce apoptosis.

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