Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma
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Elsevier Ireland Ltd
Abstract
Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (MLS402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients. © 2015 .
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Hsp90-inhibition, Liposarcoma, Myxoid, Nvp-auy922, Animals, Antineoplastic agents, Apoptosis, Cell proliferation, Cell survival, Dose-response relationship, drug, G2 phase cell cycle checkpoints, Hct116 cells, Hsp90 heat-shock proteins, Humans, Isoxazoles, Liposarcoma, myxoid, Map kinase signaling system, Mice, inbred nod, Mice, scid, Molecular targeted therapy, Phosphatidylinositol 3-kinase, Proto-oncogene proteins c-akt, Resorcinols, Time factors, Xenograft model antitumor assays, Caspase 3, Doxorubicin, Heat shock protein 90, Luminespib, Mitogen activated protein kinase, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, Phosphatidylinositol 3 kinase, Raf protein, Tanespimycin, 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide, Antineoplastic agent, Isoxazole derivative, Protein kinase b, Resorcinol derivative, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Cancer cell line, Cancer inhibition, Cell cycle arrest, Cell viability, Concentration response, Controlled study, Drug cytotoxicity, G2 phase cell cycle checkpoint, Human, Human cell, Human tissue, In vivo study, Inhibition kinetics, Mouse, Myxosarcoma, Nonhuman, Priority journal, Protein expression, Signal transduction, Animal, Antagonists and inhibitors, Dose response, Drug effects, Drug screening, Genetics, Hct116 cell line, Metabolism, Molecularly targeted therapy, Nonobese diabetic mouse, Pathology, Scid mouse, Time