Noncompetitive modulation of the proteasome by imidazoline scaffolds overcomes bortezomib resistance and delays MM tumor growth in vivo.
Noncompetitive modulation of the proteasome by imidazoline scaffolds overcomes bortezomib resistance and delays MM tumor growth in vivo.
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DOI：
10.1021/cb300568r
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发表时间：
2013-03-15
影响因子：
4
通讯作者：
Tepe, Jetze J.
中科院分区：
文献类型：
--
作者：
Lansdell, Theresa A.;Hurchla, Michelle A.;Xiang, Jingyu;Hovde, Stacy;Weilbaecher, Katherine N.;Henry, R. William;Tepe, Jetze J.
Multiple myeloma is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (~97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than one year. We describe herein the inhibition of the human proteasome via a non-competitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013 induces apoptosis a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative BM samples of MM patients. The cellular activity translated well in vivo where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.
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