Piperlongumine and some of its analogs inhibit selectively the human immunoproteasome over the constitutive proteasome
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The natural small molecule piperlongumine A is toxic selectively to cancer cells in vitro and in vivo. This toxicity has been correlated with cancer cell ROS, DNA damage and apoptotic cell death increases. We demonstrate here a new mechanistic property of piperlongumine: it inhibits selectively human immunoproteasome with no noticeable inhibition of human constitutive proteasome. This result suggests that immunoproteasome inhibition, a mechanism independent of ROS elevation, may also partly play a role in the anticancer effects observed with piperlongumine. Structure-activity relationships of piperlongumine analogs suggest that the lactam (piperidonic) ring of piperlongumine A may be replaced by the linear olefin –NHCO-CH2=CH2 to improve both in vitro inhibitory efficiency against immunoproteasome and cellular toxicity.
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Immunoproteasome, Piperlogumine, Piperlongumine analogs, Proteasome
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Inglês
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Biochemical and Biophysical Research Communications, v. 496, n. 3, p. 961-966, 2018.
