title: 2,4-Bis(4-hydroxybenzyl)phenol inhibits heat shock transcription factor 1 and sensitizes lung cancer cells to conventional anticancer modalities.
abstract: Heat shock factor 1 (HSF1) is a transcription factor that regulates expression of heat shock protein (HSP) genes in response to stress. HSPs are expressed at high levels in a wide range of tumors. It has been reported that HSF1 and HSPs are associated closely in tumorigenesis. In the present study, a screen was performed using a luciferase reporter under the control of a heat shock element to find inhibitors of HSF1 activity, and 2,4-bis(4-hydroxybenzyl)phenol (1), isolated from the rhizomes of Gastrodia elata, was identified as an active compound. This substance effectively inhibited HSF1 activity and decreased levels of HSP27 and HSP70. Compound 1 induced the degradation of HSF1 protein through dephosphorylation of HSF1 on S326, which decreases HSF1 protein stability. In addition, 1 also induced growth arrest and apoptosis of NCI-H460 human lung cancer cells. Markers of apoptosis, such as cleaved PARP and cleaved caspase-3, were detected after treatment with 1. Furthermore, cotreatment with 1 and conventional anticancer modalities such as paclitaxel, cisplatin, or ionizing radiation potentiated their effects on lung cancer cells. These results suggest that inhibition of HSF1 by 1 may help overcome resistance to conventional anticancer modalities in HSF1-overexpressed cancer cells.
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 120-750, Korea.
authors.forename: Taesook
authors.initials: T
authors.lastname: Yoon
authors.forename: Ga-Young
authors.initials: GY
authors.lastname: Kang
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Han
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Seo
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008175:Lung Neoplasms; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: D001559:Benzhydryl Compounds; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D010636:Phenols; D014157:Transcription Factors; C087793:2,4-bis(4-hydroxybenzyl)phenol; D053148:Caspase 3