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

Abstract

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 G 1 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.

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

“…Nevertheless, it also suggests that these drugs may also act by preventing cell proliferation (cytostasis) ( Figure S2E ), as cell death did not increase as much as cellular metabolic activity decreased. Indeed, BEZ235 has been reported to exhibit more cytostatic effects than cytotoxicity effects on other cell lines [ 43 ]. Similarly, HAR exhibits cytostatic effects on cells [ 44 ], while PIP is known to have a strong cytotoxic effect [ 45 ].…”

The role of CUDC‐907, a dual phosphoinositide‐3 kinase and histone deacetylase inhibitor, in inhibiting proliferation of adult T‐cell leukemia

“…Because both the PI3K and HDAC pathways are therapeutic targets in ATL, 7,8,13,14 the HTLV-1-infected T-cell line MT-2 was exposed for 24 hours to increasing concentrations of BKM120 or LBH589 ranging from 0.5 to 2 μmol/L or from 3.2 to 80 nmol/L, respectively. These concentrations were clinical acceptable doses.…”

“…The deregulation of the PI3K‐Akt pathway confers drug resistance in cancer 6 . Inhibition of PI3K induces apoptosis in HTLV‐1‐infected T cells 7,8 . However, the efficacy of PI3K inhibitors is limited by the concurrent activation of other pro‐survival and growth‐related pathways that lead to drug resistance 9 .…”

“…6 Inhibition of PI3K induces apoptosis in HTLV-1-infected T cells. 7,8 However, the efficacy of PI3K inhibitors is limited by the concurrent activation of other pro-survival and growth-related pathways that lead to drug resistance. 9 The role of histone deacetylase (HDAC) is opposite to the activity of histone acetyltransferase.…”

Biomarkers and Preclinical Models for Adult T-Cell Leukemia-Lymphoma Treatment

“…Maeda et al (2010) used non-obese diabetic (NOD)/SCID mice injected with Hut 102 cells, to assess growth inhibitory activity of anti-CD30 monoclonal antibodies. Ishikawa et al (2018) used SCID mice inoculated with Hut 102 cells to demonstrate the effects of inhibitors of mTOR and/or PI3K. Tsumuraya et al (2011) used SCID mice inoculated with Hut 102 cells to demonstrate inhibition of hippuristanol, a polyoxygenated steroid.…”