Acid-specific formaldehyde donor is a potential, dual targeting cancer chemotherapeutic/chemo preventive drug for FANC/BRCA-mutant cancer

BACKGROUND: Development of chemotherapeutic/preventive drugs that selectively kill cancer - the Holy Grail of cancer research - is a major challenge. A particular difficulty arises when chemotherapeutics and radiation are found to be rather ineffective against quiescent cancer cells in solid tumors. In the limited oxygen condition within a solid tumor, glycolysis induces an acidic environment. In such an environment the compound hexamethylenetetramine (HMTA) will act as a formaldehyde donor. HMTA has been characterized a non-carcinogen in experimental animals and causes no major adverse side-effects in humans. We previously reported that both a chicken B-lymphocyte cell line transformed with an avian leucosis virus and human colon cancer cells deficient in the FANC/BRCA pathway are hypersensitive to formaldehyde. Thus, we assessed the potential usage of HMTA as a chemotherapeutic agent. RESULTS: The differential cytotoxicity of HMTA was tested using chicken DT40 cells deficient in DNA repair under neutral and acidic conditions. While HMTA is not efficiently hydrolyzed under neutral conditions, all HR-deficient DT40 cells tested were hypersensitive to HMTA at pH 7.3. In contrast, HMTA clearly increased cell toxicity in FANCD2-, BRCA1- and BRCA2- deficient cells under acidic conditions. CONCLUSION: Here we show that in vitro experiments showed that at low pH HMTA causes drastic cytotoxicity specifically in cells deficient in the FANC/BRCA pathway. These results strongly suggest that HMTA may be an attractive, dual-targeting chemotherapeutic/preventive drug for the selective delivery of formaldehyde to solid tumors and causes cell death in FANC/BRCA-deficient cells without major adverse effects.