Overexpression of BcI-x1 by Cytotoxic Drug Exposure Confers Resistance to Ionizing Radiation-induced Internucleosomal DNA Fragmentation1

Abstrad Acquired resistance to diverse chemotherapeutic agents has been associated with overexpression of the P-glycoprotein. We have seleded human U-937 cells for clones resistant to the cytotoxic agents doxorubicin (U-A20) and vincristine (U-V20). The results demonstrate that P-glycoprotein-positive U-A20 and U-V20 cells exhibit resistance to inducers of internucleosomal DNA fragmentation. Although parental U-937 cells responded to ionizing radiation with the DNA laddering charaderistic of physiological cell death, the drug-resistant lines were insensitive to this effed. The U-A20 and U-V20 clones were also resistant to endonucleolytic DNA cleavage associated with exposure to tumor necrosis fador or ceramide. Previous work has demonstrated that physiological cell death is inhibited by overexpression of the Bcl-2 protein. However, analysis of Bcl-2 revealed similar levels in the parental and drug-resistant cells. In contrast, we show that U-A20 and U-V20 cells overexpress the Bcl-2-related protein, Bcl-x . Moreover, studies with a U-937 cell line transfeded with a Bcl-xL expression vedor confirm resistance to ionizing radiation-induced DNA fragmentation and cell killing. These findings suggest that, unlike Bcl-2, Bcl-x may be constitutively overexpressed as a result of seledion for cytotoxic drug resistance and that Bcl-xL participates in an acquired form of multimodality resistance to chemotherapeutic agents and radiation.