Less toxic treatment strategies for
testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based
chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic
flavonoid compound (MLo1302) from the 3-nitroflavanone family of
DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of
cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT
protein expression, similar to
decitabine, and showed a partial effect in cell differentiation, reducing
protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased
protein expression of cleaved
caspase 8 and activated
caspase 2, and reduced proliferation (
BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore,
synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients.