The graviola impact on human astroglioma cells: functional significance of MUDENG

Graviola (Annona muricate) is a coveted tropical plant that has been found to be effective against many human cancers. Malignant glioblastoma multiformes are the most common and aggressive malignant forms of astrocytoma in the central nervous system. MUDENG (Mu-2-related death-inducing gene, MuD) is involved in cell death signaling. In this study, we investigated the impact of extracts from graviola leaves (from Korea and Africa), fruits and seeds against human astroglioma cells. Interestingly, graviola leaf extract-Korea (GLE-K), graviola leaf extract-Africa (GLE-A) and graviola fruit extract-Africa (GFE-A) exhibited significant cytotoxic effects on the cell proliferation in a dose-dependent manner and altered the MuD expression pattern. Cell cycle analyses revealed that GLE-A and GLE-K triggered no significant induction of apoptosis at concentrations up to 5% in U251-MG cells, while in GLE-K treated cells at 10% concentrations, there were much fewer apoptotic cells (33.64%) compared to those in GLE-A (73.55%) treated cells. In the case of GFE-A treated cells, 5% graviola extract (GE) concentration resulted in predominant cells entering the apoptotic phase (59.31%), whereas almost no significant increase in apoptotic cells was observed in GSE-A treated cells (1.38%) even up to 25% of graviola extract (GE) concentration. While using stable transfectants knock-out (KO)(-)-and overexpressing (OE)-MuD(+), significant and consistent differences in the cell viability (enhanced anti-astroglioma effect of GEs) were observed in KO-MuD(-) cells. This validated the functional consequence of MuD in the anti-astroglioma activity of GEs. Our results confirmed that GFE-A possesses the highest anti-astroglioma activity followed by the leaf extracts (GLE-A/K). This is the first report that highlights the MuD aspect of GEs.