CNDAC, a nucleoside analog, is a major metabolite of oral drug sapacitabine.

CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway, whereas lethal DSBs are mainly repaired through homologous recombination and it induces DSBs, which are products of replication, rather than a consequence of induction of apoptosis. Deficiency in two Rad51 paralogs, Rad51D and XRCC3, greatly sensitizes cells to CNDAC. CNDAC shows potent activity against human fibroblasts deficient in ATM or transfected with an empty vector, approximately 30-fold more than cells repleted with full-length ATM cDNA (IC50s: 0.01 μM and 0.3 μM). The Rad51D-null cell line is approximately 50-fold more sensitive to CNDAC (IC50: 0.006 μM) compared to 51D1.3, the Rad51D-repleted line (IC50: 0.32 μM) [1]. CNDAC displays inhibitory activity against HL-60 and THP-1 cells (IC50s: 1.58 μM and 0.84 μM). CNDAC (10?μM) causes a significant drop in cell survival compared to the untreated on days 4, 7, and 14. CNDAC is more effective at reducing the viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line [2]. CNDAC causes DNA damage, and DNA-PK and ATR are dispensable for cell survival. CNDAC-induced DNA damage is repaired through the homologous recombination pathway [3].