Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer

Autophagy
Lu ZhangGangchun Sun

Abstract

Currently, particular focus is placed on the implication of autophagy in a variety of human diseases, including cancer. Discovery of small-molecule modulators of autophagy as well as their potential use as anti-cancer therapeutic agents would be of great significance. To this end, a series of curcumin analogs previously synthesized in our laboratory were screened. Among these compounds, (3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one (CA-5f) was identified as a potent late-stage macroautophagy/autophagy inhibitor via inhibiting autophagosome-lysosome fusion. We found that CA-5f neither impaired the hydrolytic function nor the quantity of lysosomes. Use of an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic screen in combination with bioinformatics analysis suggested that treatment of human umbilical vein endothelial cells (HUVECs) with CA-5f for 1 h suppressed the levels of cytoskeletal proteins and membrane traffic proteins. Subsequent studies showed that CA-5f exhibited strong cytotoxicity against A549 non-small cell lung cancer (NSCLC) cells, but low cytotoxicity to normal human umbilical vein endothelial cells (HUVECs), by increasing mitochondrial-derived ...Continue Reading

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Citations

Apr 21, 2020·Phytotherapy Research : PTR·Mahsa SalehiHamed Mirzaei
Jul 11, 2019·Journal of Experimental & Clinical Cancer Research : CR·Hongze ChenBei Sun
Sep 16, 2020·International Journal of Molecular Sciences·Monica BenvenutoRoberto Bei
Jun 3, 2021·International Journal of Molecular Sciences·Kamila BuzunAnna Bielawska

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Methods Mentioned

BETA
xenograft
Fluorescence
fluorescence microscopy
confocal microscopy
xenografts
surgical resection
transfection
Assay
transmission electron microscopy
PCR

Software Mentioned

SPSS
RTCA S16
Quantity One
Odyssey Application
Cell Quest

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