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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.

Seven new diarylheptanoids, (-)-(R)-4″-hydroxyyashabushiketol (1), (3S,5S)-alpinikatin (2), katsumain C (3), 7-epi-katsumain C (4), ent-alpinnanin B (5), ent-alpinnanin A (6), and ent-calyxin H (8), were isolated from the EtOAc extract of the seeds of Alpinia katsumadai together with three known compounds, alpinnanin B (7), epicalyxin H (9), and calyxin H (10). Each isomer mixture of 3 and 4, 5-7, and 8-10 was separated successfully by preparative HPLC using a chiral column. The three isomer mixtures (3 and 4, 5-7, 8-10) at 1 μM increased expression of heat shock factor 1 (HSF1) with fold increases of 1.438, 1.190, and 1.316, respectively, which was accompanied with increased expression of heat shock protein (HSP) 27 (1.403-, 1.250-, and 1.270-fold, respectively) and HSP70 (1.373-, 1.313-, and 1.229-fold, respectively) without cellular cytotoxicity, suggesting a possible application of these compounds as HSP inducers. Celastrol was used as a positive control of HSP induction, producing fold increases of 1.066 (HSF1), 1.216 (HSP27), and 1.371 (HSP70) at 1 μM. Compounds 1 and 2 did not affect the induction of HSF1 protein.