Date of Completion

Spring 5-1-2026

Thesis Advisor(s)

Charles Giardina

Honors Major

Physiology and Neurobiology

Disciplines

Cancer Biology | Cell and Developmental Biology | Cell Biology

Abstract

Antifolates disrupt one-carbon metabolism (OCM), which stops nucleotide synthesis and therefore slows down cell proliferation. Our experimental antifolate, UCP1162, stops de novo purine synthesis and thymidine synthesis by targeting the OCM pathway. We investigated whether the downstream metabolites of OCM pathway: methionine, thymidine, and inosine, affect the cell death caused by UCP1162 using MV4-11 leukemia cells. Thymidine was found to partially rescue MV4-11 cells from UCP1162, in contrast, inosine was found to accelerate the cell death caused by UCP1162. These cytotoxic effects of UCP1162 alone and in combination with inosine were irreversible, as removal of treatment did not restore cell viability. The cells were also supplemented with other nucleosides associated with purine synthesis (adenosine and guanosine) in combination with UCP1162 to see if there were similar effects. The cell death rate of the adenosine supplementation was similar to that of inosine supplementation, but guanosine supplementation was weaker. The combination treatment of UCP1162 and inosine had a similar effect on HeLa cells. In addition to this, the combination treatment of inosine and UCP1162 on MV4-11 cells showed an increase in DNA synthesis, sub-diploid cell appearance, and DNA fragmentation. These results suggest that the combination of UCP1162 with inosine enhances cytotoxicity and cell death; demonstrating a potential novel combination treatment.

Accessibility Requirements

1

Download

Share

COinS