Fig. 1

Hypothetical mechanisms by which HMTA causes dual targeting effects on DNA repair-deficient cells. 1st targeting: Preferential formaldehyde delivery to cancer cells. Under the acidic conditions of the extracellular environment of cancer cells, HMTA is preferentially hydrolyzed to 6 molecules of formaldehyde and 4 molecules of ammonium ions. Therefore, formaldehyde preferentially introduces DPCs in cancer cells. 2nd targeting: Selective cell death for cancer cells. Formaldehyde selectively kills FANC/BRCA- and HR-deficient cells probably due to a deficiency in DPC repair. In contrast, normal cells are resistant to HMTA because less formaldehyde is formed in a neutral environment and they are proficient in the repair of formaldehyde induced DNA damage