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In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT\u20102 cells, HTLV\u20101 infected NIH\/3T3 cells (Inf\u20103T3), and HTLV\u20101 infected patients (Carrier, HAM\/TSP, and ATLL). Furthermore, the effects of rigosertib, wortmannin, and rapamycin on the PI3K\/Akt\/mTOR pathway to inhibit the proliferation of ATLL cells were examined. The results showed that mRNA expression of Akt\/PI3K\/mTOR was down\u2010regulated in carrier, HAM\/TSP, and ATLL patients, as well as MT\u20102, and Inf\u20103T3 cells, compared to the healthy individuals and untreated MT\u20102 and Inf\u20103T3 as controls. However, western blotting revealed an increase in the phosphorylated and activated forms of AKT and mTOR. Treating the cells with rapamycin, wortmannin, and rigosertib decreased the phosphorylated forms of Akt and mTOR and restored their mRNA expression levels. Using these inhibitors also significantly boosted the expression of the pro\u2010apoptotic genes, Bax\/Bcl\u20102 ratio as well as the expression of the tumor suppressor gene p53 in the MT\u20102 and Inf\u20103T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub\u2010G1 and G2\u2010M cell cycle arrest, as well as late apoptosis in the Inf\u20103T3 and MT\u20102 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV\u20101 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K\u2010Akt\u2010mTOR phosphorylation by HTLV\u20101. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.<\/jats:p>","DOI":"10.1002\/biof.1985","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T19:05:36Z","timestamp":1687633536000},"page":"1174-1188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rigosertib is more potent than wortmannin and rapamycin against adult <scp>T\u2010<\/scp>cell leukemia\u2010lymphoma"],"prefix":"10.1002","volume":"49","author":[{"given":"Mohsen","family":"Ghorbanzadeh Neghab","sequence":"first","affiliation":[{"name":"Institute for Immunology, Philipps\u2010University Marburg  Marburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1259-4593","authenticated-orcid":false,"given":"Mohammad","family":"Jalili\u2010Nik","sequence":"additional","affiliation":[{"name":"Department of 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