Abstract
Coordinate PI3K pathway and Bcl-2 family disruption in AML
Highlights
The B-cell lymphoma-2 (Bcl-2) family of pro- and anti-apoptotic proteins controls the mitochondrial pathway of apoptosis
While mammalian target of rapamycin (mTOR) inhibitors are approved for advanced renal cell carcinoma and the PI3K delta inhibitor GS-1101 (CAL-101) appears promising in CLL, a new class of agents that inhibit both PI3K and mTOR signaling (e.g., NVP-BEZ235, GDC0980) may offer additional therapeutic advantages in AML [7]
Tet-inducible short hairpin RNA constructs directed against Akt or Bcl-2 and Bcl-xL individually or together, and studies employing pharmacologic inhibitors (e.g., NVP-BEZ235/PI-103 and ABT-737), revealed that the PI3K/Akt/mTOR pathway and Bcl-2/Bcl-xL play important coordinate roles in protecting leukemia cells from lethality
Summary
The B-cell lymphoma-2 (Bcl-2) family of pro- and anti-apoptotic proteins controls the mitochondrial pathway of apoptosis. This, along with recent evidence that Mcl-1 may be more critical to the development and maintenance of AML than Bcl-2 or Bcl-xL [4], has prompted interest in combining agents that down-regulate Mcl-1 with ABT-737 in AML to simultaneously disable multiple arms of the mitochondrial apoptotic regulatory machinery.
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