Neuroblastoma is a pediatric
tumor accounting for 15% of childhood
cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of
apigenin, a nonmutagenic dietary
flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human
neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2).
Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the
flavonoid structure correlated with the growth-inhibitory potential of
apigenin. Furthermore,
apigenin inhibited NUB-7 xenograft
tumor growth in anonobese diabetic/
severe combined immunodeficiency mouse model, likely by inducing apoptosis.
Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of
apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore,
apigenin (15-60 micromol/L) induced cell death and apoptosis of
neuroblastoma cells expressing wild-type but not mutant p53.
Apigenin increased
caspase-3 activity and PARP cleavage, and
Z-VAD-FMK, a broad-spectrum
caspase-3 inhibitor, rescued NUB-7 cells from
apigenin-mediated apoptosis indicating that
apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from
apigenin-induced cell death, suggesting that Bax activity is important for the action of
apigenin.
Apigenin is thus a candidate therapeutic for
neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.