1. ¹Department of Oncology/Hematology, Dr von Haunersches Kinderspital, München, Germany
2. ²Klinik für Kinder-und Jugendmedizin, Ulm, Germany
3. ³GSF – Research Center for Environment and Health, Munich, Germany
4. ⁴Division of Neonatology, Department of Obstetrics and Gynecology, University of Munich, Munich, Germany

Correspondence: Dr I Jeremias, GSF – Forschungszentrum für Umwelt und Gesundheit, Abteilung Genvektoren, Marchioninistrasse 25, D-81377 München, Germany. E-mail: I.Jeremias@lrz.uni-muenchen.de

Received 20 February 2007; Revised 6 June 2007; Accepted 11 June 2007; Published online 16 July 2007.

Abstract

Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.