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.

Lidocaine (Lido) is an amide local anesthetic that has both excitatory and inhibitory effects on the central nervous system, and is one of a group of commonly used local nerve block drugs that are used in the clinic. However, traditional Lido does not meet the transdermal performance requirements of surface anesthetic agents for treating pain in patients. Optimizing the preparation of a Lido transdermal preparation and improving the control of anesthetic depth and efficiency has become a challenge in the field of topical anesthesia. In this study, a new type of Lido nano-transdermal preparation, carboxymethyl chitosan-modified lidocaine liposomes (Lido-CMCSNLP), were constructed based on nano-liposomes. Carboxymethyl chitosan can enhance the permeability of hydrophilic macromolecular pathways by interacting with negatively charged membrane glycoproteins, which is beneficial for the transdermal absorption of Lido. Therefore, Lido-CMCS-NLP provides a new approach for research in clinical topical anesthesia and perioperative topical analgesics.