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Clinically relevant concentrations of lidocaine inhibit tumor angiogenesis through suppressing VEGF/VEGFR2 signaling

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Abstract

Background

Angiogenesis, the formation of blood vessel, is required for invasive tumor growth and metastasis. In this study, the effects of lidocaine, an amide-link local anesthetic, on angiogenesis and tumor growth were investigated.

Methods

In vitro angiogenesis assays were conducted using human umbilical vascular endothelial cell (HUVEC). Essential molecules involved in vascular endothelial growth factor (VEGF) signaling were analyzed. Tumor angiogenesis was analyzed using in vivo mouse tumor model.

Results

Lidocaine at clinically relevant concentrations inhibited angiogenesis. Lidocaine inhibited endothelial cell in vitro capillary network formation on Matrigel through interfering early stage of angiogenesis. In addition, lidocaine inhibited vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration and proliferation without affecting cell adhesion. Lidocaine also induced endothelial cell apoptosis in the presence of VEGF. Lidocaine suppressed VEGF-activated phosphorylation of VEGF receptor 2 (VEGFR2), PLCγ-PKC-MAPK and FAK-paxillin in endothelial cells, demonstrating that VEGF, PLC, MAPK and FAK-paxillin suppression is associated with the antiangiogenic effect of lidocaine. Importantly, the in vitro observations were translatable to in vivo B16 melanoma mouse model. Lidocaine significantly inhibited tumor angiogenesis, leading to delay of tumor growth.

Conclusions

This study is the first to report that lidocaine acts as an angiogenesis inhibitor. The findings provide preclinical evidence into the potential mechanisms by which lidocaine may negatively affect cancer growth and metastasis.

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Acknowledgements

This work was supported by a research grant provided by Hubei University of Arts and Science (RG2015668).

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  1. Jin Gao and Huimin Hu contributed to this work equally and are the co-first authors.

Authors and Affiliations

  1. Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Jingzhou Road 136, Xiangcheng District, Xiangyang, Hubei Province, 441021, China

    Jin Gao, Huimin Hu & Xuesong Wang

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  1. Jin Gao
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Correspondence to Xuesong Wang.

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All the procedures involving human participants were performed in accordance with the ethical standards of the national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All the procedures involving animals were conducted according to the guidelines approved by the Institutional Animal Care and Use Committee of Hubei University of Arts and Science

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Gao, J., Hu, H. & Wang, X. Clinically relevant concentrations of lidocaine inhibit tumor angiogenesis through suppressing VEGF/VEGFR2 signaling. Cancer Chemother Pharmacol 83, 1007–1015 (2019). https://doi.org/10.1007/s00280-019-03815-4

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