Diederich, M. | Search bioRxiv

bioRxiv2020

Asciminib mitigates DNA damage stress signalling induced by cyclophosphamide in the ovary

Cancer treatments often have adverse effects on the quality of life for young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signalling pathways activated by cyclophosphamide in mouse ovaries. Besides, we provide evidence that Asciminib did not interfere with the cytotoxic effect of cyclophosphamide in MCF7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without preventing the anticancer potential of cyclophosphamide. Altogether these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effect of cancer therapies.

cell biology↗

bioRxiv2019

Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-{gamma}H2AX-checkpoint kinase 2 (CHK2)-p53/TAp63 isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

cell biology↗