title: Inhibition of heat shock induction of heat shock protein 70 and enhancement of heat shock protein 27 phosphorylation by quercetin derivatives.
abstract: Inhibitors of heat-induced heat shock protein 70 (HSP70) expression have the potential to enhance the therapeutic effectiveness of heat-induced radiosensitization of tumors. Among known small molecule inhibitors, quercetin has the advantage of being easily modified for structure-activity studies. Herein, we report the ability of five monomethyl and five carbomethoxymethyl derivatives of quercetin to inhibit heat-induced HSP70 expression and enhance HSP27 phosphorylation in human cells. While quercetin and several derivatives inhibit HSP70 induction and enhance HSP27 phosphorylation at Ser78, other analogues selectively inhibit HSP70 induction without enhancing HSP27 phosphorylation that would otherwise aid in cell survival. We also show that good inhibitors of HSP70 induction are also good inhibitors of both CK2 and CamKII, kinases that are known to activate HSP70 expression by phosphorylation of heat shock transcription factor 1. Derivatives that show poor inhibition of either or both kinases are not good inhibitors of HSP70 induction, suggesting that quercetin's effectiveness is due to its ability to inhibit both kinases.
authors.affiliation: Department of Chemistry, Washington University, St Louis, Missouri 63130, USA.
authors.forename: Rongsheng E
authors.initials: RE
authors.lastname: Wang
authors.forename: Jeffrey L-F
authors.initials: JL
authors.lastname: Kao
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Hilliard
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Roti Roti
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.forename: John-Stephen
authors.initials: JS
authors.lastname: Taylor
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D010766:Phosphorylation; D011794:Quercetin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D011794:Quercetin; D047390:Casein Kinase II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2