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-kappaB), 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 P(3)-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. P(3)-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 P(3)-25 derivative exerts anti-tumor activities by decreasing Myc-mediated response and increasing FasL expression, which may help in designing drugs for tumor therapy.
Raghavendra
Pongali B
PB
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad 500001, India.
Pathak
Niteen
N
Manna
Sunil K
SK
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology*; D020298:U937 Cells
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C505661:FASLG protein, human; C085126:FOXO1 protein, human; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C499330:MAX protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D013830:Thiadiazoles; D051057:Proto-Oncogene Proteins c-akt