Targeting of Chk2 as a countermeasure to dose-limiting toxicity triggered by topoisomerase-II (TOP2) poisons.
The DNA damage response (DDR) gene cell cycle checkpoint kinase 2 (Chk2) triggers programmed cell death and lethal radiation-induced toxicity in mice in vivo. However, it is not well established to what extent targeting of Chk2 may protect from dose-limiting toxicities (DLT) inflicted by mainstay cancer chemotherapy. We screened different classes of chemotherapy in wild type and Chk2-deficient cells. Here we show that loss of Chk2 protect from cell death in vitro and lethal toxicity in vivo following treatment with topoisomerase II (TOP2)-inhibitors whereas no such protection was observed following treatment with topoisomerase I (TOP1) inhibitors. Furthermore, through combined in silico and functional screens of the Diversity Set II (NCI/NTP) chemical library we identified the carbanilide-derivative NSC105171, also known as ptu-23, as a novel Chk2 inhibitor (Chk2i). Indeed, NSC105171 can be administered safely to mice to countermeasure etoposide-induced toxicity. Incorporation of Chk2i into chemotherapy protocols employing TOP2-inhibitors may be an effective strategy to prevent DLT's without interfering with treatment.
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, PA 17104, USA.
Prashanth
P
Gokare
Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, PA 17104, USA.
Arunasalam
A
Navaraj
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, PA 17104, USA.
Shengliang
S
Zhang
Institute of Longevity, Department of Cognitive Brain Sciences Research Institute, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.
Noboru
N
Motoyama
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17104, USA.
Shen-Shu
SS
Sung
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.|Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, PA 17104, USA.
Niklas K
NK
Finnberg
D000818:Animals; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010670:Phenylthiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000633:toxicity*
D059005:Topoisomerase II Inhibitors; C041099:N-phenyl-N'-3-hydroxyphenylthiourea; D010670:Phenylthiourea; D064447:Checkpoint Kinase 2
Chk2; apoptosis; etoposide; myelosuppression; topoisomerase inhibitors