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

Abstract

BACKGROUND AND PROCEDURE:

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.

• Authors: S Fulda, K M Debatin
• Journal: Medical and pediatric oncology (Med Pediatr Oncol) Vol. 35 Issue 6 Pg. 616-8 (Dec 2000) ISSN: 0098-1532 [Print] United States
• PMID: 11107130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Pentacyclic Triterpenes
• Triterpenes
• Betulinic Acid

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Humans
• Mitochondria (drug effects)
• Neuroblastoma (pathology)
• Neuroectodermal Tumors (pathology)
• Pentacyclic Triterpenes
• Triterpenes (pharmacology)
• Tumor Cells, Cultured
• Betulinic Acid