NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines

Abstract

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21 waf1 , p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3a/b (GSK-3a/b) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.

Effects of HIV Protease Inhibitors on Progression of Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension in Rats

“…The HPI doses required in vitro to block PDGF-induced Akt phosphorylation and PA-SMC proliferation were also similar to those of the specific PI3K inhibitor LY294002 and to those of the HPIs shown in previous studies to inhibit tumor cell growth and to block Akt signaling. [12][13][14] Thus, our finding that the HPIs inhibited Akt suggests mediation of HPI effects by inhibition of GSK3 phosphorylation, ie, GSK3 activation. Accordingly, cell treatment with a GSK3 inhibitor completely abolished the growthinhibiting effects of amprenavir, nelfinavir, and LY294002 and markedly decreased the inhibitory effect of ritonavir.…”

“…[12][13][14] The PI3K-Akt axis is a major pathway for cell proliferation and cancer. This pathway is often activated in tumor cells but not in normal host cells and may therefore hold considerable promise as a target for future treatments against cancer.…”

“…11 HPIs have been shown to inhibit cancer cell growth in vitro and cancer growth in vivo in experimental animals. [12][13][14] One possible mechanism of this growth-inhibiting effect and perhaps also of the insulin resistance-inducing effect is inhibition of the Akt signaling pathway. [12][13][14] In pulmonary artery smooth muscle cells (PA-SMCs), Akt signaling is a downstream target of several factors such as platelet-derived growth factor (PDGF) 15,16 and serotonin, 17 which are important mediators of the pulmonary vascular remodeling process.…”

“…[12][13][14] One possible mechanism of this growth-inhibiting effect and perhaps also of the insulin resistance-inducing effect is inhibition of the Akt signaling pathway. [12][13][14] In pulmonary artery smooth muscle cells (PA-SMCs), Akt signaling is a downstream target of several factors such as platelet-derived growth factor (PDGF) 15,16 and serotonin, 17 which are important mediators of the pulmonary vascular remodeling process. 18,19 Because PH is primarily a proliferative disease and because the Akt pathway has been shown in vitro to mediate SMC proliferation via phosphorylation and inactivation of its downstream effector glycogen-synthasekinase-3␤ (GSK3␤), 20 we hypothesized that HPIs slowed PH progression by interfering with the Akt signaling pathway.…”

Repositioning therapy for thyroid cancer: new insights on established medications

“…Such concentrations correspond to the C max (w7-9 mmol/l) for NFV in HIV patients. Experiments with animal models of human cancers have demonstrated that at clinically achievable concentrations, NFV inhibited tumor growth (Pore et al 2006, Yang et al 2006, Gills et al 2007, Shim et al 2012. NFV contains a unique cis-decahydroisoquinoline-2-carboxamide moiety, which may provide the structural basis for its increased efficacy against cancer compared with other HIV protease inhibitors.…”