https://orcid.org/0000-0002-3569-6066
Figures & data
Figure 1. Dexmedetomidine: chemical formula and mode of action.
(a) Chemical formula of dexmedetomidine (4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1 H-imidazole). (b) Upon ligation to α2-adrenoceptor, a G-protein coupled receptor (GPCR), dexmedetomidine (DEX) provokes a conformational change from the GDP-bound to the GTP-bound state, inducing the efflux of potassium and a hyperpolarization of the plasma membrane. Membrane hyperpolarization in turn inhibits the gating of voltage-dependent Ca2+ channels, blocking the release of neurotransmitters. Created with https://www.BioRender.com
Figure 2. Sympatholytic and analgesic effects of dexmedetomidine through the α2-adrenoceptors.
(a, b, c) α2-adrenoceptors (α2-AR) are composed of four subtypes: α2A, α2B, α2C, and α2D. By acting on α2A-AR and α2C-AR in the locus coeruleus (LC), dexmedetomidine (DEX) decreases the release of norepinephrine from presynaptic neurons inducing sedative and anxiolytic effects. DEX could also disinhibit the ventrolateral preoptic nucleus (VLPN) promoting the release of GABA, which in turn suppresses the tuberomammillary nucleus involved in arousal. The sympatholytic action of DEX on α2A-AR in the rostral ventrolateral medulla (RVLM) and on α2B-AR in the nucleus ambiguous (NA) decreases the heart rate. On the vessels, DEX induces a transient vasoconstriction through α2B-AR, while the link to α2A-AR rather triggers a vasodilatation leading to hypotension. Moreover, DEX was described to act on α-ARs located on the surface of cancer cells, thereby exerting potential both pro- or antitumor effects. (d) DEX exhibits its analgesic properties by binding to the α2A-AR receptors in the dorsal horn of the spinal cord thus decreasing the release of nociceptive molecules such as norepinephrine, substance P and calcitonin gene-related protein (CGRP). In addition, DEX reduces neuropathic pain-induced inflammation and hyperalgesia by increasing the rate of acetylcholine (ACh) and cholinergic signaling through cholinergic receptors (Chol-R). The exact mechanism by which DEX increases the level of ACh, either through α2-AR mediated positive feedback or by inhibiting acetylcholinesterase (AChE) in the synaptic cleft, is unclear. Created with https://www.BioRender.com
Table 1. Preclinical research describing protumor effects of dexmedetomidine.
Figure 3. Molecular mechanisms of dexmedetomidine-mediated anti-tumor effects.
DEX suppresses esophagus cancer progression via miR-143-3p/EGFR, by repressing c-MYC, MALAT1 and ERK1/2 expression, by increasing E-cadherin expression, and by regulating circ -0003340/miR-198/HMGA2. Furthermore, DEX promotes ferroptosis in gastric adenocarcinoma through the inhibition of the circ0008035/miR-302a/E2F7 axis. It decreases the proliferation and migration of human osteosarcoma cells and triggers apoptosis via the up-regulation of miR-520a-3p that targets YOD1 and the inhibition of miR-1307. Moreover, DEX inhibits lung tumor growth and favors apoptosis via an up-regulation of miR-493-5p, which targets RASL11B and inhibits aberrant inflammasome activation. DEX induces ovarian cancer cell apoptosis via the up-regulation of miR-185 that inactivates SOX9/Wnt/B-catenin and decreases the invasion and migration by inhibiting IGF2 pathway. Created with https://www.BioRender.com
Abbreviations: DEX, dexmedetomidine; EGFR, epidermal growth factor receptor; ERK, extracellular regulated kinase; HMGA2, high mobility group AT-hook 2; IGF, insulin-like growth factor; IL, interleukin; IRS1, insulin receptor substrate 1; MALAT1, metastasis associated lung adenocarcinoma transcript 1; MMP, matrix metalloproteinase; NLRP3, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3; SOX9, Sry (Sex determining region Y)-box 9
Table 2. Preclinical research describing antitumor effects of dexmedetomidine.
Table 3. Published clinical trials studying the dexmedetomidine-induced biological effects potentially related to oncological outcome.
Table 4. Completed trials investigating the role of dexmedetomidine on cancer outcome.
Table 5. Ongoing trials investigating the role of dexmedetomidine on cancer outcome.
Table 6. Completed and ongoing trials investigating the role of OFA on cancer outcome.
Figure 4. Scheme of central and peripheral actions of dexmedetomidine.
Surgery-induced inflammatory pain activates the corticotropic axis via the stimulation of afferent nociceptive pathways and promotes local production of protumor cytokines such as IL-1β, IL-6 and TNF-α. The hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the synthesis of adrenocorticotropic hormone (ACTH) by the pituitary gland. In response to ACTH, adrenal glands release cortisol and catecholamines (epinephrine and norepinephrine) into the systemic circulation. Catecholamines, potentiated by tumorigenic cytokines, act on α- and β-adrenoceptors (α-AR, β-AR) located on the surface of tumor cells to enhance their proliferation, survival and migration. These protumor molecules inhibit the chemotaxis and cytotoxicity of the immune effectors (T, B, NK cells) in the tumor bed and its microenvironment (TME). Dexmedetomidine (DEX) could alleviate both corticotropic axis activity and the release of protumor cytokines by optimally controlling inflammatory pain. Through its agonist effect on α-adrenoceptor, DEX might also impair the malignant properties of tumor cells directly. Created with https://www.BioRender.com
