Bortezomib prevents acute doxorubicin ovarian insult and follicle demise, improving the fertility window and pup birth weight in mice

• Published in: PloS one Vol. 9; no. 9; p. e108174
• Main Authors: Roti Roti, Elon C, Ringelstetter, Ashley K, Kropp, Jenna, Abbott, David H, Salih, Sana M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.09.2014; Public Library of Science (PLoS)
• Subjects: Animals; Antibiotics, Antineoplastic - adverse effects; Antineoplastic Agents - therapeutic use; Apoptosis; Biology and Life Sciences; Birth weight; Birth Weight - drug effects; Boronic Acids - therapeutic use; Bortezomib; Cancer; Cancer therapies; Cell division; Chemoprotection; Chemotherapy; Complications; Damage accumulation; Damage prevention; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Doxorubicin; Doxorubicin - adverse effects; Female; Fertility; Fertility - drug effects; Follicles; Gynecology; Humans; Infertility; Litter Size - drug effects; Medical research; Medicine and Health Sciences; Melanoma; Menopause; Mice; Obstetrics; Ovarian Follicle - drug effects; Ovarian Follicle - pathology; Ovarian Neoplasms - drug therapy; Ovaries; Ovary - drug effects; Ovary - pathology; Pediatrics; Phosphorylation; Preservation; Primary Ovarian Insufficiency - chemically induced; Primary Ovarian Insufficiency - pathology; Primary Ovarian Insufficiency - prevention & control; Pyrazines - therapeutic use; Reproductive status; Skin cancer; Surgery; Toxicology; Tumors; Womens health; United States > US; Wisconsin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108174

Increasing numbers of female patients survive cancer, but succumb to primary ovarian insufficiency after chemotherapy. We tested the hypothesis that Bortezomib (Bort) protects ovaries from doxorubicin (DXR) chemotherapy by treating female mice with Bort 1 hour prior to DXR. By preventing DXR accumulation in the ovary, Bort attenuated DXR-induced DNA damage in all ovarian cell types, subsequent γH2AFX phosphorylation, and resulting apoptosis in preantral follicles. Bort pretreatment extended the number of litters per mouse, improved litter size and increased pup weight following DXR treatment, thus increasing the duration of post-chemotherapy fertility and improving pup health. As a promising prophylactic ovoprotective agent, Bort does not interfere with cancer treatment, and is currently used as a chemotherapy adjuvant. Bort-based chemoprotection may preserve ovarian function in a non-invasive manner that avoids surgical ovarian preservation, thus diminishing the health complications of premature menopause following cancer treatment.