Lovastatin Inhibits VEGFR and AKT Activation: Synergistic Cytotoxicity in Combination with VEGFR Inhibitors

Abstract

BackgroundIn a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics.Methodology/Principal FindingsThe VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses.Conclusions/SignificanceThese results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors.

HMG-CoA reductase inhibitors as adjuvant treatment for hematologic malignancies: what is the current evidence?

“…Zhao et al demonstrated a novel mechanism in which lovastatin inhibits both ligand-induced VEGFR-2 activation through inhibition of receptor internalization and VEGF activation of PI3K/AKT pathway in endothelial cells [72]. Since angiogenesis has a central role in clinically aggressive hematologic malignancies such as nonHodgkin lymphomas [73][74][75], angioimmunoblastic T-cell lymphoma [76,77], ALL [78], AML [79], and multiple myeloma [80], inhibition of the VEGF-mediated intracellular signal via bevacizumab could be further facilitated by blocking the mevalonate pathway.…”

Monensin Inhibits Epidermal Growth Factor Receptor Trafficking and Activation: Synergistic Cytotoxicity in Combination with EGFR Inhibitors

“…We then demonstrated the potential of lovastatin to induce synergistic cytotoxicity in combination with EGFR-TKIs (29). The mechanism of action revolves around the ability of lovastatin to target the activity of EGFR and other RTKs enhancing the cytotoxicity of EGFR-TKIs in HNSCC cells (30,31). These studies eventually led to a phase I clinical trial of rosuvastatin and erlotinib at our Institute that showed disease stabilization, although the high dose of statins used had undesirable muscle pathologies in a significant number of patients (ClinicalTrials.gov Identifier: NCT00966472), suggesting an alternative approach to improve cancer targeting while minimizing the side effects of the treatment regimen.…”

The Impact of Extracellular Low pH on the Anti-Tumor Efficacy Against Mesothelioma

“…To this end, drugs which show higher cytotoxicity at low pH, including statins and cantharidins would be conventional candidates for co-treatment of mesothelioma. In fact, the combination treatment of solid tumors with statins enhanced anti-tumor drugs in vivo (Agarwal et al, 1999;Gao et al, 2010;O'Brien et al 2003;Zhao et al, 2010). So the development of new compounds with anti-tumor activity preferentially at low pH would be useful for chemotherapy of mesothelioma.…”