Cyproheptadine-induced myeloma cell apoptosis is associated with inhibition of the PI3K/AKT signaling.

Recent studies revealed that the anti-allergic cyproheptadine displays anti-blood cancer activity. However, its mechanism is still elusive. In this study, cyproheptadine was found to decrease the expression of anti-apoptotic proteins, including Bcl-2, Mcl-1, and XIAP. More importantly, cyproheptadine-induced apoptosis was accompanied by suppressing AKT activation in myeloma cells. In the subsequent study, cyproheptadine was found to inhibit insulin-like growth factor 1-triggered AKT activation in a time- and concentration-dependent manner. Specifically, cyproheptadine blocked AKT translocation from nuclei for phosphorylation. This inhibition led to suppressed activation of p70S6K and 4EBP1, two key downstream signaling proteins in the PI3K/AKT pathway. However, cyproheptadine did not display inhibition on activation of IGF-1R or STAT3, possible upstream signals of AKT activation. These results further demonstrated that cyproheptadine suppresses the PI3K/AKT signaling pathway, which is probably critical for cyproheptadine-induced MM cell apoptosis.