Doxorubicin induces the acetylation of histone Hl in a human colon cancer cell line (LoVo/DX) selected for resistance to the drug, but not in the sensitive parental line (LoVo)

The effect of doxorubicin (DX) treatment on Hl synthesis and acetylation was studied in two human colon adenocarcinoma cell lines, sensitive (LoVo) and resistant (LoVo/DX) to this drug. Histone variants were resolved by a high resolution two-dimensional gel electrophoresis system coupled to fluorography for the detection of radioactive incorporation. The relative synthesis of H1.4 and H1.5 variants was slightly reduced by DX. This is probably related to the inhibition of DNA synthesis consequent to drug treatment. The main effect is that DX induces the acetylation of H1 isoproteins in the LoVo/DX resistant line but not in the parental line, which is 30 times more sensitive to anthracyclines. The different behavior of the two cell lines cannot be attributed to different cellular drug retention since the DX doses chosen (1.25 for LoVo and 40 μg/ml for LoVo/DX cells) correspond to similar intracellular drug concentrations. H1 acetylation persisted after exposure to cycloheximide in DX treated LoVo/DX cells, indicating that it is a postranslational event.The induction of H1 acetylation appears rather specific since no increase was found in ³H-acetate incorporation on the total cellular TCA-precipitable fraction. In addition DX treatment did not modify the acetylation of core histones in either LoVo or LoVo/DX cell lines.