Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin.

ABSTRACT: Brostallicin is a DNA minor groove binder in phase II clinical trials. Here, we show that brostallicin induces gamma-H2AX nuclear foci that colocalize with 53BP1 and are dependent on glutathione, as shown by inhibition of those gamma-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 gamma-H2AX and antiproliferative 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 gamma-H2AX foci by brostallicin was partially dependent on the repair nuclease Mre11. Pretreatment with aphidicolin partially

SUBMITTER: Guirouilh-Barbat J 

PROVIDER: S-EPMC2760303 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature