BACKGROUND: APR-246 belongs to a new generation of the compounds that restore normal p53 function in cells with mutated or wild type p53. The purpose of this study was to examine the effects of APR-246 alone and in combination with other drugs in acute myeloid leukemia (AML) cells. METHODS: Primary leukemic cells from patients with AML and AML cell lines were studied with respect to cytotoxic and apoptotic effects and mechanism of action of APR-246, alone and in combination with Ara-C, daunorubicin and fludarabine. RESULTS: APR-246 showed dose-dependent cytotoxic and apoptotic effects in AML cell lines as well as in primary AML patient cells. Cells from patients with TP53 mutation and complex karyotype were more resistant to conventional drugs while these factors did not significantly affect the sensitivity to APR-246. APR-246 increased active caspase-3, upregulated p53 protein levels, and increased the bax/bcl-2 ratio independently of TP53 mutational status in patient cells sensitive to APR-246. AML cells with high p14(ARF) expression were significantly more sensitive to APR-246. APR-246 induced significant synergistic effects in combination with conventional chemotherapeutic agents. Pre-incubation with APR-246 induced more synergistic effects compared to other schedules. In patient cells, pronounced synergism was found when combining APR-246 with danuorubicin. CONCLUSION: We conclude that APR-246 is effective in AML cells irrespectively of TP53 mutational status and that it has promising properties for combination studies in AML.
BACKGROUND:APR-246 belongs to a new generation of the compounds that restore normal p53 function in cells with mutated or wild type p53. The purpose of this study was to examine the effects of APR-246 alone and in combination with other drugs in acute myeloid leukemia (AML) cells. METHODS: Primary leukemic cells from patients with AML and AML cell lines were studied with respect to cytotoxic and apoptotic effects and mechanism of action of APR-246, alone and in combination with Ara-C, daunorubicin and fludarabine. RESULTS:APR-246 showed dose-dependent cytotoxic and apoptotic effects in AML cell lines as well as in primary AMLpatient cells. Cells from patients with TP53 mutation and complex karyotype were more resistant to conventional drugs while these factors did not significantly affect the sensitivity to APR-246. APR-246 increased active caspase-3, upregulated p53 protein levels, and increased the bax/bcl-2 ratio independently of TP53 mutational status in patient cells sensitive to APR-246. AML cells with high p14(ARF) expression were significantly more sensitive to APR-246. APR-246 induced significant synergistic effects in combination with conventional chemotherapeutic agents. Pre-incubation with APR-246 induced more synergistic effects compared to other schedules. In patient cells, pronounced synergism was found when combining APR-246 with danuorubicin. CONCLUSION: We conclude that APR-246 is effective in AML cells irrespectively of TP53 mutational status and that it has promising properties for combination studies in AML.
Authors: Richard J Jones; Chad C Bjorklund; Veerabhadran Baladandayuthapani; Deborah J Kuhn; Robert Z Orlowski Journal: Mol Cancer Ther Date: 2012-08-28 Impact factor: 6.261
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