Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A

• Published in: Nature communications Vol. 10; no. 1; pp. 1387 - 17
• Main Authors: Im, Eun-Ju, Lee, Chan-Hyeong, Moon, Pyong-Gon, Rangaswamy, Gunassekaran Gowri, Lee, Byungheon, Lee, Jae Man, Lee, Jae-Chul, Jee, Jun-Goo, Bae, Jong-Sup, Kwon, Taeg-Kyu, Kang, Keon-Wook, Jeong, Myeong-Seon, Lee, Joo-Eun, Jung, Hyun-Suk, Ro, Hyun-Joo, Jun, Sangmi, Kang, Wonku, Seo, Seung-Yong, Cho, Young-Eun, Song, Byoung-Joon, Baek, Moon-Chang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-03-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 38/1; 38/61; 49/98; 631/67/1059/153; 631/67/1347; 631/80/313/2376; 82/29; 82/58; 96/1; 96/63; Animal models; Animals; Anti-Infective Agents - pharmacology; Antibiotics; Anticancer properties; Biology; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Endosomes; Endosomes - drug effects; Endosomes - metabolism; Endothelins; Exosomes; Extracellular vesicles; Extracellular Vesicles - drug effects; Extracellular Vesicles - metabolism; Female; Humanities and Social Sciences; Humans; Localization; Lysosomes; Lysosomes - drug effects; Lysosomes - metabolism; Male; MCF-7 Cells; Metastases; Mice; Mice, Nude; multidisciplinary; Neoplasm Metastasis; Organelle Biogenesis; Pharmacology; Proteins; Receptor, Endothelin A - drug effects; Receptor, Endothelin A - metabolism; Science; Science (multidisciplinary); Secretion; Sulfisoxazole; Sulfisoxazole - pharmacology; Vesicles; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09387-4

Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.
Extracellular vesicles are released from cells and permit communication between different cell types. Here, the authors identify that the FDA approved antibiotic sulfisoxazole, can block the release of these vesicles in breast cancer cells resulting in reduced cell growth in vitro and in vivo.