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¹ Cancer Research Program, The Hospital for Sick Children; ² Department of Laboratory Medicine and Pathobiology; ³ Institute of Medical Sciences; and ⁴ Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada USA

Requests for reprints: Herman Yeger, Cancer Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8. Phone: 416-813-5937; Fax: 416-813-5974. E-mail: hermie{at}sickkids.ca

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 p21^WAF1/CIP1 and Bax. Furthermore, apigenin (15–60 µmol/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.

Key Words: neuroblastoma • apoptosis • apigenin • caspases • p53

Grant support: This study was supported by operating grants to H. Yeger from the Canadian Cancer Society, National Cancer Institute of Canada, the Canadian Institutes for Health Research, and the James Birrell Neuroblastoma Research Fund; and to D.R. Kaplan from the National Cancer Institute of Canada; R. Torkin was supported by RESTRACOM from the Hospital for Sick Children Research Institute. D.R. Kaplan is a recipient of a Canada Research Chair.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Dr. J. Squire, personal communication .

⁶ R. Torkin and H. Yeger, unpublished data.

⁷ R. Torkin, S. Der, and H. Yeger, unpublished data.

Received 9/14/04; revised 10/28/04; accepted 11/ 8/04.