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

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.

Antitumor effects of local anesthetics in breast cancer

Des études cliniques rétrospectives ont suggéré un effet protecteur de l’anesthésie locorégionale contre les récidives après chirurgie carcinologique, donnant une nouvelle dimension à la prise en charge de la douleur périopératoire. Le premier objectif de ce travail était de montrer les effets antitumoraux directs de la lidocaïne, un anesthésique local couramment utilisé en pratique clinique. L’impact de la lidocaïne a été mesuré in vitro sur la viabilité, la prolifération et la migration de plusieurs lignées humaines de cellules de cancer du sein, ainsi qu’in vivo sur la progression métastatique péritonéale de cellules triple négatives. Le second objectif était de déterminer par quels mécanismes moléculaires la lidocaïne exerçait cette action antitumorale. Des approches globales par analyses transcriptomiques et métabolomiques ont mis en exergue de nouvelles hypothèses mécanistiques, en particulier relatives à des modifications de la composition lipidique des membranes cellulaires. Enfin une approche par gène candidat a suggéré un mode d’action de la lidocaïne indépendant du canal sodique voltage-dépendant.Retrospective clinical studies have suggested a protective effect of regional anesthesia against recurrences after cancer surgery, bringing the management of perioperative pain to a new level. Prospective studies are underway to support these results. The first objective of this work was to show the direct antitumor effect of lidocaine, a local anesthetic commonly used in clinical practice. The impact of lidocaine was measured in vitro on viability, proliferation and migration of several human breast cancer cell lines, as well as in vivo on the metastatic peritoneal progression of triple negative cells. The second objective was to determine by which molecular mechanisms lidocaine exerts this antitumor action. Global approaches by transcriptomic and metabolomic analyses have highlighted new mechanistic hypotheses, notably in relation to the lipid composition of cell membrane. Finally, a candidate gene approach suggested that the mode of action of lidocaine is independent of the voltage-gated sodium channel

Effets antitumoraux des anesthésiques locaux dans le cancer du sein

Retrospective clinical studies have suggested a protective effect of regional anesthesia against recurrences after cancer surgery, bringing the management of perioperative pain to a new level. Prospective studies are underway to support these results. The first objective of this work was to show the direct antitumor effect of lidocaine, a local anesthetic commonly used in clinical practice. The impact of lidocaine was measured in vitro on viability, proliferation and migration of several human breast cancer cell lines, as well as in vivo on the metastatic peritoneal progression of triple negative cells. The second objective was to determine by which molecular mechanisms lidocaine exerts this antitumor action. Global approaches by transcriptomic and metabolomic analyses have highlighted new mechanistic hypotheses, notably in relation to the lipid composition of cell membrane. Finally, a candidate gene approach suggested that the mode of action of lidocaine is independent of the voltage-gated sodium channel.Des études cliniques rétrospectives ont suggéré un effet protecteur de l’anesthésie locorégionale contre les récidives après chirurgie carcinologique, donnant une nouvelle dimension à la prise en charge de la douleur périopératoire. Le premier objectif de ce travail était de montrer les effets antitumoraux directs de la lidocaïne, un anesthésique local couramment utilisé en pratique clinique. L’impact de la lidocaïne a été mesuré in vitro sur la viabilité, la prolifération et la migration de plusieurs lignées humaines de cellules de cancer du sein, ainsi qu’in vivo sur la progression métastatique péritonéale de cellules triple négatives. Le second objectif était de déterminer par quels mécanismes moléculaires la lidocaïne exerçait cette action antitumorale. Des approches globales par analyses transcriptomiques et métabolomiques ont mis en exergue de nouvelles hypothèses mécanistiques, en particulier relatives à des modifications de la composition lipidique des membranes cellulaires. Enfin une approche par gène candidat a suggéré un mode d’action de la lidocaïne indépendant du canal sodique voltage-dépendant

Antitumor effects of local anesthetics in breast cancer

Des études cliniques rétrospectives ont suggéré un effet protecteur de l’anesthésie locorégionale contre les récidives après chirurgie carcinologique, donnant une nouvelle dimension à la prise en charge de la douleur périopératoire. Le premier objectif de ce travail était de montrer les effets antitumoraux directs de la lidocaïne, un anesthésique local couramment utilisé en pratique clinique. L’impact de la lidocaïne a été mesuré in vitro sur la viabilité, la prolifération et la migration de plusieurs lignées humaines de cellules de cancer du sein, ainsi qu’in vivo sur la progression métastatique péritonéale de cellules triple négatives. Le second objectif était de déterminer par quels mécanismes moléculaires la lidocaïne exerçait cette action antitumorale. Des approches globales par analyses transcriptomiques et métabolomiques ont mis en exergue de nouvelles hypothèses mécanistiques, en particulier relatives à des modifications de la composition lipidique des membranes cellulaires. Enfin une approche par gène candidat a suggéré un mode d’action de la lidocaïne indépendant du canal sodique voltage-dépendant.Retrospective clinical studies have suggested a protective effect of regional anesthesia against recurrences after cancer surgery, bringing the management of perioperative pain to a new level. Prospective studies are underway to support these results. The first objective of this work was to show the direct antitumor effect of lidocaine, a local anesthetic commonly used in clinical practice. The impact of lidocaine was measured in vitro on viability, proliferation and migration of several human breast cancer cell lines, as well as in vivo on the metastatic peritoneal progression of triple negative cells. The second objective was to determine by which molecular mechanisms lidocaine exerts this antitumor action. Global approaches by transcriptomic and metabolomic analyses have highlighted new mechanistic hypotheses, notably in relation to the lipid composition of cell membrane. Finally, a candidate gene approach suggested that the mode of action of lidocaine is independent of the voltage-gated sodium channel

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

PMCID: PMC5742360Surgical 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.

