gdc-0152 and Leukemia

The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling.

Topics: Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Caspase 9; Cell Proliferation; Cyclohexanes; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Inhibitor of Apoptosis Proteins; Leukemia; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrroles; Signal Transduction; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein