Fertility protection during chemotherapy treatment by boosting the NAD(P)+ metabolome

Wing Hong Jonathan, Ho, Maria B., Marinova, Dave R., Listijono, Michael J., Bertoldo, Dulama, Richani, Lynn Jee, Kim, Amelia, Brown, Angelique H., Riepsamen, Safaa, Cabot, Emily R., Frost, Sonia, Bustamante, Ling, Zhong, Kaisa, Selesniemi, Derek, Wong, Romanthi, Madawala, Maria, Marchante, Dale M., Goss, Catherine, Li, Toshiyuki, Araki, David J., Livingston, Nigel, Turner, David A., Sinclair, Kirsty A., Walters, Hayden A., Homer, Robert B., Gilchrist, Lindsay E., Wu

EMBO Molecular Medicine |

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.