The sesquiterpene lactone, parthenolide, is a natural product found in the medicinal plant feverfew. It has both anti-inflammatory effects and chemotherapeutic potential for the treatment of cancers. Parthenolide contains an electrophilic gamma-butyrolactone functional group that will covalently modify biological nucleophiles prevalent in proteins. Similar to endogenous electrophiles, such as 4-hydroxynonenal, parthenolide induces the heat shock system in mammalian cells. In order to investigate this effect, we have synthesized derivatives of parthenolide that allow us to detect protein modification through affinity or fluorescence labeling using copper-catalyzed azide-alkyne Huisgen cycloaddition (CUAAC). We can identify members of the heat shock protein family that are modified by these parthenolide derivatives using affinity capture and immunoblotting. We have demonstrated the covalent modification of heat shock protein 70, in vitro, using our derivatives. We are also determining the effects of chaperone protein modification using luciferase refolding assays. Downstream transcriptional effects of parthenolide and our derivatives are being determined using quantitative PCR.

Effects of sesquiterpene lactones on the heat shock response system

248th National Meeting (2014)

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