Antibiotic identified as potential anti-cancer candidate
Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics
A molecular mechanism that was formerly thought to be important only in bacteria has now been shown to be a potential target for an anticancer therapy based on antibiotic use. David Scheinberg and colleagues, at the Sloan-Kettering Institute, have been investigating an enzyme in humans that is similar to one in bacteria called peptide deformylase (Pdf) and have found that an antibiotic called actinonin, which inhibits the human Pdf, also inhibits tumor growth. Pdf was thought to be important only to bacteria and the bacterially-related organelles of cells of higher organisms.
Pdf is an enzyme that, during protein production, removes a modification called an N-formyl group from the first amino acid, a methionine, in the protein chain. While work began on the development of antibiotics against what was thought to be a bacterial-exclusive enzyme, genome-based data searches identified several classes of Pdf-like sequences in parasites, plants and mammals. Subsequent studies showed that the Pdfs were active both in culture and in the living organism, thus potentially derailing the usefulness of these antibiotics for specifically combating infectious agents. In previous studies, Scheinberg and colleagues had found that actinonin had an antiproliferative effect on human cancer cell lines and on tumor growth in a mouse model. They theorized this growth inhibitory activity might be related to actinonins inhibition of human Pdf.
The researchers now provide the evidence to support this theory. They show that human Pdf is active in the mitochondria and is essential for cellular growth and proliferation. They have designed and created a class of new actinonin-based Pdf inhibitors, and have demonstrated that they selectively inhibit growth in several human tumor cell lines. They further demonstrate that human tumor growth in mice can be suppressed by these Pdf inhibitors and suggest a mechanism of actinonin action. Taken together, these data have significant implications for the understanding and development of various Pdf-based therapeutic strategies for bacteria, mycobacteria, parasites, or cancer.
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