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

Ishikawa,Chie; Senba,Masachika; Mori,Naoki

doi:10.3892/ol.2018.7979

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
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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
Published online on: February 7, 2018 https://doi.org/10.3892/ol.2018.7979
Pages: 5311-5317

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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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1	Yoshida M, Seiki M, Yamaguchi K and Takatsuki K: Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci USA. 81:pp. 2534–2537. 1984; View Article : Google Scholar : PubMed/NCBI
2	Vose J, Armitage J and Weisenburger D; International T-Cell Lymphoma Project, : International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol. 26:4124–4130. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ishida T, Hishizawa M, Kato K, Tanosaki R, Fukuda T, Taniguchi S, Eto T, Takatsuka Y, Miyazaki Y, Moriuchi Y, et al: Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: A nationwide retrospective study. Blood. 120:1734–1741. 2012. View Article : Google Scholar : PubMed/NCBI
4	Rosich L, Saborit-Villarroya I, López-Guerra M, Xargay-Torrent S, Montraveta A, Aymerich M, Villamor N, Campo E, Pérez-Galán P, Roué G and Colomer D: The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells. Haematologica. 98:1739–1747. 2013. View Article : Google Scholar : PubMed/NCBI
5	Liu P, Cheng H, Roberts TM and Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 8:627–644. 2009. View Article : Google Scholar : PubMed/NCBI
6	Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, et al: Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun. 5:33932014. View Article : Google Scholar : PubMed/NCBI
7	Rodon J, Dienstmann R, Serra V and Tabernero J: Development of PI3K inhibitors: Lessons learned from early clinical trials. Nat Rev Clin Oncol. 10:143–153. 2013. View Article : Google Scholar : PubMed/NCBI
8	Zheng Y, Yang J, Qian J, Zhang L, Lu Y, Li H, Lin H, Lan Y, Liu Z, He J, et al: Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone. J Mol Med (Berl). 90:695–706. 2012. View Article : Google Scholar : PubMed/NCBI
9	Ren H, Zhao L, Li Y, Yue P, Deng X, Owonikoko TK, Chen M, Khuri FR and Sun SY: The PI3 kinase inhibitor NVP-BKM120 induces GSK3/FBXW7-dependent Mcl-1 degradation, contributing to induction of apoptosis and enhancement of TRAIL-induced apoptosis. Cancer Lett. 338:229–238. 2013. View Article : Google Scholar : PubMed/NCBI
10	Zang C, Eucker J, Liu H, Coordes A, Lenarz M, Possinger K and Scholz CW: Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma. Leuk Lymphoma. 55:425–434. 2014. View Article : Google Scholar : PubMed/NCBI
11	Rodon J, Braña I, Siu LL, De Jonge MJ, Homji N, Mills D, Di Tomaso E, Sarr C, Trandafir L, Massacesi C, et al: Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs. 32:670–681. 2014. View Article : Google Scholar : PubMed/NCBI
12	Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J and Topisirovic I: Targeting the translation machinery in cancer. Nat Rev Drug Discov. 14:261–278. 2015. View Article : Google Scholar : PubMed/NCBI
13	O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66:1500–1508. 2006. View Article : Google Scholar : PubMed/NCBI
14	Bhatt AP, Bhende PM, Sin SH, Roy D, Dittmer DP and Damania B: Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 115:4455–4463. 2010. View Article : Google Scholar : PubMed/NCBI
15	Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, et al: Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 7:1851–1863. 2008. View Article : Google Scholar : PubMed/NCBI
16	Bhende PM, Park SI, Lim MS, Dittmer DP and Damania B: The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. Leukemia. 24:1781–1784. 2010. View Article : Google Scholar : PubMed/NCBI
17	Shortt J, Martin BP, Newbold A, Hannan KM, Devlin JR, Baker AJ, Ralli R, Cullinane C, Schmitt CA, Reimann M, et al: Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas. Blood. 121:2964–2974. 2013. View Article : Google Scholar : PubMed/NCBI
18	Chiarini F, Grimaldi C, Ricci F, Tazzari PL, Evangelisti C, Ognibene A, Battistelli M, Falcieri E, Melchionda F, Pession A, et al: Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res. 70:8097–8107. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ishiyama M, Miyazono Y, Sasamoto K, Ohkura Y and Ueno K: A highly water-soluble disulfonated tetrazolium salt as a chromogenic indicator for NADH as well as cell viability. Talanta. 44:1299–1305. 1997. View Article : Google Scholar : PubMed/NCBI
20	Zhang C, Ao Z, Seth A and Schlossman SF: A mitochondrial membrane protein defined by a novel monoclonal antibody is preferentially detected in apoptotic cells. J Immunol. 157:3980–3987. 1996.PubMed/NCBI
21	Tomayko MM and Reynolds CP: Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 24:148–154. 1989. View Article : Google Scholar : PubMed/NCBI
22	Ikezoe T, Nishioka C, Bandobashi K, Yang Y, Kuwayama Y, Adachi Y, Takeuchi T, Koeffler HP and Taguchi H: Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk Res. 31:673–682. 2007. View Article : Google Scholar : PubMed/NCBI
23	Weinberg RA: The retinoblastoma protein and cell cycle control. Cell. 81:323–330. 1995. View Article : Google Scholar : PubMed/NCBI
24	Kamihira S, Atogami S, Sohda H, Momita S, Yamada Y and Tomonaga M: Significance of soluble interleukin-2 receptor levels for evaluation of the progression of adult T-cell leukemia. Cancer. 73:2753–2758. 1994. View Article : Google Scholar : PubMed/NCBI
25	Nishioka C, Takemoto S, Kataoka S, Yamanaka S, Moriki T, Shoda M, Watanabe T and Taguchi H: Serum level of soluble CD30 correlates with the aggressiveness of adult T-cell leukemia/lymphoma. Cancer Sci. 96:810–815. 2005. View Article : Google Scholar : PubMed/NCBI
26	Martelli AM, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, Fini M and McCubrey JA: Two hits are better than one: Targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 3:371–394. 2012. View Article : Google Scholar : PubMed/NCBI
27	Huang Z, Wu Y, Zhou X, Qian J, Zhu W, Shu Y and Liu P: Clinical efficacy of mTOR inhibitors in solid tumors: A systematic review. Future Oncol. 11:1687–1699. 2015. View Article : Google Scholar : PubMed/NCBI