Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma

Abstract

The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression.

RETRACTED: Study on Attenuating Angiogenesis and Epithelial–Mesenchymal Transition (EMT) of Non-Small Cell Lung Carcinoma (NSCLC) by Regulating MAGEC2

“… 31 , 32 Vascular endothelial growth factor overexpression is related to intratumoral microvessel density and a poor prognosis in varieties of cancers. 33 Downregulation of VEGF could inhibit cell proliferation and lead to tumor cell apoptosis. 34 In our study, we found that MAGEC2 could enhance the expression and secretion of VEGF, and silencing MAGEC2 could significantly suppress the expression of VEGF and the progression of angiogenesis, indicating that MAGEC2 could positively regulate VEGF activation and it might be a potential target for antiangiogenesis therapy.…”

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

“…The activation of mTOR pathway is a prognostic factor for MPM, in particular P-mTOR expression during induction chemotherapy was associated with shorter overall survival [ 8 ]. Moreover, mTOR inhibition has shown evidences of efficacy in MPM preclinical models [ 22 , 23 ]. In the present work, we confirmed that mTOR pathway is activated in MPM.…”

“…Being merlin an interesting biomarker in MPM [ 31 ], reciprocal ezrin and merlin coordination in MPM onset and their influence on response to drugs deserve further investigations. The mTOR pathway is involved in ezrin- induced malignant phenotype [ 15 ], moreover the mTOR inhibition has shown antitumor effect in mesothelioma preclinical models [ 5 , 6 , 22 , 23 ]. To further investigate the effect of combining sorafenib and everolimus treatment in in vivo models of MPM, we set up MSTO-H211 xenografts into NOD/SCID mice.…”

Osteonecrosis of the Jaw Associated with Antiangiogenics in Antiresorptive-Naïve Patient: A Comprehensive Review of the Literature

“…Antiangiogenic inhibitors can be categorised into three major groups based on their mechanism of action: anti-VEGF monoclonal antibody (e.g., bevacizumab), VEGF decoy receptors or VEGF-Trap (e.g., aflibercept), and small molecule tyrosine kinase inhibitors (TKI) that block the VEGF receptors downstream signaling pathways (e.g., sunitinib, cabozantinib, and sorafenib) [ 15 ] ( Table 1 ). Additionally, the mammalian target of rapamycin (mTOR) inhibitors also seems to have antiangiogenic effects by inhibiting the production of VEGF and platelet-derived growth factors (PDGF) [ 16 – 18 ].…”