Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Ayman,Simioni,Carolina,Martelli,Alberto,Zauli,Gior A.,Gonelli,Arianna,Marisi,Giorgia,Ulivi,Paola,Capi Alameen (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: An attractive molecular target for novel anti-cancer therapies is thephosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)pathway which is commonly deregulated in many types of cancer. Nevertheless, theeffects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immuneresponses, have been seldom explored. In this study we investigated the effects onhuman CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, MK2206, and ZSTK474. We also assessed their efficacy against two acute leukemia Tcell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effectson cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity wasassessed by MTT assays. In addition, the activation status of the pathway as well asinduction of autophagy were analyzed by Western blotting.Quiescent healthy T lymphocytes were unaffected by the drugs whereas mitogenstimulated lymphocytes as well as leukemic cell lines displayed a cell cycle block,caspase-dependent apoptosis, and dephosphorylation of key components of thesignaling pathway. Autophagy was also induced in proliferating lymphocytes and inJURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3-methyladenineor Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is aprotective mechanism.Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preservelymphocyte viability. This is a valuable result to be taken into account when selectingdrugs for targeted cancer therapy in order to minimize detrimental effects on immunefunction.

Additional Information

Publication

Other

Language: English

Date: 2016

Keywords

T lymphocytes, PI3K/Akt/mTOR signaling, T-acute lymphoblastic leukemia, targeted therapies, autophagy

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