Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

Structural modifications of the antibacterial drug nitrofurantoin
were envisioned, employing drug repurposing and biology-oriented drug
synthesis, to serve as possible anticancer agents. Eleven compounds
showed superior safety in non-cancerous human cells. Their antitumor
efficacy was assessed on colorectal, breast, cervical, and liver cancer
cells. Three compounds induced oxidative DNA damage in cancer cells
with subsequent cellular apoptosis. They also upregulated the expression
of Bax while downregulated that of Bcl-2 along with activating caspase
3/7. The DNA damage induced by these compounds, demonstrated by pATM
nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53
mutant) cell lines. Mechanistic studies confirmed the dependence of
these compounds on p53-mediated pathways as they suppressed the p53–MDM2
interaction. Indeed, exposure of radiosensitive prostatic cancer cells
to low non-cytotoxic concentrations of compound 1 enhanced
the cytotoxic response to radiation indicating a possible synergistic
effect. In vivo antitumor activity was verified in
an MCF7-xenograft animal model.