Shogo Suzuki1, Atsushi Mori2, Aya Fukui1, Yoshiaki Ema1, Kimitoshi Nishiwaki3. 1. Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan. 2. Department of Perioperative Management System, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan. 3. Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan. nishi@med.nagoya-u.ac.jp.
Abstract
PURPOSE: Angiogenesis is closely related to the pathophysiology of diseases such as cancer or ischemia. Here, we investigated the effect of lidocaine at clinically effective blood concentrations on vascular endothelial growth factor A (VEGF-A)-induced angiogenesis. In addition, we aimed to clarify the mechanisms by which lidocaine could inhibit angiogenesis. METHODS: Angiogenesis was analyzed using commercially available in vitro assay kits in human umbilical vein endothelial cells (HUVECs)/normal human dermal fibroblast co-culture systems. The effects of lidocaine on cytotoxicity, VEGF-induced cell migration, and VEGF-induced cell proliferation were examined in HUVECs using lactate dehydrogenase cytotoxic, Boyden chamber, and WST-8 assays, respectively. The VEGF signaling pathway via VEGF receptor 2 (VEGFR-2) was analyzed by western blotting. RESULTS: Lidocaine elicited a significant dose-dependent, angiogenesis-inhibitory effect at a concentration range of 1-10 μg/ml. At this concentration range, cell death was not observed. Lidocaine, at a concentration of 10 μg/ml, significantly inhibited cell proliferation but not cell migration, induced by VEGF-A in HUVECs. Furthermore, lidocaine, in a dose-dependent manner, significantly inhibited the VEGF-A-induced phosphorylation of VEGFR-2 at 3 and 10 μg/ml. CONCLUSION: We demonstrated that lidocaine has an anti-angiogenesis effect on clinically effective blood concentrations without causing cell death. This finding could represent a new avenue for future research into anesthesia, cancer-related analgesia, and revascularization therapy.
PURPOSE: Angiogenesis is closely related to the pathophysiology of diseases such as cancer or ischemia. Here, we investigated the effect of lidocaine at clinically effective blood concentrations on vascular endothelial growth factor A (VEGF-A)-induced angiogenesis. In addition, we aimed to clarify the mechanisms by which lidocaine could inhibit angiogenesis. METHODS: Angiogenesis was analyzed using commercially available in vitro assay kits in human umbilical vein endothelial cells (HUVECs)/normal human dermal fibroblast co-culture systems. The effects of lidocaine on cytotoxicity, VEGF-induced cell migration, and VEGF-induced cell proliferation were examined in HUVECs using lactate dehydrogenase cytotoxic, Boyden chamber, and WST-8 assays, respectively. The VEGF signaling pathway via VEGF receptor 2 (VEGFR-2) was analyzed by western blotting. RESULTS: Lidocaine elicited a significant dose-dependent, angiogenesis-inhibitory effect at a concentration range of 1-10 μg/ml. At this concentration range, cell death was not observed. Lidocaine, at a concentration of 10 μg/ml, significantly inhibited cell proliferation but not cell migration, induced by VEGF-A in HUVECs. Furthermore, lidocaine, in a dose-dependent manner, significantly inhibited the VEGF-A-induced phosphorylation of VEGFR-2 at 3 and 10 μg/ml. CONCLUSION: We demonstrated that lidocaine has an anti-angiogenesis effect on clinically effective blood concentrations without causing cell death. This finding could represent a new avenue for future research into anesthesia, cancer-related analgesia, and revascularization therapy.
Entities:
Keywords:
Anti-angiogenesis; Ketamine; Lidocaine; Vascular endothelial growth factor A