期刊
MOLECULAR CANCER THERAPEUTICS
卷 8, 期 7, 页码 1985-1994出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-09-0320
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类别
资金
- National Cancer Institute
- Center for Cancer Research, Bethesda, Maryland
Brostallicin is a DNA minor groove binder in phase 11 clinical trials. Here, we show that brostallicin induces Y-H2AX nuclear foci that colocalize with 53BP1 and are dependent on glutathione, as shown by inhibition of those Y-H2AX foci by L-buthionine sulfoximine. To differentiate brostallicin from the clinically approved minor groove binder trabectedin (ecteinascidin 743), we tested whether the brostallicin-induced Y-H2AX and anti proliferative responses were dependent on nucleotide excision repair and found that, unlike trabectedin, they are not. Additionally, brostallicin retained activity in the trabectedin-resistant HCT116-ER5 cell line. Induction of Y-H2AX foci by brostallicin was partially dependent on the repair nuclease Well. Pretreatment with aphidicolin partially reduced brostallicin-induced Y-H2AX foci, suggesting that brostallicin induces both replication-associated and replication-independent DNA damage. Replication-associated DNA damage was further shown by the colocalization of Y-H2AX foci with replication foci and by the rapid inhibition of DNA synthesis and accumulation of cells in S phase in response to brostallicin. In addition, brostallicin was able to induce lower intensity Y-H2AX foci in human circulating lymphocytes. Together, our results indicate that brostallicin induces DNA double-strand breaks and suggest Y-H2AX as a pharmacodynamic biomarker for brostallicin. [Mol Cancer Ther 2009;8(7):1985-94]
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