Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Abstract

This review describes the pivotal roles of cell cycle and checkpoint regulators and discusses development of specific cell cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the crosstalk of signals activated by cell cycle arrest, as well as pediatric-focused drug development are critical for the advancement of drugs for rare childhood diseases.

Limited antitumor activity of combined BET and MEK inhibition in neuroblastoma

“…In addition to the MAPK family, multiple kinases, including ALK (anaplastic lymphoma kinase), 18–21 AURKA (aurora kinase A), 34–36 CDK4 (Cyclin‐dependent kinase 4), 37,38 and CHK1 (Checkpoint kinase 1), 39,40 play prominent roles in neuroblastoma tumorigenesis. Inhibitors directed against these kinases are being studied for incorporation into the treatment of subsets of patients with neuroblastoma, with ALK inhibitors currently being studied with the frontline standard of care therapy 1,41 .…”

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

“…Microtubules are important in maintaining the structure of cells and have become an excellent drug target in chemotherapy . Currently, Taxol is widely used in the treatment of NSCLC in the clinics.…”

“…Microtubules are important in maintaining the structure of cells and have become an excellent drug target in chemotherapy. [41][42][43] Currently, Taxol is widely used in the treatment of NSCLC in the clinics. However, many patients have acquired resistance to Taxol, and even those who initially respond will eventually exhibit MDR.…”

Norcantharidin inhibits viability and induces cell cycle arrest and apoptosis in osteosarcoma

“…Interestingly, human fibroblasts exhibited resistance to NCTD and the IC 50 value for 24 h was 58.82 µΜ (data not shown). Cell cycle imbalance is an essential mechanism involved in the proliferation of malignant tumor cells (14)(15)(16). Certain studies have supported the hypothesis that the induction of cell cycle arrest may be an effective method for controlling tumor proliferation (17)(18)(19).…”