15d-PGJ(2) Induces Apoptosis by Reactive Oxygen Species-mediated Inactivation of Akt in Leukemia and Colorectal Cancer Cells and Shows In vivo Antitumor Activity

Purpose: Recent studies have shown that 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor-gamma (PPAR gamma), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ(2) has antitumor activity in vitro and in vivo, and investigated the underlying mechanism. Experimental Design: We examined 15d-PGJ(2)-induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ(2) in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model. Results: 15d-PGJ(2) induced apoptosis in leukemia and colorectal cancer cells in a dose-dependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ(2)-mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ(2) in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover, 15d-PGJ(2) markedly reduced growth of mouse CT-26 s.c. tumors and HL-60 xenograft tumors and down-regulated p-Akt and Akt expression in vivo. Conclusions: These results suggest that Akt inactivation through ROS production may contribute to 15d-PGJ(2)-induced apoptosis in leukemia and colorectal cancer cell lines and that 15d-PGJ(2) may have therapeutic relevance in the treatment of human leukemia and colorectal cancer. (Clin Cancer Res 2009;15(17):5414-25)