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Article

Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

  • Authors:
    • Chie Ishikawa
    • Masachika Senba
    • Naoki Mori
  • View Affiliations / Copyright

    Affiliations: Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of The Ryukyus, Nishihara, Okinawa 903‑0213, Japan, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852‑8523, Japan, Department of Microbiology and Oncology, Graduate School of Medicine, University of The Ryukyus, Nishihara, Okinawa 903‑0215, Japan
  • Pages: 5311-5317
    |
    Published online on: February 7, 2018
       https://doi.org/10.3892/ol.2018.7979
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Abstract

Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1). In ATL, the phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP‑BKM120 (a pan‑PI3K inhibitor) and NVP‑BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV‑1‑infected T‑cell lines were compared. The results demonstrated that NVP‑BEZ235 was more efficacious compared with RAD001 and NVP‑BKM120 at inhibiting cell growth. NVP‑BEZ235 exhibited cytostatic rather than cytotoxic effects on various HTLV‑1‑infected T‑cell lines, where it induced cell cycle arrest at G1 phase. NVP‑BEZ235 downregulated cyclin D1, cyclin D2, cyclin E, cyclin dependent kinase (CDK)2 and CDK4 expression, and the phosphorylation of retinoblastoma protein. In C.B‑17/Icr‑severe combined immune deficiency mice implanted with HTLV‑1‑infected HUT‑102 cells, oral NVP‑BEZ235 caused marked retardation of tumor growth compared with the control. The present in vitro and in vivo studies highlight the efficacious dual inhibition of PI3K, and mTOR following NVP‑BEZ235 treatment. Thus, the results of the current study provide preclinical rationale for phase I clinical studies to examine the effects of NVP-BEZ235 in patients with ATL.
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Copy and paste a formatted citation
Spandidos Publications style
Ishikawa C, Senba M and Mori N: Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines. Oncol Lett 15: 5311-5317, 2018.
APA
Ishikawa, C., Senba, M., & Mori, N. (2018). Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines. Oncology Letters, 15, 5311-5317. https://doi.org/10.3892/ol.2018.7979
MLA
Ishikawa, C., Senba, M., Mori, N."Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines". Oncology Letters 15.4 (2018): 5311-5317.
Chicago
Ishikawa, C., Senba, M., Mori, N."Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines". Oncology Letters 15, no. 4 (2018): 5311-5317. https://doi.org/10.3892/ol.2018.7979
Copy and paste a formatted citation
x
Spandidos Publications style
Ishikawa C, Senba M and Mori N: Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines. Oncol Lett 15: 5311-5317, 2018.
APA
Ishikawa, C., Senba, M., & Mori, N. (2018). Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines. Oncology Letters, 15, 5311-5317. https://doi.org/10.3892/ol.2018.7979
MLA
Ishikawa, C., Senba, M., Mori, N."Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines". Oncology Letters 15.4 (2018): 5311-5317.
Chicago
Ishikawa, C., Senba, M., Mori, N."Effects of NVP‑BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines". Oncology Letters 15, no. 4 (2018): 5311-5317. https://doi.org/10.3892/ol.2018.7979
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