Characterizing the sphingomyelinase pathway triggered by PRIMA-1 derivatives in lung cancer cells with differing p53 status.

BACKGROUND/AIM Derivatives of PRIMA-1 compound, 8a and 8b have been shown to increase cytotoxicity in lung cancer cells through sphingomyelinase pathways in IR and 8a or 8b co-treated lung cancer cells. The goal of the present study was to further elaborate the molecular mechanism of 8a- or 8b-treated lung cancer cells in order to understand their potential as anti-cancer drugs. MATERIALS AND METHODS Biochemical assays, western blot, flow cytometry and gene array analyses were employed to distinguish these mechanisms. RESULTS Herein we demonstrated that 8a and 8b cause apoptosis with S-phase arrest in lung cancer cells by activating neutral sphingomyelinase with ceramide production. 8a induces expression of TNF family genes while 8b induces p53-mediated apoptosis genes. Protein analysis shows an increased expression in caspase 8, bcl-2, bax, caspase 9 and cytochrome c. CONCLUSION PRIMA-1 derivatives provoke cytotoxicity in lung cancer cells mainly through the neutral sphingomyelinase-dependent apoptosis pathway.