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- Title
CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy‐induced diarrhea.
- Authors
Xiang, Jinnan; Wang, Haoyu; Tao, Qianqian; Li, Wenxi; Huang, Yanfei; Zhang, Yushuo; Yang, Linan; Zhang, Shiyi
- Abstract
Chemotherapy‐induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)‐approved drugs for treatment of chemotherapy‐induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.
- Subjects
UNITED States. Food &; Drug Administration; CYCLIN-dependent kinase inhibitors; STEM cells; CYCLIN-dependent kinases; CHEMOTHERAPY complications; CANCER chemotherapy; DIARRHEA
- Publication
Journal of Pathology, 2023, Vol 260, Issue 3, p235
- ISSN
0022-3417
- Publication type
Article
- DOI
10.1002/path.6078