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

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

Tong T. Zhao, Diane Trinh, Christina L. Addison, Jim Dimitroulakos

PLoS ONE 5(9): e12563. doi:10.1371/journal.pone.0012563

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Background
In 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 Findings
The 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/Significance
These 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.

  1. #1 par Mathgon le septembre 7, 2010 - 10:56

    Si je me souviens bien, la lovastatin est également utilisée comme marqueur de sélection après transformation chez les Archaea… un lien avec des mécanismes de réplication et de régulation similaires?

  2. #2 par Oldcola le septembre 8, 2010 - 7:27

    Heu… Ce n’est pas inhibiteur de la synthèse du cholestérol ?
    Je ne connaissais pas son utilisation avec les Archea, vais regarder ça.

  3. #3 par Oldcola le septembre 8, 2010 - 8:25

    Je viens de chercher « lovastatin & Archea » et la première référence me donne :
    doi:10.1016/j.ics.2006.01.031Control of rumen methanogenesis by inhibiting the growth and activity of methanogens with hydroxymethylglutaryl-SCoA inhibitors
    M.J. Wolin, and T.L. Miller
    The CH4-forming bacteria in the rumen are Archaea. All Archaea have unique membrane lipids that contain glycerol joined by ether linkages to long chain isoprenoid alcohols. Mevalonate is a key precursor for isoprenoid synthesis by methanogens and is also essential for the production of cholesterol by humans. Mevalonate is produced by reduction of hydroxymethylglutaryl-SCoA (HMG-CoA). HMG-CoA reductase is a target of HMG-CoA inhibitors (statins) used to inhibit human cholesterol synthesis. Statins would be expected to specifically inhibit growth of rumen methanogenic bacteria by inhibiting their synthesis of mevalonate. Rumen fermentative bacteria would not be inhibited because they are eubacteria and most of their lipids are glycerol esters of long chain fatty acids. These predictions are supported by the results of our study of the effect of statins on the growth of pure cultures of rumen methanogenic and fermentative bacteria. The HMG-CoA reductase inhibitors, mevastatin and lovastatin (ca. 10 nM), inhibited the growth of strains of rumen Methanobrevibacter. They did not inhibit the growth of strains of Ruminococcus albus, R. flavefaciens, Butyrivibrio fibrisolvens, Fibrobacter succinogenes and Selenomonas ruminantium. These eubacterial species are essential for ruminal fermentation of cellulose, starch and other plant polysaccharides.

    Même mécanisme en fait.

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