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Model of Inhibition of the NPM-ALK Kinase Activity by Herbimycin A¹

Human Gene Therapy Research Institute, John Stoddard Cancer Center, Des Moines, Iowa 50309 [F. T., M. D. A., A. Y. F.]; Division of Hematology-Oncology, VA Central Iowa Health Care System, Des Moines, Iowa 50310 [F. T.]; and Nuffield Department, Clinical Laboratory Sciences, Room 5501, Level 5, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom [K. P.]

Anaplastic large cell lymphoma (ALCL) exhibiting the t(2;5) translocation is characterized by the resulting expression of the oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) gene product. The ALK domain of NPM-ALK contains kinase activity, which is responsible for the autophosphorylation of tyrosine residues of the oncogenic protein and phosphorylation of SH2-protein substrates. Herbimycin A is a general protein tyrosine kinase inhibitor active as an antiproliferative compound against different types of mammalian cells. Herbimycin A inhibited the NPM-ALK-associated autophosphorylating activity in an in vitro cell-free kinase assay. The inhibition was specific when tested against other kinase inhibitors and extended to other cell lines derived from t(2;5)-ALCL. SUDHL-1 cells showed increasing percentage of cells in G₁ after 18 h of incubation with a dose of herbimycin A. NPM-ALK, Akt, and pAkt were down-regulated after 24 h of incubation with herbimycin A. Apoptosis was observed only if the dose of inhibitor was given every 12 h for prolonged time. Our results show that herbimycin A interferes with NPM-ALK and Akt pathways in SUDHL-1 cells. It seems that prolonged inhibition of these biochemical pathways may lead to cell cycle arrest and apoptosis. This study supports the idea of investigating protein kinase inhibitors as therapeutic compounds for t(2;5)-ALCL.

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