PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells.

Abstract

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.

• Authors: Laurence Booth, Nichola Cruickshanks, Thomas Ridder, Yun Dai, Steven Grant, Paul Dent
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 14 Issue 5 Pg. 458-65 (May 2013) ISSN: 1555-8576 [Electronic] United States
• PMID: 23917378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• H2AX protein, human
• Histones
• Poly(ADP-ribose) Polymerase Inhibitors
• Protein Kinase Inhibitors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Death (drug effects)
• Checkpoint Kinase 1
• DNA Damage
• Female
• Histones (metabolism)
• Humans
• MAP Kinase Kinase 1 (metabolism)
• MCF-7 Cells
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (genetics, metabolism)
• Signal Transduction
• Transfection