The anti-cancer properties of members of the Brassica family have been recognized since the 1970s and one component, indole-3-carbinol, is already undergoing clinical trials. Indole-3-carbinol induces a G1 cell-cycle arrest of human breast cancer cells, but the underlying molecular mechanisms were not understood. A group at the University of California has now shown that indole-3-carbinol prevents proteolytic processing of the 50-kDa form of cyclin E to a 35-kDa form by neutrophil elastase. The 50-kDa form is typically expressed in normal mammary tissue whereas the 35 kDa form is linked with cancer progression and poor clinical outcomes. Using either cyclin E or the synthetic substrate, N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide, the group were able to demonstrate that indole-3-carbinol inhibits neutrophil elastase with an inhibitory constant of ca 12µM. Neutrophil elastase is the first specific target to be identified for the anti-cancer properties of indole-3-carbinol. The study points to the use of elastase inhibitors for the treatment of cancers where high levels of proteolytic activity are associated with a poor prognosis. The group has already identified compounds that are greater than 100-fold more active in cell culture experiments and hopes that these will play an important role in combination with other cancer therapies. The study is published in the journal PNAS.
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