Abstract
The molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood. In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo. CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug-resistant and CD95-resistant cell lines. Furthermore, up-regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95-L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy.
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Friesen, C., Fulda, S. & Debatin, KM. Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia 11, 1833–1841 (1997). https://doi.org/10.1038/sj.leu.2400827
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2400827
- Springer Nature Limited
Keywords
This article is cited by
-
Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma
Leukemia (2019)
-
Tea (Camellia sinensis) infusions ameliorate cancer in 4TI metastatic breast cancer model
BMC Complementary and Alternative Medicine (2017)
-
Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer
Breast Cancer Research (2016)
-
CD74 interferes with the expression of fas receptor on the surface of lymphoma cells
Journal of Experimental & Clinical Cancer Research (2014)
-
Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells
Cell Death & Disease (2013)