2,4-Bis(4-hydroxybenzyl)phenol Inhibits Heat Shock Transcription Factor 1 and Sensitizes Lung Cancer Cells to Conventional Anticancer Modalities

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 (<b>1</b>), isolated from the rhizomes of <i>Gastrodia elata</i>, was identified as an active compound. This substance effectively inhibited HSF1 activity and decreased levels of HSP27 and HSP70. Compound <b>1</b> induced the degradation of HSF1 protein through dephosphorylation of HSF1 on S326, which decreases HSF1 protein stability. In addition, <b>1</b> 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 <b>1</b>. Furthermore, cotreatment with <b>1</b> 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 <b>1</b> may help overcome resistance to conventional anticancer modalities in HSF1-overexpressed cancer cells