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High-throughput Screening Identified Selective Inhibitors of Exosome Biogenesis and Secretion: A Drug Repurposing Strategy for Advanced Cancer

High-throughput Screening Identified Selective Inhibitors of Exosome Biogenesis and Secretion: A Drug Repurposing Strategy for Advanced Cancer

Amrita Datta, Hogyoung Kim, Lauren McGee, Adedoyin E Johnson, Sudha Talwar, Juan Marugan, Noel Southall, Xin Hu, Madhu Lal, Debasis Mondal, Marc Ferrer, Asim B Abdel-Mageed

Sci Rep. 2018 May 25;8(1):8161.

PMID: 29802284

Abstract:

Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP38083179-A	Climbazole		38083-17-9	Price

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