Effects of the novel DNA dependent protein kinase inhibitor, IC486241, on the DNA damage response to doxorubicin and cisplatin in breast cancer cells

被引：23

作者：

Davidson, David ^{[1
]}

Grenier, Jeremy ^{[1
]}

Martinez-Marignac, Veronica ^{[1
]}

Amrein, Lilian ^{[1
]}

Shawi, May ^{[1
]}

Tokars, Marc ^{[2
]}

Aloyz, Raquel ^{[1
]}

Panasci, Lawrence ^{[1
]}

机构：

[1] McGill Univ, Jewish Gen Hosp, Montreal Ctr Expt Therapeut Canc, Segal Canc Ctr,Lady Davis Inst, Montreal, PQ H3T 1E2, Canada

[2] Luitpold Pharmaceut Inc, Preclin Dev, Norristown, PA 19403 USA

来源：

INVESTIGATIONAL NEW DRUGS | 2012年 / 30卷 / 04期

关键词：

PK; CYTOTOXICITY; REPAIR; ATM; COMBINATION; RADIATION; TARGET; LINES; ASSAY; H2AX;

D O I：

10.1007/s10637-011-9678-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The purpose of this study was to determine the degree to which the novel DNA-PKcs inhibitor, IC486241 (ICC), synergizes the cytotoxicity of DNA damaging agents in 3 genetically diverse breast cancer cell lines. The sulforhodamine B (SRB) assay was employed as a primary screening method to determine the in-vitro cytotoxicity and the degree of synergy of ICC in combination with the topoisomerase II inhibitor, doxorubicin, or the DNA cross linking agent, cisplatin. Molecular mechanisms underlying drug toxicity were probed using immunostaining and flow cytometry, as well as, the alkaline comet assay to detect DNA damage. In this study, improved cytotoxicity and significant synergy were observed with both anticancer agents in the presence of nontoxic concentrations of ICC. Moreover, ICC decreased doxorubicin-induced DNA-PKcs autophosphorylation on Ser2056 and increased doxorubicin-induced DNA fragmentation. In conclusion, the novel DNA-PKcs inhibitor, ICC, synergistically sensitized 3 breast cancer cell lines to doxorubicin and cisplatin. Enhanced efficacy of doxorubicin was achieved by inhibiting non-homologous end joining resulting in increased accumulation of DNA damage.

引用

页码：1736 / 1742

页数：7

共 29 条

[1] Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)benzo-[h]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase [J].