Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
Cancer Biol Ther. 2013 May;14(5):458-65. doi: 10.4161/cbt.24424.
The present studies examined viability and DNA damage levels in mammary carcinoma cells following PARP1 and CHK1 inhibitor drug combination exposure. PARP1 inhibitors [AZD2281 ; ABT888 ; NU1025 ; AG014699] interacted with CHK1 inhibitors [UCN-01 ; AZD7762 ; LY2603618] to kill mammary carcinoma cells. PARP1 and CHK1 inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased γH2AX phosphorylation. Treatment of cells with CHK1 inhibitors increased the phosphorylation of CHK1 and ERK1/2. Knock down of ATM suppressed the drug-induced increases in CHK1 and ERK1/2 phosphorylation and enhanced tumor cell killing by PARP1 and CHK1 inhibitors. Expression of dominant negative MEK1 enhanced drug-induced DNA damage whereas expression of activated MEK1 suppressed both the DNA damage response and tumor cell killing. Collectively our data demonstrate that PARP1 and CHK1 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination.
本研究探讨了 PARP1 和 CHK1 抑制剂药物联合暴露后乳腺癌细胞的活力和 DNA 损伤水平。PARP1 抑制剂[AZD2281；ABT888；NU1025；AG014699]与 CHK1 抑制剂[UCN-01；AZD7762；LY2603618]相互作用，杀死乳腺癌细胞。PARP1 和 CHK1 抑制剂相互作用，增加单链和双链 DNA 断裂，与增加 γH2AX 磷酸化相关。用 CHK1 抑制剂处理细胞会增加 CHK1 和 ERK1/2 的磷酸化。敲低 ATM 会抑制药物诱导的 CHK1 和 ERK1/2 磷酸化增加，并增强 PARP1 和 CHK1 抑制剂对肿瘤细胞的杀伤作用。表达显性失活的 MEK1 增强了药物诱导的 DNA 损伤，而表达激活的 MEK1 则抑制了 DNA 损伤反应和肿瘤细胞杀伤。总之，我们的数据表明，PARP1 和 CHK1 抑制剂相互作用可杀死乳腺癌细胞，增加的 DNA 损伤是细胞对这种药物组合反应的替代标志物。
