Novel role of thiadiazolidine derivatives in inducing cell death through Myc-Max, Akt, FKHR, and FasL pathway

The 1,2,4-thiadiazolidine derivatives show anti-fungal and anti-inflammatory activities. We previously reported that these derivatives inhibit nuclear factor-kappaB (NF-κB), a transcription factor that induces tumorigenesis through activation of several genes. We have aimed to elucidate the mechanism of apoptosis mediated by these derivatives. In this study we provide evidence that dichlorophenyl form of thiadiazolidine (designated as P₃-25) is a potential inducer of cell death by arresting cell cycle at G1 phase and decreases the amounts of cyclin D1 and cyclin E without interfering p16 and p27. It decreased c-Myc level and thereby inhibited DNA binding ability of Myc-Max complex. P₃-25 dephosphorylated Rb and Akt facilitating nuclear translocation of FKHR that then expressed gene FasL. Activated FasL inhibited cell proliferation and induced cell death. Our results suggest that P₃-25 derivative exerts anti-tumor activities by decreasing Myc-mediated response and increasing FasL expression, which may help in designing drugs for tumor therapy.