Cyclophosphamide- and doxorubicin-induced impairment of high affinity choline uptake and spatial memory can be prevented by dietary choline supplementation in breast tumor bearing mice

AC chemotherapy (Adriamycin and Cytoxan, i.e., doxorubicin and cyclophosphamide, respectively), a common treatment for breast cancer, can lead to significant cognitive side effects, known as Chemotherapy-Related Cognitive Impairments (CRCIs). These cognitive impairments can persist over 20 years and significantly affect the quality of life for cancer patients and survivors. AC chemotherapy is known to impair ovarian function and reduce circulating estradiol (E2), an effect that can decrease high-affinity choline uptake (HACU) and reduce acetylcholine (ACh) availability. Because ACh is involved in attention, learning and memory function we hypothesized that the cognitive deficits observed during and after adjuvant chemotherapy (AC) are associated with compromised high affinity choline uptake (HACU) due to suppressed ovarian function. Increasing available choline has been demonstrated to enhance HACU under conditions of demand for ACh, therefore we propose that choline supplementation can mitigate CRCIs by maintaining cholinergic function throughout and following chemotherapy treatment. Our study demonstrates cognitive deficits in tumor-bearing but not non-tumor-bearing mice during and following AC chemotherapy, suggesting that tumors enhance vulnerability to CRCIs. We found that HACU was impaired in tumor-bearing mice administered AC chemotherapy and that a choline-enriched diet can mitigate both the reduction of HACU induced by chemotherapy and deficits in spatial memory, suggesting a protective role of dietary choline against disruptions in HACU and cognitive impairment caused by chemotherapy. This underscores the potential use of dietary choline supplementation as a part of chemotherapeutic interventions.