Anticancer drugs: Proteasome inhibitor unleashes three-pronged attack

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The myxobacterium peptide argyrin A is a promising novel anti-cancer compound that mediates stabilization of the p27^KIP1 tumor suppressor through proteasomal inhibition.

The loss of tumour suppressor proteins is a frequent event in the development of cancer. A prominent example for this is the cell-cycle regulator p27^KIP1, the expression levels of which often correlate directly with patient prognosis. In a quest to find compounds that boost the cellular levels of p27^KIP1, Nickeleit and colleagues have now identified a promising novel proteasome inhibitor that exerts multiple antitumoural activities through p27^KIP1 stabilization.

The compound, argyrin A, a cyclical peptide from the myxobacterium Archangium gephyra, was found to mediate p27^KIP1 stabilization through proteasomal inhibition, and induce apoptosis in several different cancer cell lines. The level of inhibition and apoptosis induction was comparable with the first-in-class proteasome inhibitor bortezomib (Velcade), which was approved for the treatment of multiple myeloma in 2003. Unlike bortezomib, argyrin A induced apoptosis only in the presence of p27^KIP1. Interestingly, the apoptosis-inducing function of p27^KIP1 was independent of its well-known function as a cyclin kinase inhibitor; instead, caspase 3 was identified as a critical downstream effector.

The antitumour activity of argyrin A was further tested in vivo in mice with human colon-cancer-derived xenografts. Intraperitoneal injection of argyrin A induced a significant reduction in tumour size, with similar or more rapid kinetics compared with bortezomib treatment. The treatment appeared to be well tolerated, and in contrast to bortezomib, it did not induce weight loss.

It was also found that argyrin-A-treated tumours contain large necrotic areas, a phenomenon often observed with compounds that affect blood-vessel formation. In vitro analysis showed that argyrin A can indeed interfere with neovascularization, and ultrastructural analysis of tumour tissue also revealed that argyrin A, like bortezomib, can target blood vessels directly. While bortezomib induces apoptosis of endothelial cells, blood vessels in argyrin-A-treated tumours contained endothelial cells that appeared to swell and detach from the basal membrane, causing occlusion of tumour blood vessels. Like apoptosis, neovascularization and vessel damage by argyrin A depended on p27^KIP1 stabilization. The detachment of endothelial cells was caused by p27^KIP1-dependent activation of RhoA.

To further compare the activities of bortezomib and argyrin A, gene-expression signatures of cancer cell lines after treatment with either compound were analysed. Cells treated with argyrin A revealed very limited changes in gene expression ( $sim$ 500 genes affected), whereas extensive changes after treatment with bortezomib (more than 10,900 genes) were found, indicating that the two agents cause different perturbations at the cellular level. It was also shown that apoptosis induction via proteasomal inhibition is strictly dependent on p27^KIP1, indicating that bortezomib can induce apoptosis via mechanisms unrelated to proteasomal inhibition.

The authors propose that the toxicity profile of bortezomib might reflect the disruption of multiple cellular systems, and that argyrin A might allow higher levels of proteasome inhibition at tolerable levels of toxicity. Besides facilitating fascinating new insights into proteasomal biology, argyrin A could therefore be an exciting new candidate for further clinical development.

Alexandra Flemming

References

Nickeleit, I. et al. Argyrin A reveals a critical role for the tumor suppressor protein p27^kip1 in mediating antitumor activities in response to proteasome inhibition. Cancer Cell 14, 23–35 (2008) | Article | PubMed |