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The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF 3 and the DNA damage response in cancer cells
Author(s) -
Deng Shiwei,
Yan Tiandong,
Nikolova Teodora,
Fuhrmann Dominik,
Nemecek Andrea,
GödtelArmbrust Ute,
Kaina Bernd,
Wojnowski Leszek
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13046
Subject(s) - dexrazoxane , dna damage , topoisomerase , chemistry , microbiology and biotechnology , apoptosis , cancer research , biology , dna , biochemistry , cancer , anthracycline , genetics , breast cancer
Background and Purpose The catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response. Experimental Approach We investigated the DNA damage response and the role of the activating transcription factor 3 ( ATF 3) accumulation in tumour cells exposed to dexrazoxane. Key Results Dexrazoxane exposure induced topoisomerase II α ( TOP2A )‐dependent cell death, γ‐ H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of γ‐ H2AX / 53BP1 foci, ATM (ataxia telangiectasia mutated), ATR ( ATM and R ad3‐related), C hk1 and C hk2 phosphorylation, and by p53 accumulation. Dexrazoxane‐induced γ‐ H2AX accumulation was dependent on ATM . ATF 3 protein was induced by dexrazoxane in a concentration‐ and time‐dependent manner, which was abolished in TOP2A ‐depleted cells and in cells pre‐incubated with ATM inhibitor. Knockdown of ATF 3 gene expression by si RNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane ‐treated cells. This was accompanied by increased γ‐ H2AX accumulation. ATF 3 knockdown also delayed the repair of dexrazoxane ‐induced DNA double‐strand breaks. Conclusions and Implications As with other TOP2A poisons, dexrazoxane induced DNA double‐strand breaks followed by activation of the DNA damage response. The DNA damage‐triggered ATF 3 controlled p53 accumulation and generation of double‐strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.