Differential oncogene expression and susceptibility to apoptosis in the human leukemia HL60 cell lines: implications for etoposide resistance.
Mechanisms of etoposide (VP-16) resistance have been evaluated in a human promyelocytic leukemia HL60 cell line. HL60 resistant (HL60/AR) cells were selected for resistance with adriamycin and were 250-fold resistant to VP-16. We have found that while a significantly higher (10 to 15-fold more) dose of VP-16 was required to induce similar amounts of SDS-KCI-precipitable DNA-protein complex formation in the resistant cell line, there was no difference in the repair of VP-16-induced DNA damage, indicating that differential DNA repair was not involved in VP-16 resistance in HL60 cells. VP-16 treatment significantly inhibited c-myc expression and induced c-jun and c-fos expressions in sensitive cells. In contrast, VP-16 had no effect on c-myc, c-jun or c-fos expressions in resistant cells. The level of bcl2 oncogene was similar in both cell lines; however, treatment with VP-16 resulted in a time- and dose-dependent degradation of the genomic DNA into oligo-sized DNA only in the sensitive cells, indicating that differential expressions of oncogenes (c-myc, c-jun, and c-fos) and susceptibility to apoptosis may play important roles in the sensitivity and resistance to VP-16 in HL60 cells.
Eliot
H E
HE
Biochemical and Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Borner
M M
MM
Sinha
B K
BK
D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D009857:Oncogenes / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide