Rigosertib is more potent than wortmannin and rapamycin against adult T‐cell leukemia‐lymphoma

Abstract

Human T lymphotropic virus type 1 (HTLV‐1) infection can cause adult T‐cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy‐resistant malignancy. In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT‐2 cells, HTLV‐1 infected NIH/3T3 cells (Inf‐3T3), and HTLV‐1 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‐regulated in carrier, HAM/TSP, and ATLL patients, as well as MT‐2, and Inf‐3T3 cells, compared to the healthy individuals and untreated MT‐2 and Inf‐3T3 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‐apoptotic genes, Bax/Bcl‐2 ratio as well as the expression of the tumor suppressor gene p53 in the MT‐2 and Inf‐3T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub‐G1 and G2‐M cell cycle arrest, as well as late apoptosis in the Inf‐3T3 and MT‐2 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV‐1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K‐Akt‐mTOR phosphorylation by HTLV‐1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.