Effets direct de la lidocaïne sur la prolifération et la migration de cellules cancéreuses du sein

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Metabolomic Impact of Lidocaine on a Triple Negative Breast Cancer Cell Line

International audienceBackground: Metabolomics and onco-anesthesia are two emerging research fields in oncology. Metabolomics (metabolites analysis) is a new diagnostic and prognostic tool that can also be used for predicting the therapeutic or toxic responses to anticancer treatments. Onco-anesthesia studies assess the impact of anesthesia on disease-free and overall survival after cancer surgery. It has been shown that local anesthetics (LA), particularly lidocaine (LIDO), exert antitumor properties both in vitro and in vivo and may alter the biologic fingerprints of cancer cells. As LA are known to impair mitochondrial bioenergetics and byproducts, the aim of the present study was to assess the impact of LIDO on metabolomic profile of a breast cancer cell line.Methods: Breast cancer MDA-MB-231 cells were exposed for 4 h to 0.5 mM LIDO or vehicle (n = 4). The metabolomic fingerprint was characterized by high resolution magic angle spinning NMR spectroscopy (HRMAS). The multivariate technique using the Algorithm to Determine Expected Metabolite Level Alteration (ADEMA) (Cicek et al., PLoS Comput. Biol., 2013, 9, e1002859), based on mutual information to identify expected metabolite level changes with respect to a specific condition, was used to determine the metabolites variations caused by LIDO.Results: LIDO modulates cell metabolites levels. Several pathways, including glutaminolysis, choline, phosphocholine and total choline syntheses were significantly downregulated in the LIDO group.Discussion: This is the first study assessing the impact of LIDO on metabolomic fingerprint of breast cancer cells. Among pathways downregulated by LIDO, many metabolites are reported to be associated with adverse prognosis when present at a high titer in breast cancer patients. These results fit with the antitumor properties of LIDO and suggest its impact on metabolomics profile of cancer cells. These effects of LIDO are of clinical significance because it is widely used for local anesthesia with cutaneous infiltration during percutaneous tumor biopsy. Future in vitro and preclinical studies are necessary to assess whether metabolomics analysis requires modification of local anesthetic techniques during tumor biopsy

Antitumor Effects of Lidocaine on Human Breast Cancer Cells: An In Vitro and In Vivo Experimental Trial

AIM: Retrospective studies have suggested a protective effect of regional anesthesia against recurrence after cancer surgery. But confirmation of the in vivo antitumor effects is lacking. We examined the in vitro antitumor effects of lidocaine on various breast cancer cell lines and then assessed these properties in vivo at clinically relevant concentrations. MATERIALS AND METHODS: In vitro experiments: normal breast epithelial cells (NBEC) MCF-10A and three tumor breast epithelial cells (TBEC) lines (MCF-7 luminal A, MDA-MB-231 triple-negative and SKBr3 HER2 positive) were exposed to increasing concentrations of lidocaine. Cell viability, migration and anchorage-independent growth were assessed by MTT, wound healing, and soft-agar growth assays. In vivo experiments: 6-week-old severe combined immunodeficient mice were injected intraperitoneally with MDA-MB-231 cells and were treated with intraperitoneal lidocaine or phosphate-buffered saline. The mice were euthanized when they reached experimental endpoints or sacrificed to determine peritoneal carcinomatosis index and global tumor volumes. RESULTS: Lidocaine reduced the viability of all the cell lines, inhibited migration of TBEC compared to the NBEC, and compromised the anchorage-independent growth of the triple-negative cells. Intraperitoneal lidocaine improved survival of mice with MDA-MB-231 peritoneal carcinomatosis using doses that are consistent with the current clinical settings for analgesia. CONCLUSION: In agreement with the notion that local anesthesia may be beneficial for cancer therapy, lidocaine has a protective effect against breast cancer cells in experimental studies. However, the beneficial impact of local anesthetics on breast cancer needs to be strengthened by additional preclinical and clinical trials

Detection of Pneumocystis jirovecii in Patients with Severe COVID-19: Diagnostic and Therapeutic Challenges

Cases of Pneumocystis jirovecii pneumonia (PCP) in patients suffering from COVID-19 were described in patients with various comorbidities and outcomes. The diagnosis of PCP in these patients is difficult due to clinical and radiological similarities. We carried out this study in order to better describe potentially at-risk patients and their outcomes. We retrospectively analyzed all patients with a P. jirovecii PCR performed in bronchoalveolar lavage fluid, tracheal aspirate, or sputum within a month after the COVID-19 diagnosis. Fifty-seven patients with COVID-19 infection were tested for P. jirovecii. Among 57 patients with COVID-19, four patients had a concomitant positive P. jirovecii PCR. These four patients were elderly with a mean age of 78. Two patients were immunocompromised, and the two others presented only diabetes mellitus. Three patients presented an ARDS requiring transfer to the ICU and mechanical ventilation. All patients presented lymphocytopenia. Three patients had probable PCP, and one had proven PCP. All patients died within two months after hospital admission. These co-infections are rare but severe, therefore, PCP should be considered in case of worsening of the condition of patients with severe COVID-19

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis