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. 2012 Aug;82(2):322–332. doi: 10.1124/mol.112.078907

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Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics

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Fig. 1. — PARP1 and CHK1 inhibitors interact in a greater than additive fashion in killing triple-negative and fulvestrant-resistant mammary carcinoma cells. A, BT549 and HCC1187 cells were treated with CHK1 inhibitor, UCN-01 (50 nM), PARP1 inhibitor, AZD2281 (1 μM), or UCN-01+AZD2281 for 24 or 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). B, BT549 and HCC1187 cells were treated with CHK1 inhibitor, AZD7762 (50 nM), PARP1 inhibitor, ABT888 (1.0 μM), PARP1 inhibitor, AZD2281 (1 μM), AZD7762+AZD2281, or ABT888+AZD7762 for 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). C, HCC38 and HCC1954 cells were treated with AZD7762 (50 nM), ABT888 (1.0 μM), AZD2281 (1 μM), AZD7762+AZD2281, or ABT888+AZD7762 for 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). D, MCF7 and fulvestrant-resistant MCF7 (MCF7 F) cells were treated with AZD7762 (50 nM), AZD2281 (1 μM), or AZD7762+AZD2281 for 48 h. Floating and attached cells were isolated after drug exposure, and viability was measured by trypan blue exclusion (±S.E.M., n = 3). E, BT549 cells were infected with empty vector virus (CMV) or with viruses to express dominant-negative caspase 9 (dn Casp9), BCL-XL, or c-FLIP-s. Twenty-four hours after infection, cells were treated with vehicle (DMSO) or with AZD7762 (50 nM)+AZD2281 (1 μM). Cells were fixed 48 h later, and viability was determined using TUNEL assay (±S.E.M., n = 3). Upper inset blot, BT549 cells were isolated 24 h after drug exposure, and immunoblotting was performed to detect the levels of cleaved caspase 3 (n = 2). F, MCF7 cells were pretreated for 30 min with vehicle (DMSO) or the JNK inhibitory peptide (10 μM, JNK IP). After 30 min, cells were treated with vehicle (DMSO) or with AZD7762 (50 nM)+AZD2281 (1 μM). Cells were isolated 48 h later, and viability was determined by trypan blue exclusion (±S.E.M., n = 3). Upper inset blot, cells were isolated 24 h after drug exposure, and immunoblotting was performed to detect the levels of JNK1/2 phosphorylation (n = 2). VEH, vehicle; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Fig. 1. — PARP1 and CHK1 inhibitors interact in a greater than additive fashion in killing triple-negative and fulvestrant-resistant mammary carcinoma cells. A, BT549 and HCC1187 cells were treated with CHK1 inhibitor, UCN-01 (50 nM), PARP1 inhibitor, AZD2281 (1 μM), or UCN-01+AZD2281 for 24 or 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). B, BT549 and HCC1187 cells were treated with CHK1 inhibitor, AZD7762 (50 nM), PARP1 inhibitor, ABT888 (1.0 μM), PARP1 inhibitor, AZD2281 (1 μM), AZD7762+AZD2281, or ABT888+AZD7762 for 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). C, HCC38 and HCC1954 cells were treated with AZD7762 (50 nM), ABT888 (1.0 μM), AZD2281 (1 μM), AZD7762+AZD2281, or ABT888+AZD7762 for 48 h. Floating and attached cells were isolated after drug exposure, and cell viability was measured by trypan blue exclusion (±S.E.M., n = 3). D, MCF7 and fulvestrant-resistant MCF7 (MCF7 F) cells were treated with AZD7762 (50 nM), AZD2281 (1 μM), or AZD7762+AZD2281 for 48 h. Floating and attached cells were isolated after drug exposure, and viability was measured by trypan blue exclusion (±S.E.M., n = 3). E, BT549 cells were infected with empty vector virus (CMV) or with viruses to express dominant-negative caspase 9 (dn Casp9), BCL-XL, or c-FLIP-s. Twenty-four hours after infection, cells were treated with vehicle (DMSO) or with AZD7762 (50 nM)+AZD2281 (1 μM). Cells were fixed 48 h later, and viability was determined using TUNEL assay (±S.E.M., n = 3). Upper inset blot, BT549 cells were isolated 24 h after drug exposure, and immunoblotting was performed to detect the levels of cleaved caspase 3 (n = 2). F, MCF7 cells were pretreated for 30 min with vehicle (DMSO) or the JNK inhibitory peptide (10 μM, JNK IP). After 30 min, cells were treated with vehicle (DMSO) or with AZD7762 (50 nM)+AZD2281 (1 μM). Cells were isolated 48 h later, and viability was determined by trypan blue exclusion (±S.E.M., n = 3). Upper inset blot, cells were isolated 24 h after drug exposure, and immunoblotting was performed to detect the levels of JNK1/2 phosphorylation (n = 2). VEH, vehicle; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.