Nitroreductase enzymes in the Fight Against Cancer

Application of Nitroreductases in Enzyme-Prodrug Therapy

Enzyme based prodrug therapy (EPT) has received considerable interest in recent years and represents a very promising strategy to address the problems that usually associated with chemotherapy in cancer treatment. Among the enzyme classes used in EPT, nitroreductases are being given special attentions. Activation of prodrugs by bacterial nitroreductases (NTRs) is particularly important because of having differential effects between tumor and normal cells in cancer prodrug therapy. The basis of the activation is that NTRs catalyze the reduction of nitro groups in substrates to form the corresponding hydroxylamine derivatives, which can be further metabolized by cellular enzymes to form cytotoxic agents that cross link with DNA, resulting in rapid cell deaths (Figure). Such reduction properties establish NTRs as prodrug activators and NTR based EPT has reached clinical trial stages.

There are however several limitations present for currently available NTRs; mainly stability and low level of activity when conjugated with an antibody for an effective delivery. To tackle such limitations, we have studied properties of two novel enzymes of thermophilic and mesophilic origins. Recombinant protein expression systems were developed and biochemical characterizations of NTRs have been completed. To prove the principle, both NTR have been used with a cancer prodrug of CB1954 and related substrates for prodrug activations.

Our preliminary results using cancer cell lines have indicated that both enzymes present great potentials for suitability in the cancer therapy.

This has been supported by Tubitak with project number of 110T754.