Abstract
Cranberry’s role as a potential chemopreventive agent has been examined by various studies since 1996. One of the proposed mechanisms is to eliminate cancerous cells by inducing apoptosis. A limited number of studies have shown that cranberry can activate apoptosis in cancer cells. Therefore, we sought to determine the mechanism by which cranberry extract initiates apoptosis. In our study, HL-60 cells were incubated with 25 μg/mL of cranberry extract for 24 hours. Cranberry treatment caused a significant increase in caspase-3/7 activity. In addition, the data showed a significant increase in the concentration of caspase-9, but no change in the level of caspase-8. Moreover, cranberry treatment caused a loss of mitochondrial transmembrane permeability, leading to a significant increase in release of cytochrome C and Smac. These results indicate that cranberry treatment initiates a cascade of events associated with intrinsic apoptosis. These apoptotic events were correlated with a significant decrease in Akt phosphorylation at both Ser473 and Thr308 sites, followed by a significant increase of Bad (pro-apoptotic regulator) dephosphorylation at Ser136. Together, these findings provide an important molecular framework for the apoptosis initiated by cranberry extract in HL-60 cells. The overall mechanism includes the suppression of Akt phosphorylation, causing an increase in dephosphorylated Bad. Active (dephosphorylated) Bad then promotes the permeability of the mitochondrial outer membrane and the subsequent release of pro-apoptotic proteins, including cytochrome C and Smac, into the cytosol. These pro-apoptotic proteins activate caspase-9, which causes a caspase cascade and leads to intrinsic apoptosis. This sequence of events describes a novel mechanism to explain how cranberry extract can trigger intrinsic apoptosis in HL-60 cells. This may give direction to future studies investigating the effect of cranberry extract on cancer in vivo.