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

Abstract

Background: 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.

Comparative Metabolomics Study of the Impact of Articaine and Lidocaine on the Metabolism of SH-SY5Y Neuronal Cells

“…Exposure to LA additionally triggered a dose-dependent decrease in the intracellular levels of myo-inositol, similarly to the variation observed in breast cancer cells treated with LDC [ 31 ]. This polyalcohol is a component of membrane phospholipids, mediates osmoregulation, and its phosphorylated derivatives participate in signal transduction pathways and other important cellular functions [ 60 ].…”

“…Indeed, the interference of LDC in mitochondrial metabolism has been reported in previous studies [22,30,31,44,55]. For instance, LDC induced oxidative modification of the TCA cycle enzyme aconitase and of multiple ATP synthase subunits in model yeast cells, causing a reduced ATP content [30,44], and disturbed the levels of TCA cycle intermediates in breast cancer cells [31]. This LA was also reported to suppress the mitochondrial ETC in SH-SY5Y cells, thereby attenuating the mitochondrial membrane potential and triggering excessive ROS production [22].…”

“…In this work, we hypothesize that LDC and ATC reduce the anaplerotic use of amino acids, affecting energy production. Indeed, the interference of LDC in mitochondrial metabolism has been reported in previous studies [22,30,31,44,55]. For instance, LDC induced oxidative modification of the TCA cycle enzyme aconitase and of multiple ATP synthase subunits in model yeast cells, causing a reduced ATP content [30,44], and disturbed the levels of TCA cycle intermediates in breast cancer cells [31].…”

“…Metabolites 2022, 12, x FOR PEER REVIEW 3 of 18 [29]. However, its application to the study of LAs has been limited to characterizing the effects of LDC in yeast [30] and in breast cancer cells [31]. To our knowledge, the work hereby presented is the first metabolomics report on the neurotoxicity of LAs.…”

“…Metabolomics has been widely explored in the field of toxicology, including in studies aimed at assessing the neurotoxic effects of different drugs [ 29 ]. However, its application to the study of LAs has been limited to characterizing the effects of LDC in yeast [ 30 ] and in breast cancer cells [ 31 ]. To our knowledge, the work hereby presented is the first metabolomics report on the neurotoxicity of LAs.…”