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Here, we evaluated the induction of autophagy by the thiopurines AZA, mercaptopurine (6-MP) and thioguanine (6-TG) in THP-1 macrophages and investigated the mechanism of action in the context of this cellular process. The cytotoxicity of thiopurines was evaluated using an LDH assay. Induction of endogenous LC3 by thiopurines was evaluated using immunostaining. To confirm autophagy activation by thiopurines, a GFP-RFP-LC3 reporter plasmid was used to monitor the maturation of autophagosomes to autolysosomes. Induction of apoptosis by thiopurines was evaluated using Annexin V\/PI staining, and ER stress was assessed via RT\u2012PCR analysis of <jats:italic>XBP1<\/jats:italic> splicing. To gain insight into the mechanism of action of thiopurines, mTORC1 activity and eIF2\u03b1-S51 phosphorylation were evaluated by immunoblotting. Thiopurines were not cytotoxic to cells and induced strong time- and concentration-dependent autophagy. Thiopurines activate autophagy with complete progression through the pathway. Induction of autophagy by thiopurines occurred independently of apoptosis and ER stress. Immunoblotting revealed that AZA inhibited mTORC1 activity, and AZA and 6-TG increased eIF2\u03b1-S51 phosphorylation. In contrast, 6-MP had a minor effect on either signalling pathway. Thiopurines are strong inducers of autophagy, and autophagy induction should be considered among the mechanisms responsible for patient response to thiopurines.<\/jats:p>","DOI":"10.1007\/s00210-024-03563-0","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T13:02:14Z","timestamp":1730466134000},"page":"4467-4478","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterisation of autophagy induction by the thiopurine drugs azathioprine, mercaptopurine and thioguanine in THP-1 macrophages"],"prefix":"10.1007","volume":"398","author":[{"given":"Connan D.","family":"Masson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fern","family":"Findlay-Greene","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filipa Henderson","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter G.","family":"Barlow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,1]]},"reference":[{"key":"3563_CR1","doi-asserted-by":"publisher","first-page":"379748","DOI":"10.1155\/2014\/379748","volume":"2014","author":"A Al Maruf","year":"2014","unstructured":"Al Maruf A, Wan L, O\u2019Brien PJ (2014) Evaluation of azathioprine-induced cytotoxicity in an in vitro rat hepatocyte system. 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