No abstract

Summary 5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are Highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug-resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.

The overexpression of matrix metalloproteinase (MMP) plays an important role in the context of tumor invasion and metastasis, and MMP-2 has been characterized as the most validated target for cancer. Therefore, it is necessary to design matrix metalloproteinase inhibitors (MMPIs) that would be active and selective against MMP-2 but non-selective toward other MMPs. Areas covered: This article clearly describes the structural character of MMP-2 followed by a review of the recent development of selective MMP-2 inhibitors based on their basic structures. Expert opinion: Over the past 30 years, MMPs have been considered to be attractive cancer targets, and several different types of synthetic inhibitors have been identified as anticancer agents, but only a small number of small MMPIs have been examined in clinical trials, and none of these molecules has been established as anticancer drugs due to their adverse effects. One major possibility is that the MMPIs used in clinical trials were broad-spectrum drugs that also inhibited the anti-tumor effects and influenced the mediation of the normal physiological processes of MMPs. MMP-2 has recently been characterized as the most validated target for cancer. Therefore, the design and synthesis of selective MMP-2 inhibitors would be helpful for the treatment of cancer.