Differential effect of camptothecin treatment on topoisomerase IIα expression in ML-1 and HL-60 leukemia cell lines

Derivatives of camptothecin, an inhibitor of human TOPI, are increasingly being used in treatment of cancers, including leukemia. Sequential combination therapy with inhibitors of TOP2 holds potential promise. Binding of p53 has been shown to inhibit transcription of TOP2 alpha. Down-regulation of TOP2 alpha gene expression by the camptothecin induced DNA damage response may adversely affect the effectiveness of sequential therapy To address this question, two leukemia cell lines, ML-1 (with wild type p53) and HL-60 (p53 null) were treated with camptothecin to induce similar degree of apoptosis and residual survival Western blot analysis indicated rapid induction of p53 in ML-1 followed by significant decrease of TOP2 alpha mRNA and protein levels. The expression level of TOP2 alpha in HL60 did not decrease after camptothecin treatment. These results demonstrated that induction of p53 by camptothecin treatment can lead to a decreased level of TOP2 alpha and should be consider ed in design of combination therapy.