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

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    Author
    Alameen, Ayman A.M.; Simioni, Carolina; Martelli, Alberto; Zauli, Giorgio; Ultimo, Simona; McCubrey, James A.; Gonelli, Arianna; Marisi, Giorgia; Ulivi, Paola; Capitani, Silvano; Neri, Luca
    Abstract
    An attractive molecular target for novel anti-cancer therapies is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which is commonly deregulated in many types of cancer. Nevertheless, the effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune responses, have been seldom explored. In this study we investigated the effects on human 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 T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effects on cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity was assessed by MTT assays. In addition, the activation status of the pathway as well as induction 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 the signaling pathway. Autophagy was also induced in proliferating lymphocytes and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3-methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is a protective mechanism. Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result to be taken into account when selecting drugs for targeted cancer therapy in order to minimize detrimental effects on immune function.
    URI
    http://hdl.handle.net/10342/8316
    Subject
    T lymphocytes, PI3K/Akt/mTOR signaling, T-acute lymphoblastic leukemia, targeted therapies, autophagy
    Date
    2016-08-01
    Citation:
    APA:
    Alameen, Ayman A.M., & Simioni, Carolina, & Martelli, Alberto, & Zauli, Giorgio, & Ultimo, Simona, & McCubrey, James A., & Gonelli, Arianna, & Marisi, Giorgia, & Ulivi, Paola, & Capitani, Silvano, & Neri, Luca. (August 2016). Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia. , (), - . Retrieved from http://hdl.handle.net/10342/8316

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    MLA:
    Alameen, Ayman A.M., and Simioni, Carolina, and Martelli, Alberto, and Zauli, Giorgio, and Ultimo, Simona, and McCubrey, James A., and Gonelli, Arianna, and Marisi, Giorgia, and Ulivi, Paola, and Capitani, Silvano, and Neri, Luca. "Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia". . . (), August 2016. September 21, 2023. http://hdl.handle.net/10342/8316.
    Chicago:
    Alameen, Ayman A.M. and Simioni, Carolina and Martelli, Alberto and Zauli, Giorgio and Ultimo, Simona and McCubrey, James A. and Gonelli, Arianna and Marisi, Giorgia and Ulivi, Paola and Capitani, Silvano and Neri, Luca, "Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia," , no. (August 2016), http://hdl.handle.net/10342/8316 (accessed September 21, 2023).
    AMA:
    Alameen, Ayman A.M., Simioni, Carolina, Martelli, Alberto, Zauli, Giorgio, Ultimo, Simona, McCubrey, James A., Gonelli, Arianna, Marisi, Giorgia, Ulivi, Paola, Capitani, Silvano, Neri, Luca. Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia. . August 2016; (): . http://hdl.handle.net/10342/8316. Accessed September 21, 2023.
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