Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors.
METHODS
We identified BetA as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing sarcoma cells, representing the most common solid tumors of childhood.


RESULTS
BetA induced apoptosis by a direct effect on mitochondria independent of accumulation of wild-type p53 protein and independent of death-inducing ligand/receptor systems such as CD95. Mitochondrial perturbations on treatment with BetA resulted in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol, where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L) that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria also conferred resistance to BetA. Most importantly, BetA exhibited potent antitumor activity on neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis and on primary tumor cells from patients with neuroectodermal tumors.


CONCLUSIONS
Thus, BetA may be a promising new agent in the treatment of neuroectodermal tumors including neuroblastoma in vivo.
Fulda
S
S
University Children's Hospital, Ulm, Germany.
Debatin
K M
KM
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D009447:Neuroblastoma / Q000473:pathology*; D017599:Neuroectodermal Tumors / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid