TP53 inhibitor PFTα increases the sensitivity of arsenic trioxide in TP53 wild type tumor cells

Arsenic trioxide (ATO) has been shown to be effective in treating acute promyelocytic leukemia. TP53 mutated/null tumor cells are more sensitive to ATO treatment compared to tumor cells carrying wild type TP53 gene copies. However, it is unclear whether TP53 inhibitors can increase the sensitivity of TP53 wild type tumor cells to ATO. Here, we show that breast, colon and lung cancer cell lines with mutated/null TP53 are more sensitive to ATO-induced cell growth inhibition than cells with wild type TP53. Moreover, inhibition of TP53 by a TP53 inhibitor, PFTα, increased the ATO sensitivity of TP53 wild type tumor cells, coincident with ATO-induced cell growth arrest and cell apoptosis. Furthermore, combined treatment with ATO and PFTα synergistically inhibited tumor growth in mouse xenografts in vivo. Through microarray transcriptional analysis, we found that ATO-regulated genes were associated with TP53 and cell cycle signaling pathways. Co-treatment with PFTα enhanced ATO induced dynamic transcriptional changes. Overall, our results provide evidences in using TP53 chemical inhibitors to enhance the ATO-mediated therapeutic response against TP53 wild type tumor cells.