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Subject Keyword APPLIED LIFE SCIENCES ♦ ADP ♦ AMINES ♦ ANIMAL TISSUES ♦ ANTINEOPLASTIC DRUGS ♦ APOPTOSIS ♦ CARCINOMAS ♦ ENZYME ACTIVITY ♦ IN VITRO ♦ IN VIVO ♦ LACTATE DEHYDROGENASE ♦ LACTATES ♦ LUNGS ♦ LYSOSOMES ♦ MEMBRANE PROTEINS ♦ MEMBRANES ♦ METABOLISM ♦ MICE ♦ POLYMERASES ♦ RIBOSE ♦ SPHINGOMYELINS ♦ THERAPY ♦ THIN FILMS ♦ THIN-LAYER CHROMATOGRAPHY
Abstract Lysosomes are important targets for anticancer drug discovery. Our previous study showed that Riccardin D-N (RD-N), a natural macrocylic bisbibenzyl derivative produced by Mannich reaction, induced cell death by accumulating in lysosomes. Experiments were performed on human lung squamous cell carcinoma tissue from left inferior lobar bronchus of patient xenografts and H460 cells. RD-N was administrated for 25 days. The specimens of xenografts in Balb/c athymic (nu +/nu +) male mice were removed for immunohistochemistry, subcellular fractionation, enzyme activities and Western blotting analysis. mRFP-GFP-LC3 reporter was used to examine autophagy in H460 cells. Sphingomyelin assay was evaluated by thin-layer chromatography and assay kit. Lysosomal membrane permeabilization (LMP) caused by acid sphingomyelinase (ASM) inhibition and subsequent changes of sphingomyelin (SM) metabolism selectively destabilized the cancer cell lysosomes in RD-N-treated H460 cells in vitro and tumor xenograft model in vivo. The destabilized lysosomes induced the release of cathepsins from the lysosomes into the cytosol and further triggered cell death. These results explain the underlying mechanism of RD-N induced LMP. It can be concluded that a more lysosomotropic derivative was synthesized by introduction of an amine group, which could have more potential applications in cancer therapy. - Highlights: • Riccardin D-N (RD-N) significantly downregulated LAMP1 expressions. • RD-N inhibited the acid sphingomyelinase activity. • RD-N induced lysosomal membrane permeabilization in vivo. • RD-N induced SM accumulation in the lysosomal membranes. • RD-N also induced the release of cathepsins from destabilized lysosomes.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-11-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 310


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