Received for publication February 25, 2005.
Revised May 3, 2005.
Accepted for publication May 4, 2005.

Resistance of human astrocytoma cells to apoptosis induced by mitochondria-damaging agents: possible implications for anticancer therapy

Abstract

The success of anti-cancer chemotherapy is often hampered by resistance to apoptosis, which may depend on defects in intracellular cell death pathways. Characterizing the alterations of these pathways is a prerequisite for developing alternative and effective anti-tumoral strategies. Here, we investigated the susceptibility of a human astrocytoma cell line (ADF cells) to apoptotic cell death induced by mitochondria-damaging agents. Neither the anti-cancer agent Betulinic Acid nor the "mitochondriotropic" poisons 2-deoxy-D-ribose and KCN induced apoptosis of these cells, despite induction of highly significant mitochondrial depolarization, eventually resulting in necrotic death. Resistance to apoptosis was not due to presence of the multidrug resistance pump, nor to impaired expression of caspase-8, caspase-9 or "executioner" caspase-3. Cloning of caspase-9 revealed the presence of full-length caspase-9a and a short variant (caspase-9b), which, in other tumors, acts as a dominant negative of the long isoform. All analyzed clones showed a point mutation in the prodomain region that is known to interact with mitochondria-released factors. Thus, in these human astrocytoma cells, mitochondria-damaging agents induce a regulated form of mitochondrial-dependent necrotic cell death (oncosis). Resistance to apoptosis is due to an intrinsic defect of caspase-9 leading to inhibition of enzyme activation and/or impaired interaction with proteins released from depolarized mitochondria. These results may have implications for developing strategies aimed at overcoming tumor resistance to chemotherapy.

Key words: Apoptosis, Betulinic Acid, Caspase-9, Chemotherapy, Human Astrocytoma, Mitochondria

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