Targeting of Chk2 as a countermeasure to dose-limiting toxicity triggered by topoisomerase-II (TOP2) poisons

• Published in: Oncotarget Vol. 7; no. 20; pp. 29520 - 29530
• Main Authors: Gokare, Prashanth, Navaraj, Arunasalam, Zhang, Shengliang, Motoyama, Noboru, Sung, Shen-Shu, Finnberg, Niklas K
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 17.05.2016
• Subjects: Animals; Checkpoint Kinase 2 - antagonists & inhibitors; Male; Maximum Tolerated Dose; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylthiourea - analogs & derivatives; Phenylthiourea - pharmacology; Research Paper; Topoisomerase II Inhibitors - toxicity; apoptosis; etoposide; topoisomerase inhibitors; Chk2; myelosuppression
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8790

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.