Do Amide Local Anesthetics Play a Therapeutic Role in the Perioperative Management of Cancer Patients?

Piegeler, Tobias; Hollmann, Markus W.; Borgeat, Alain; Lirk, Philipp

doi:10.1097/aia.0000000000000119

Cited by 14 publications

(15 citation statements)

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“…Anti-inflammatory effects of LAs are well-known and have been studied extensively ( 21 ). However, the influence of LAs on the integrity of the endothelial barrier might be crucial for a possible inhibitory effect on the generation of metastasis during the perioperative period ( 14 ). CTCs—released into the circulation from the primary tumor during surgical removal of the latter—are able to form new (microscopic) metastatic lesions ( 22 , 23 ), which will finally determine the patient’s fate, even after a complete surgical removal of the primary tumor ( 24 , 25 ).…”

Section: Anti-inflammatory Effects Of Las In Vitro mentioning

confidence: 99%

“…Src is activated by certain inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), which is released at increasing concentrations—possibly due to surgical stress—during the perioperative period ( 32 , 33 ). Therefore, the endothelial barrier might be impaired and the formation of new metastatic sites might be favored ( 14 , 34 ). However, there is evidence that the amide LAs, such as lidocaine and ropivacaine, might be able to attenuate the inflammatory response in the endothelium, which might then lead to a preservation of endothelial barrier integrity ( 35 , 36 ).…”

Section: Anti-inflammatory Effects Of Las In Vitro mentioning

confidence: 99%

“…So far, no data from adequately powered randomized controlled trials (RCTs) are available and therefore the authors of a recent Cochrane review concluded that there is currently only “inadequate” evidence for a potential beneficial effect of the perioperative use of regional anesthesia in cancer patients ( 67 ). However, these inconclusive findings might, at least in part, be explainable by the large heterogeneity of studies, tumors, and patients alike ( 14 ). Moreover, the intermediate outcomes of RCT so far have been encouraging: in a pilot study utilizing blood samples from patients undergoing breast cancer surgery (NCT 00418457), the serum of women anesthetized with propofol and paravertebral block induced more apoptosis in a triple-negative breast cancer cell line compared to serum derived from women exposed to sevoflurane and an opioid-based regimen ( 68 ).…”

Section: Anti-inflammatory = Antimetastatic?mentioning

confidence: 99%

“…On the one hand, some anesthetic and analgesic drug receptors are overexpressed in tumor tissues and are associated with metastasis ( 10 ). On the other hand, several retrospective studies have suggested an impact of anesthesia on cancer survival ( 11 ); notably, regional anesthesia might be associated with a reduced risk of cancer relapse or recurrence in some studies, although there are also studies reporting no effect ( 12 – 14 ). One of the proposed hypotheses to explain these observations may be related to the anti-inflammatory effects of local anesthetics (LAs) affecting proliferation, migration, or invasion of cancer cells as well ( 15 – 17 ).…”

Section: Introductionmentioning

confidence: 99%

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The Amide Local Anesthetic Lidocaine in Cancer Surgery—Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review

Chamaraux-Tran

Piegeler

2017

Front. Med.

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Surgical removal of the primary tumor in solid cancer is an essential component of the treatment. However, the perioperative period can paradoxically lead to an increased risk of cancer recurrence. A bimodal dynamics for early-stage breast cancer recurrence suggests a tumor dormancy-based model with a mastectomy-driven acceleration of the metastatic process and a crucial role of the immunosuppressive state during the perioperative period. Recent evidence suggests that anesthesia could also influence the progress of the disease. Local anesthetics (LAs) have long been used for their properties to block nociceptive input. They also exert anti-inflammatory capacities by modulating the liberation or signal propagation of inflammatory mediators. Interestingly, LAs can reduce viability and proliferation of many cancer cells in vitro as well. Additionally, retrospective clinical trials have suggested that regional anesthesia for cancer surgery (either with or without general anesthesia) might reduce the risk of recurrence. Lidocaine, a LA, which can be administered intravenously, is widely used in clinical practice for multimodal analgesia. It is associated with a morphine-sparing effect, reduced pain scores, and in major surgery probably also with a reduced incidence of postoperative ileus and length of hospital stay. Systemic delivery might therefore be efficient to target residual disease or reach cells able to form micrometastasis. Moreover, an in vitro study has shown that lidocaine could enhance the activity of natural killer (NK) cells. Due to their ability to recognize and kill tumor cells without the requirement of prior antigen exposure, NKs are the main actor of the innate immune system. However, several perioperative factors can reduce NK activity, such as stress, pain, opioids, or general anesthetics. Intravenous lidocaine as part of the perioperative anesthesia regimen would be of major interest for clinicians, as it might bear the potential to reduce the risk of cancer recurrence or progression patients undergoing cancer surgery. As a well-known pharmaceutical agent, lidocaine might therefore be a promising candidate for oncological drug repurposing. We urgently need clinical randomized trials assessing the protective effect of lidocaine on NKs function and against recurrence after cancer surgery to achieve a “proof of concept.”

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Section: Anti-inflammatory Effects Of Las In Vitro mentioning

confidence: 99%

Section: Anti-inflammatory Effects Of Las In Vitro mentioning

confidence: 99%

Section: Anti-inflammatory = Antimetastatic?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Amide Local Anesthetic Lidocaine in Cancer Surgery—Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review

Chamaraux-Tran

Piegeler

2017

Front. Med.

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“…Amide local anesthetics act on nerve cells by blocking voltage-gated sodium channels, resulting in decreased depolarization and repolarization rates of excitatory nerve cell membranes [30,31]. It has been shown that common amide linked local anesthetics exhibit anticancer activity in a variety of cancers, including lung cancer, hepatocellular carcinoma, and thyroid cancer [32,33].…”

Section: Discussionmentioning

confidence: 99%

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

Fan

Yang

Zhao

et al. 2020

Preprint

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BackgroundA large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms.MethodsThe effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., cell counting kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The Acyl biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs.ResultsIn this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. ConclusionsIn conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

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Systemische Effekte der Amid-Lokalanästhetika

Piegeler

Werdehausen

2018

Anaesthesist

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Besides the well-known analgesic effects of amide-linked local anesthetics exerted via the inhibition of the voltage-gated sodium channel, these substances also possess a certain number of properties, which bear the potential to positively influence the outcome after surgery. The results of several experimental as well as clinical studies suggest the possibility of an enhanced recovery after surgery, reduction in the incidence of chronic pain, preservation of endothelial barrier function during acute lung injury and the prevention of metastasis of solid tumors by systemic effects of local anesthetic administration. Mechanistic studies were able to identify several "new targets", such as the inhibition of spinal glycine transporters or of inflammatory signaling as induced by tumor necrosis factor alpha. Further elucidation of these mechanistic pathways as well as the translation of these promising experimental results into clinical practice is a crucial component of research activities in the field of anesthesia.

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Do Amide Local Anesthetics Play a Therapeutic Role in the Perioperative Management of Cancer Patients?

Cited by 14 publications

References 98 publications

The Amide Local Anesthetic Lidocaine in Cancer Surgery—Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review

The Amide Local Anesthetic Lidocaine in Cancer Surgery—Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

Systemische Effekte der Amid-Lokalanästhetika

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