title: Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors.
abstract: The present studies sought to define whether checkpoint kinase 1 (CHK1) inhibitors and poly(ADP-ribose) polymerase 1 (PARP1) inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill estrogen receptor (ER)+, ER+ fulvestrant-resistant, HER2+, or triple-negative mammary carcinoma cells in a manner that was not apparently affected by phosphatase and tensin homolog deleted on chromosome 10 functional status. Expression of dominant-negative CHK1 enhanced and overexpression of wild-type CHK1 suppressed the toxicity of PARP1 inhibitors in a dose-dependent fashion. Knockdown of PARP1 enhanced the lethality of CHK1 inhibitors in a dose-dependent fashion. PARP1 and CHK1 inhibitors interacted in vivo both to suppress the growth of large established tumors and to suppress the growth of smaller developing tumors; the combination enhanced animal survival. PARP1 and CHK1 inhibitors profoundly radiosensitized cells in vitro and in vivo. In conclusion, our data demonstrate that the combination of PARP1 and CHK1 inhibitors has antitumor activity in vivo against multiple mammary tumor types and that translation of this approach could prove to be a useful anticancer therapeutic approach.
authors.affiliation: Massey Cancer Center, Department of Neurosurgery, Virginia Commonwealth University, 401 College St., Richmond, VA 23298-0035, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse