https://orcid.org/0000-0002-3569-6066
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ABSTRACT
Preclinical evidence indicates potent antitumor properties of local anesthetics. Numerous underlying mechanisms explaining such anticancer effects have been identified, suggesting direct cytotoxic as well as indirect immunemediated effects that together reduce the proliferative, invasive and migratory potential of malignant cells. Although some retrospective and correlative studies support these findings, prospective randomized controlled trials have not yet fully confirmed the antineoplastic activity of local anesthetics, likely due to the intricate methodology required for mitigating confounding factors. This trial watch aims at compiling all published preclinical and clinical research, along with completed and ongoing trials, that explore the potential antitumor effects of local anesthetics.
KEYWORDS:
Abbreviations
| ATF4 | = | activating transcription factor 4 |
| ATF6 | = | activating transcription factor 6 |
| ATP | = | adenosine triphosphate |
| CDK | = | cyclin-dependent kinase |
| CHOP | = | C/EBP homologous protein |
| circRNA | = | circular RNA |
| CPEB3 | = | cytoplasmic polyadenylation element-binding protein 3 |
| CYTC | = | cytochrome C |
| DAMPs | = | danger associated molecular patterns |
| DC | = | dendritic cell |
| DFS | = | disease-free survival |
| DNMTs | = | DNA methyltransferases |
| EGFR | = | epithelial growth factor receptor |
| EIF2alpha | = | eukaryotic initiation factor 2 alpha |
| ER | = | endoplasmic reticulum |
| ERK | = | extracellular signal-regulated kinases |
| GA | = | general anesthesia |
| HB-EGF | = | heparin-binding epidermal growth factor-like growth factor |
| HIF | = | hypoxia-inducible factor |
| HMGB1 | = | high mobility group box 1 |
| ICD | = | immunogenic cell death |
| ICU | = | intensive care unit |
| IFN | = | interferon |
| IL | = | interleukin |
| IRE1 | = | inositol-requiring enzyme 1 |
| KAT8 | = | lysine acetyltransferase 8 |
| LA | = | local anesthetics |
| LC3B | = | lipidation of autophagy-related protein light-chain 3B |
| lncRNA | = | long non-coding RNA |
| MAPK | = | mitogen-activated protein kinase |
| MEG | = | maternally expressed gene |
| miRNA | = | microRNA |
| MMP | = | matrix metalloproteinase |
| NA | = | non-applicable |
| NK | = | natural killer |
| NF-kB | = | nuclear factor-kappa B |
| OGFRP1 | = | opioid growth factor receptor pseudogene 1 |
| OS | = | overall survival |
| PARP | = | poly ADP-ribose polymerase |
| PCS/MCS | = | Physical and Mental Health Composite Scores |
| PD(L)1 | = | Programmed cell Death (Ligand) protein 1 |
| PERK | = | protein kinase RNA-like endoplasmic reticulum kinase |
| PI3K/Akt/Mtorc | = | phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex |
| PONV | = | postoperative nausea and vomiting |
| RAC1/JNK/paxillin/FAK | = | RAS-related C3 botulinum toxin substrate 1/c-JUN N-terminal kinase/paxillin/focal adhesion kinase |
| RHO-A/ROCK/MLC | = | RHO-associated protein kinase/myosin light chain |
| RFS | = | recurrence-free survival |
| Src | = | Src protein tyrosine kinase |
| STAT3 | = | Signal transducer and activator of transcription 3 |
| Th | = | T helper cells |
| TGF | = | tumor growth factor |
| TIVA | = | total intravenous anesthesia |
| TNF | = | tumor necrosis factor |
| Treg | = | regulatory T cells |
| TRPM7 | = | transient receptor potential melastatin 7 |
| VEGF | = | vascular endothelium growth factor |
| WIF-1 | = | Wnt inhibitory factor-1 |
| YAP | = | Yes-associated protein 1 |
| XBP1 | = | X-box binding protein 1 |
Acknowledgments
KCLP receives funding from Agence Régionale en Santé (ARS) Ile de France Année-Recherche Pharmacie; OK receives funding from Institut National du Cancer (INCa) and Agence National de la Recherche (ANR); GK is supported by the Ligue contre le Cancer (équipe labellisée); ANR – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; INCa; Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. LB receives funding from the Societé Française d’Anesthésie-Réanimation (SFAR), the Ligue contre le cancer, the foundation Monahan.
Disclosure statement
OK and GK have been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. OK is a scientific co-founder of Samsara Therapeutics. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK’wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results. The other authors declare no conflicts of interest.