PU-H71 effectively induces degradation of IκB kinase β in the presence of TNF-α

Abstract

This study is to determine if PU-H71, a heat shock protein inhibitor, induces killing of malignant breast cells together with treatment of tumor necrosis factor-α (TNF-α). The related molecular mechanisms were also studied. A primary mammary epithelial cell line HMEC2595 cells and the highly metastatic breast cell line MDA-MB-231, the HER2-positive BT-474 cells, and the ER-positive MCF7 cells were treated with PU-H71 in the presence or absence of TNF-α. The effects of PU-H71 and TNF-α treatments on cells viabilities and on intracellular signaling pathway proteins were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis assays, immunoblot assays, and luciferase assays. It was found that TNF-α enhances the toxic effects of PU-H71 on tumor cells but not normal cells. PU-H71 treatments lead to degradation of IKKβ. Moreover, PU-H71 down-regulates the NF-κB transcriptional activity induced by TNF-α treatment. The experimental results indicated PU-H71 effectively induces cell killing of malignant breast cells in the presence of TNF-α, possibly through a mechanism related to degradation of IKKβ. It is suggested that combination of PU-H71 and TNF-α treatments might be an effective therapeutic strategy of breast malignancies.

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

“…The preferential activity of PU-H71 against cancerous tissue under concentrations that do not perturb normal cells has been confirmed in multiple cell types (Fig. 3B) [71][72][73]. Since this initial study, PU-H71 has been shown to be highly effective in vitro and in vivo against several malignancies, each of which will be briefly highlighted to exemplify the potential PU-H71 has in cancer chemotherapy.…”

Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma

“…Synergy between these drugs was associated with more potent suppression of BTK and NF-κB activation. Naturally, PU-H71 suppression of other teHSP90 actions could also contribute to these synergistic effects, such as its effects on BCL6 and IKK (3,26). If anything, this adds to the potential appeal of using PU-H71 to anchor combinatorial therapy for DLBCL.…”