Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or bcl-2.
p53 has been implicated as a determinant of chemosensitivity and radiosensitivity. We measured chemosensitivity of human tumor cell lines (n = 11), with or without wild-type p53, following exposure to clinically useful chemotherapeutic drugs (n = 4). Chemosensitivity and apoptosis induction were correlated independently of p53 status or Bcl-2 protein levels in vitro. Wild-type p53 correlated with chemosensitivity in ovarian carcinoma and some Burkitt's lymphoma cells, but not in leukemia or lung cancer. Bcl-2 levels correlated with chemoresistance only in Burkitt's lymphoma. p53-dependent p21(WAF1/CIP1) induction and cell cycle arrest occurred at sublethal doses of chemotherapy, whereas at lethal doses of chemotherapy apoptotic death was observed, consistent with models proposing a relationship between the level of DNA damage versus survival or death. Loss of apoptosis induction was observed in drug-resistant ML-1 and HL-60 leukemia cells, without changes in p53 or Bcl-2. Targeted loss of p53 protein in H460 lung cancer cells using HPV-16 E6 inhibited the etoposide-induced G1 checkpoint but did not decrease chemosensitivity. Our studies suggest that the simple measurement of apoptosis induction may be a useful predictor of chemosensitivity, at least in vitro, and confirm that p53 status and Bcl-2 expression may be useful predictors of chemosensitivity in certain cell types.
Wu
G S
GS
Howard Hughes Medical Institute, Laboratory of Molecular Oncology, Department of Medicine and Genetics, University of Pennsylvania School of Medicine and Comprehensive Cancer Center, Philadelphia, USA.
El-Deiry
W S
WS
D017209:Apoptosis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53