期刊
EMBO MOLECULAR MEDICINE
卷 11, 期 10, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201911031
关键词
chemotherapy; hair loss; palbociclib; taxol; taxotere
资金
- NIHR Manchester Biomedical Research Centre (Inflammatory Hair Diseases Programme)
- MRC DTP Research Experience Placement at the University of Manchester
- SEI Learning Through Research at the University of Manchester
- MBChB APEP at the University of Manchester
Taxanes are a leading cause of severe and often permanent chemotherapy-induced alopecia. As the underlying pathobiology of taxane chemotherapy-induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell-rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy-induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy-induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell-protective therapy in taxane-based oncotherapy, and provides preclinical proof-of-principle in a healthy human (mini-) organ that G1 arrest therapy can limit taxane-induced tissue damage.
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