A common side-effect of cancer chemotherapy is hair loss, termed chemotherapy-induced alopecia (CIA). CIA is perhaps the most visual of the side-effects of chemotherapy and is highly distressing for patients who experience it. In most patients, this effect is temporary and the lost hair will regrow within 3 months. In the remaining, the lost hair may not grow back: permanent CIA (pCIA) is diagnosed when there is incomplete or no hair regrowth 6 months after the end of chemotherapy. The causes of pCIA are poorly understood and likely to vary between different treatment regimens. However, it is believed that pCIA occurs due to damage to epithelial hair follicle stem cells (eHFSCs) and irreversible loss of functional hair follicles. Indeed, different drugs used in chemotherapy, such as cyclophosphamide, can directly kill or damage eHFSCs.

In the present study, the authors studied the effects of cyclophosphamide on cultured full-length human hair follicles. As expected, the active form of cyclophosphamide (4-hydroperoxycyclophosphamide [4-HC]) promoted hair bulb dystrophy and DNA damage, as well as cell death and pathological epithelial-mesenchymal transition in eHFSCs. This cumulative damage to eHFSCs led to the loss of hair follicle progenitor cells ex vivo, suggesting that a similar effect could occur in vivo and contribute to the development of pCIA.

Because other permanent forms of hair loss go hand-in-hand with damage to the hair follicle, characterized by eHFSCs death, the scientists wanted to understand if pCIA can be prevented by mitigating drug-induced damage to the hair follicle. To this end, they took advantage of a novel drug named N-Acetyl-GED-0507-34-Levo (NAGED). NAGED activates a protein named PPARγ, which is important for a myriad of biological functions in the hair follicle. After applying NAGED to the hair follicle cultures, it was observed that damage to the hair follicle (namely hair bulb dystrophy and eHFSCs cell death) was reduced. These protective effects were sufficient to prevent the loss of eHFSCs that was found to occur after treatment with 4-HC.

Taken together, the results from the present study suggest that NAGED may promote faster hair recovery after chemotherapy, highlighting the hitherto unknown therapeutic potential of PPARγ stimulation as a preventive strategy for pCIA and, quite possible, other alopecias characterized by eHFSC apoptosis. These promising findings pave the way for clinical trials in the future, which will be necessary to understand if NAGED may decrease the incidence of pCIA in patients who undergo chemotherapy.

Reference:

I Piccini, L Brunken, J Chéret , S Ghatak, Y Ramot, M Alam , T S Purba , J Hardman , H Erdmann , F Jimenez , R Paus , M Bertolini

‘PPARg signaling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition’

Br J Dermatol. 2021 Sep 8. doi: 10.1111/bjd.20745.