https://orcid.org/0000-0002-3569-6066
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ABSTRACT
Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist that is widely used in intensive and anesthetic care for its sedative and anxiolytic properties. DEX has the capacity to alleviate inflammatory pain while limiting immunosuppressive glucocorticoid stress during major surgery, thus harboring therapeutic benefits for oncological procedures. Recently, the molecular mechanisms of DEX-mediated anticancer effects have been partially deciphered. Together with additional preclinical data, these mechanistic insights support the hypothesis that DEX-induced therapeutic benefits are mediated via the stimulation of adaptive anti-tumor immune responses. Similarly, published clinical trials including ancillary studies described an immunostimulatory role of DEX during the perioperative period of cancer surgery. The impact of DEX on long-term patient survival remains elusive. Nevertheless, DEX-mediated immunostimulation offers an interesting therapeutic option for onco-anesthesia. Our present review comprehensively summarizes data from preclinical and clinical studies as well as from ongoing trials with a distinct focus on the role of DEX in overcoming (tumor microenvironment (TME)-imposed) cancer therapy resistance. The objective of this update is to guide clinicians in their choice toward immunostimulatory onco-anesthetic agents that have the capacity to improve disease outcome.
Abbreviations
| Ach | = | Acetylcholine |
| AChE | = | Acetylcholinesterase |
| aHSC | = | Activated hepatic stellate cells |
| AR | = | Adrenoceptor |
| ASC | = | Adapter protein apoptosis speck-like protein containing a CARD |
| AVP | = | Arginine-vasopressin |
| CI | = | Confidence interval |
| CPT1A | = | Carnitine palmitoyltransferase 1A |
| DC | = | Dendritic cell |
| DEX | = | Dexmedetomidine |
| EGFR | = | Epidermal growth factor receptor |
| ENT | = | Ear-Nose-Throat |
| ERK | = | Extracellular regulated kinase |
| ESR | = | Erythrocyte sedimentation rate |
| GA | = | General anesthesia |
| GABA | = | Gamma-aminobutyric acid |
| HCC | = | Hepatocellular carcinoma |
| HIF | = | Hypoxia-inducible factor |
| HIPEC | = | Hyperthermic intraperitoneal chemotherapy |
| HMGA2 | = | High mobility group AT-hook 2 |
| HR | = | Hazard ratio |
| IFN | = | Interferon |
| IGF | = | Insulin-like growth factor |
| IL | = | Interleukin |
| IRS1 | = | Insulin receptor substrate 1 |
| IV | = | Intravenous |
| LMR | = | lymphocyte-to-monocyte ratio |
| MALAT1 | = | Metastasis associated lung adenocarcinoma transcript 1 |
| MMP | = | Matrix metalloproteinase |
| NETs | = | Neutrophil extracellular traps |
| NK | = | Natural killer |
| NF-Κb | = | Nuclear factor kappa B |
| NLR | = | neutrophil-to-lymphocyte ratio |
| NLRP3 | = | NOD-like receptor family pyrin domain containing 3 |
| OFA | = | Opioid-free-anesthesia |
| OGD | = | Oxygen-glucose deprivation |
| OS | = | overall survival |
| PI3K/Akt | = | Phosphoinositide 3 kinase/Protein kinase B |
| PLR | = | platelet-to-lymphocyte ratio |
| RFS | = | Recurrence-free survival |
| ROS | = | Reactive oxygen species |
| SOX9 | = | Sry (Sex determining region Y)-box 9 |
| STAT3 | = | Signal transducer and activator of transcription 3 |
| TMPRSS2 | = | Transmembrane protease serine 2 |
| TNF | = | Tumor necrosis factor |
| TXNIP | = | Thioredoxin (TRX)-interacting protein |
| VEGF | = | Vascular endothelial growth factor |
| VLPN | = | Ventrolateral preoptic nucleus |
| WBC | = | White blood cells |
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 Association pour la recherche sur le cancer (ARC); GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (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 Société Française d’anesthésie-réanimation (SFAR); the Ligue contre le Cancer, and the Fondation Monahan.
Disclosures 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’s 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.