Abstract
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 wildtype TP53 gene copies. However, it is unclear whether TP53 inhibitors can increase the sensitivity of TP53 wildtype 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 wildtype TP53. Moreover, inhibition of TP53 by a TP53 inhibitor, PFTα, increased the ATO sensitivity of TP53 wildtype 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. Cotreatment with PFTα enhanced ATO-induced dynamic transcriptional changes. Overall, our results provide evidence for using TP53 chemical inhibitors to enhance the ATO-mediated therapeutic response against TP53 wildtype tumor cells.