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Differential effect of camptothecin treatment on topoisomerase II alpha expression in ML-1 and HL-60 leukemia cell
J Nair1, F Traganos, Y C Tse-Dinh
1Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.
Abstract:
Derivatives of camptothecin, an inhibitor of human TOP1, 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 considered in design of combination therapy.
Insights
Camptothecin, a topoisomerase I inhibitor, can decrease topoisomerase II alpha levels in leukemia cells with wild-type p53. This p53-dependent down-regulation may impact sequential combination cancer therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Camptothecin derivatives are used in cancer treatment, particularly leukemia.
- Sequential combination therapy with topoisomerase II (TOP2) inhibitors shows promise.
- p53 binding can inhibit TOP2 alpha transcription.
Purpose of the Study:
- To investigate if camptothecin-induced DNA damage response down-regulates TOP2 alpha expression.
- To assess the impact of p53 status on TOP2 alpha levels after camptothecin treatment.
- To inform the design of sequential combination cancer therapies.
Main Methods:
- Treatment of two leukemia cell lines (ML-1 with wild-type p53, HL-60 with p53 null) with camptothecin.
- Induction of similar apoptosis and residual survival levels in both cell lines.
- Western blot analysis to measure TOP2 alpha mRNA and protein levels.
Main Results:
- Camptothecin rapidly induced p53 in ML-1 cells.
- ML-1 cells showed a significant decrease in TOP2 alpha mRNA and protein levels post-treatment.
- HL-60 cells (p53 null) did not exhibit decreased TOP2 alpha expression after camptothecin treatment.
Conclusions:
- Camptothecin-induced p53 activation leads to decreased TOP2 alpha levels in leukemia cells.
- This p53-dependent down-regulation of TOP2 alpha is a critical consideration for sequential combination therapy design.
- Understanding p53's role is essential for optimizing cancer treatment strategies involving topoisomerase inhibitors.
