Ropivacaine inhibits tumor angiogenesis via sodium-channel-independent mitochondrial dysfunction and oxidative stress
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The anti-cancer role of local anesthetics has garnered attention in recent years because increasing evidence show that local anesthetics reduce the risk of tumor metastasis and recurrence. Angiogenesis, the formation of new blood vessels, is fundamental for tumor growth and metastasis. The role of local anesthetics on tumor angiogenesis still remains unknown. Using human lung tumor-associated endothelial cell (HLT-EC) and angiogenesis models, our work shows that ropivacaine at the clinically relevant concentration is active against multiple biological functions of HLT-EC but not lung tumor cells. Ropivacaine inhibits HLT-EC capillary network formation, growth and survival. The anti-angiogenic activity of ropivacaine is further confirmed in in vivo angiogenesis mouse model. Mechanistically, we show that ropivacaine inhibits HLT-EC mitochondrial respiration via specifically targeting mitochondrial respiratory complex II. As a consequence of mitochondrial respiration inhibition, we observe the energy depletion, oxidative stress and damage in HLT-EC after ropivacaine exposure. Additionally, an antioxidant agent completely reverses the inhibitory effects of ropivacaine, suggesting that oxidative stress is required for the action of ropivacaine in HLT-EC. Interestingly, mitochondrial dysfunction and oxidative stress induced by ropivacaine is sodium channel-independent. Our work demonstrates the potent inhibitory effects of ropivacaine in lung tumor angiogenesis by inducing mitochondrial dysfunction. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect tumor reoccurrence and metastasis.
KeywordsRopivacaine Tumor angiogenesis Mitochondrial respiration VGSC
This work was supported by research grants provided by Guangdong Qingyuan Municipal Science and Technology (Grant No. 2013A008 and 2011B011112002).
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Conflict of interest
All authors declare no conflict of interest.
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