Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade

Dan, Jiapeng; Gong, Xing; Li, Dezhan; Zhu, Guanhua; Li-shen, Wang; Fang, Li

doi:10.1016/j.biopha.2018.04.106

Cited by 55 publications

(58 citation statements)

References 30 publications

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“…Although the anti-cancer activity of bupivacaine has been demonstrated in various cancers, including gastric cancer, prostate cancer and ovarian cancer [9,28], our work and Li et al's work demonstrate that bupivacaine does not affect melanoma migration, growth and survival [29]. In addition, bupivacaine does not inhibit breast cancer cell function [30].…”

Section: Discussioncontrasting

confidence: 53%

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

2020

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Background: Substantial clinical and preclinical evidence have indicated the association between amide-linked local anesthesia and the long-term outcomes of cancer patients. However, the potential effects of local anesthesia on cancer recurrence are inconclusive and the underlying mechanisms remain poorly understood. Methods: We systematically examined the effects of three commonly used local anesthetics in melanoma cells and analyzed the underlying mechanisms focusing on small GTPases. Results: Ropivacaine and lidocaine but not bupivacaine inhibited migration and proliferation, and induced apoptosis in melanoma cells. In addition, ropivacaine and lidocaine but not bupivacaine significantly augmented the in vitro efficacy of vemurafenib (a B-Raf inhibitor for melanoma with BRAF V600E mutation) and dacarbazine (a chemotherapeutic drug). Mechanistically, ropivacaine but not bupivacaine decreased the activities of Ras superfamily members with the dominant inhibitory effects on RhoA and Ras, independent of sodium channel blockade. Rescue studies using constitutively active Ras and Rho activator calpeptin demonstrated that ropivacaine inhibited migration mainly through RhoA whereas growth and survival were mainly inhibited through Ras in melanoma cells. We further detected a global reduction of downstream signaling of Ras and RhoA in ropivacainetreated melanoma cells. Conclusion: Our study is the first to demonstrate the anti-melanoma activity of ropivacaine and lidocaine but not bupivacaine, via targeting small GTPases. Our findings provide preclinical evidence on how amide-linked local anesthetics could affect melanoma patients.

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Section: Discussioncontrasting

confidence: 53%

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

2020

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“…In in vitro studies examining local anaesthetic effects on metastatic colon cancer cells, ropivacaine demonstrated inhibitory properties to these cells . Thus, the higher cancer specific mortality suggested in this follow‐up analysis was surprising …”

Section: Discussionmentioning

confidence: 71%

Association between perioperative intraperitoneal local anaesthetic infusion and long‐term survival and cancer recurrence after colectomy: follow‐up analysis of a previous randomized controlled trial

MacFater

Xia

Barazanchi

et al. 2020

ANZ Journal of Surgery

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Background: High concentrations of local anaesthetic have an anti-proliferative effect on colonic cancer in vitro. Intraperitoneal local anaesthetic (IPLA) has shown analgesic benefit and improved recovery in the perioperative setting. The long-term effects of IPLA in colon cancer resection have not been examined. This study aims to review the survival and oncological outcomes of a previously conducted trial that compared perioperative IPLA with placebo. Methods: Sixty patients underwent colonic resection for benign and malignant disease as part of a double-blinded, randomized, placebo-controlled study between September 2008 and November 2009. The IPLA group received instillation of intraperitoneal ropivacaine before dissection followed by a 3-day infusion. The placebo group was treated identically but with 0.9% saline solution. A follow-up analysis was conducted to evaluate overall survival, disease-free survival and recurrence specifically for patients undergoing resection for stages I-III colon cancer. Kaplan-Meier analysis was performed, and the log-rank test was used to evaluate difference in survival between groups. Results: Thirty-seven of the 60 patients had stages I-III colon cancer and were included in this analysis. Nineteen patients were in the placebo group. There was no significant difference in overall survival or all-cause mortality. There was a higher incidence of cancerspecific mortality in the local anaesthetic group (P < 0.046). Conclusion: It does not appear that IPLA is associated with a significant survival benefit in patients with colonic malignancy undergoing colectomy. Other studies are needed to analyse the long-term outcomes.© 2020 Royal Australasian College of Surgeons ANZ J Surg 90 (2020) 802-806ANZJSurg.com

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“…Antibodies for phospho-and total AMPK, ACC, mTOR, and Akt were from Cell Signaling Technology, USA. Cell proliferation, apoptosis, and migration were determined using the same method as described in our previous studies [13,14]. Quantitative HUVEC adhesion was measured using Vybrant TM Cell Adhesion Assay kit according to manufacturer's instructions.…”

Section: A T E R I a L S A N D M E T H O D Smentioning

confidence: 99%

“…Oxygen consumption rate (OCR) was determined using the same protocol as described in our previous studies on a Seahorse XF24 extracellular flux analyzer (Seahorse Bioscience, USA) under both basal and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated conditions [13,14]. To investigate at what time bupivacaine affects OCR, time course analysis was performed using untreated cells both at basal conditions and after injection of bupivacaine.…”

Section: Mitochondrial Oxygen Consumption Ratementioning

confidence: 99%

“…We previously demonstrated that bupivacaine at millimolar concentrations acts on cells through inducing mitochondrial dysfunctions [14]. Given the essential roles of mitochondria in endothelial cells [18], we examined the effects of bupivacaine on physiological function of mitochondria in endothelial cells.…”

Section: Bupivacaine Induces Mitochondrial Dysfunctions and Oxidativementioning

confidence: 99%

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Bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK

Zhu

Dan

et al. 2020

Fundamemntal Clinical Pharma

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Although substantial evidence shows the link of local anesthesia and decreased tumor recurrence, the role of amide‐linked local anesthetics, particularly bupivacaine, on angiogenesis (a hallmark of tumor progression and metastasis) has not been revealed. In this work, we demonstrate the anti‐angiogenic activity of bupivacaine and its underlying mechanism in endothelial cells. We show that bupivacaine inhibits early stage of capillary network formation via suppressing endothelial cell migration without affecting adhesion to matrix. Bupivacaine also inhibits endothelial cell growth and survival. Mechanism analysis indicates that bupivacaine inhibits mitochondrial respiration via decreasing mitochondrial respiratory activity of complex I and II but not IV or V, resulting in energy depletion, oxidative stress, inhibition of Akt/mTOR, and activation of AMPK pathway. The rescue of an antioxidant NAC on the effects of bupivacaine confirms that bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK. Our work clearly demonstrates the inhibitory effects of bupivacaine on angiogenesis via targeting mitochondria. Our findings are in line with the previous work providing the preclinical evidence on how local anesthetics could influence the outcome of cancer patients.

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Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade

Cited by 55 publications

References 30 publications

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

Association between perioperative intraperitoneal local anaesthetic infusion and long‐term survival and cancer recurrence after colectomy: follow‐up analysis of a previous randomized controlled trial

Bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK

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