Oxidized methylcytidines 5-hydroxymethyl-2'deoxycytidine (5hmdC) and 5-formy-2'deoxycytidine (5fdC) are deaminated by
cytidine deaminase (CDA) into genome-toxic variants of
uridine, triggering DNA damage and cell death. These compounds are promising chemotherapeutic agents for
cancer cells that are resistant to
pyrimidine derivative drugs, such as
decitabine and
cytarabine, which are inactivated by CDA. In our study, we found that
cancer cells infected with mycoplasma exhibited a markedly increased sensitivity to 5hmdC and 5fdC, which was independent of CDA expression of
cancer cells. In vitro biochemical assay showed that the homologous CDA
protein from mycoplasma was capable of deaminating 5hmdC and 5fdC into their
uridine form. Moreover,
mycoplasma infection increased the sensitivity of
cancer cells to 5hmdC and 5fdC, whereas administration of
Tetrahydrouridine (THU) attenuated this effect, suggesting that mycoplasma CDA confers a similar effect as human CDA. As
mycoplasma infection occurs in many primary
tumors, our findings suggest that intratumoral microbes could enhance the
tumor-killing effect and expand the utility of oxidized methylcytidines in
cancer treatment.