Epithelial to mesenchymal transition (EMT) promotes cellular motility, invasiveness and metastasis during embryonic development and tumorigenesis. Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of EMT. A lot of evidences suggest that this process is Smad3-dependent. Herein we showed that exposure of aspc-1 and panc-1 pancreatic cancer cells to TGF-β1 resulted in characteristic morphological alterations of EMT, and enhancement of cell motility and gemcitabine (Gem) resistance along with an up-regulation of EMT markers genes such as vimentin, N-cadherin, MMP2 and MMP9. Naringenin (Nar) down-regulated EMT markers expression in both mRNA and protein levels by inhibiting TGF-β1/Smad3 signal pathway in the pancreatic cancer cells. Consequently, Nar suppressed the cells migration and invasion and reversed their resistance to Gem.
The rapid developments in nanotechnology have brought with them a deep concern over the safety of nanomaterials. Investigating the molecular mechanisms underlying their toxicity in different cell lines will help us better understand and apply nanomaterials appropriately. Poly(ethylene glycol)-phosphoethanolamine (PEG-PE) is an FDA-approved nonionic diblock copolymer and is widely used in drug delivery systems. Here, we find that PEG-PE accumulates in the endoplasmic reticulum (ER) and induces ER stress and that cancer cells and normal cells have different cell fates as a result of this stress. In A549 cancer cells, PEG-PE damages ER functions and triggers apoptosis by activating proapoptotic UPR signaling and high expression of cell death effector CHOP and proapoptotic Bax/Bak. In addition, PEG-PE-induced ER stress also up-regulates lipid synthesis and triggers lipid droplet formation in cancer cells. By contrast, in MRC-5 and 293T cells, high expression of the UPR feedback protein GADD34 which inhibits proapoptotic UPR signaling, and antiapoptotic Bcl-2 and Bcl-xl which down-regulate Bax/Bak, protect these normal cells from PEG-PE-induced apoptosis. When gadd34, bcl-2, or bcl-xl is knocked down, apoptosis occurs in PEG-PE-treated normal cells. In summary, we demonstrate the safety of PEG-PE in normal cells and elaborate the molecular mechanism underlying its nanotoxicity in cancer cells. This study implies PEG-PE-based drug delivery system has the potential to alter the sensitivity of cancer cells to some chemotherapeutic agents by selectively activating unfolded protein response (UPR) in cancer cells, and it also provides a useful foundation for research on ER stress-induced nanotoxicity and other lipid-based nanomaterials.
Since polymeric micelles are promising and have potential in drug delivery systems, people have become more interested in studying the compatibility of polymeric carriers and drugs, which might help them to simplify the preparation method and increase the micellar stability. In this article, we report that cationic amphiphilic drugs can be easily encapsulated into PEGylated phospholipid (PEG–PE) micelles by self-assembly method and that they show high encapsulation efficiency, controllable drug release and better micellar stability than empty micelles. The representative drugs are doxorubicin and vinorelbine. However, gemcitabine and topotecan are not suitable for PEG–PE micelles due to lack of positive charge or hydrophobicity. Using a series of experiments and molecular modelling, we figured out the assembly mechanism, structure and stability of drug-loaded micelles, and the location of drugs in micelles. Integrating the above information, we explain the effect of the predominant force between drugs and polymers on the assembly mechanism and drug release behaviour. Furthermore, we discuss the importance of p K a and to evaluate the compatibility of drugs with PEG–PE in self-assembly preparation method. In summary, this work provides a scientific understanding for the reasonable designing of PEG–PE micelle-based drug encapsulation and might enlighten the future study on drug–polymer compatibility for other polymeric micelles.
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