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. Copyright 2000 Wiley-Liss, Inc.
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. Copyright 2000 Wiley-Liss, Inc.
Authors: Wojciech Rzeski; Andrzej Stepulak; Marek Szymański; Marco Sifringer; Józef Kaczor; Katarzyna Wejksza; Barbara Zdzisińska; Martyna Kandefer-Szerszeń Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2006-09-09 Impact factor: 3.000