Anticancer Effects And Mechanisms Of SNX-2112, A Novel Hsp90 Inhibitor

SNX-2112 is a novel Hsp90 inhibitor in recent years. Previously, our group conducted a research of SNX-2112 on preclinical pharmacology and toxicology, and anticancer effects and mechanisms in K562 and A375 cells. The results have proven its significant antitumor effect.The researches of this thesis were as follows:1. Screening the SNX-2112-sensitive tumor cell line. MTT assay was employed to deter mine the growth inhibition of SNX-2112 in normal cells, cancer cells and multidrug-resistant cancer cells. MCF-7 cell line was used as the major cell model for mechanism research.2. Effects and mechanisms of SNX-2112-induced growth inhibition in MCF-7 cells. After treated with SNX-2112, cell shape, cell cycle, cell apoptosis and Hsp90 client proteins were analyzed by the fluorescence confocal microscopy, flow cytometry and western blot.3. Unfolded protein response (URP) induced by SNX-2112 in MCF-7 cells. The expression and cellular position of UPR-related proteins were analyzed by the fluorescence confocal microscopy and western blot.4. Mechanisms of SNX-2112-induced Hsp90 cleavage. The causes and effects of SNX-2112-induced Hsp90 cleavage were analyzed by western blot, co-precipitation, mass spectrometry and method interfered with signal pathway inhibitors.5. Effects and mechanisms of SNX-2112-induced growth inhibition in multidrug-resistant MCF-7/ADR cells. Cell shape, surface morphology, apoptosis, P-gp, and drug combination index were analyzed by MTT assay, fluorescence confocal microscopy, atomic force microscopy, flow cytometry and western blot.Results were as follows:1. SNX-2112 showed the significant antitumor effect in cancer cells and multidrug-resistant cancer cells with litter toxicity in normal cells.2. SNX-2112 induced G2/M cell cycle arrest and apoptosis through the mitochondrial apoptotic pathway, and targeted degradation of Hsp90 client proteins HER2, Akt, Raf-1 and IKKαin MCF-7 cells.3. SNX-2112 activated the unfolded protein response (URP) in MCF-7 cells.4. SNX-2112 induced caspase-mediated cleavage of the middle domain of Hsp90.5. SNX-2112 induced S cell cycle arrest and apoptosis, and had synergistic anticancer activity with cisplatin and ADR in MCF-7/ADR cells.These anticancer mechanisms of SNX-2112 might provide a foundation for further clinical applications of SNX-2112.