Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors

Background and Procedure. We identified BetA as a new cytotoxic agent activ e against neuroectodermal tumor cells including neuroblastoma, medulloblast oma, glioblastoma and Ewing sarcoma cells, representing the most common sol id tumors of childhood. Results. BetA induced apoptosis by a direct effect on mitochondria independent of accumulation of wild-type p53 protein and in dependent of death-inducing ligand/receptor systems such as CD95. Mitochond rial perturbations on treatment with BetA resulted in the release of solubl e apoptogenic factors such as cytochrome c or AlF from mitochondria into th e cytosol, where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X-L that blocked loss of the mitochon drial membrane potential and cytochrome c release from mitochondria also co nferred resistance to BetA. Most importantly, BetA exhibited potent antitum or activity on neuroblastoma cells resistant to CD95- or doxorubicin-trigge red apoptosis and on primary tumor cells from patients with neuroectodermal tumors. Conclusions. Thus, BetA may be a promising new agent in the treatm ent of neuroectodermal tumors including neuroblastoma in vivo. (C) 2000 Wil ey-Liss, Inc.