The immunomodulatory effect of ketamine in colorectal cancer surgery: a randomized-controlled trial

Cho, Jin Sun; Kim, Na Young; Shim, Jæ Kwang; Jun, Ji Hae; Lee, Sugeun; Kwak, Young Lan

doi:10.1007/s12630-021-01925-3

Cited by 22 publications

(19 citation statements)

References 39 publications

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“…Emerging findings from clinical and evidence-based medicine indicated that the use of ketamine perioperatively appeared to be more efficacious in larger procedures that led to extensive tissue damage and accelerated systemic inflammation and markedly inhibited the early postoperative IL-6 inflammatory response and natural killer (NK) cell activity [ 26 , 49 , 50 ]. Moreover, the immunoprotective effect of perioperative low-dose administration of ketamine [ 51 , 52 ], as well as the alleviation of sepsis-associated MODS by inhibiting LPS-induced HGMB1 release, were confirmed by a previous publication [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS

Deng

Yang

et al. 2022

Cell Death Discov.

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Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.

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Section: Discussionmentioning

confidence: 99%

Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS

Deng

Yang

et al. 2022

Cell Death Discov.

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“…Clinical studies are scarce and partially conflicting. In a prospective and randomized study of patients with colorectal cancer, Cho et al found that the administration of intraoperative low-dose ketamine did not have a favorable impact on overall postoperative NK cell activity, inflammatory response, and prognosis (132). In a small randomized trial in patients undergoing minimally invasive prostatectomy for prostate cancer, Kawaguchi et al also failed to detect an immunomodulatory effect by ketamine (131).…”

Section: Ketaminementioning

confidence: 99%

Anesthesia and Oncology: Friend or Foe?

Buddeberg

Seeberger

2022

Front. Oncol.

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Cancer is a leading cause of death, and surgery is an important treatment modality. Laboratory research and retrospective studies have raised the suspicion that the choice of anesthetics for cancer surgery might affect the course of cancerous disease. The aim of this review is to provide a critical overview of the current state of knowledge. Inhalational anesthesia with volatiles or total intravenous anesthesia (TIVA) with propofol are the two most commonly used anesthetic techniques. Most data comparing volatile anesthetics with TIVA is from either in vitro or retrospective studies. Although conflicting, data shows a trend towards favoring propofol. Opioids are commonly used in anesthesia. Data on potential effects of opioids on growth and recurrence of cancer are scarce and conflicting. Preclinical studies have shown that opioids stimulate cancer growth through the µ-opioid receptor. Opioids also act as immunosuppressants and, therefore, have the potential to facilitate metastatic spread. However, the finding of an adverse effect of opioids on tumor growth and cancer recurrence by some retrospective studies has not been confirmed by prospective studies. Regional anesthesia has not been found to have a beneficial effect on the outcome of surgically treated cancer patients, but prospective studies are scarce. Local anesthetics might have a beneficial effect, as observed in animal and in vitro studies. However, prospective clinical studies strongly question such an effect. Blood products, which may be needed during extensive cancer surgery suppress the immune system, and data strongly suggest a negative impact on cancer recurrence. The potential effects of other commonly used anesthetic agents on the outcome of cancer patients have not been sufficiently studied for drawing valid conclusions. In conclusion, laboratory data and most retrospective studies suggest a potential advantage of TIVA over inhalational anesthesia on the outcome of surgical cancer patients, but prospective, randomized studies are missing. Given the state of weak scientific evidence, TIVA may be used as the preferred type of anesthesia unless there is an individual contraindication against it. Studies on the effects of other drugs frequently used in anesthesia are limited in number and quality, and have found conflicting results.

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“…Furthermore, treatment of ketamine can suppress proliferation and induces ferroptosis, a type of cell death driven by iron-dependent, multiple cellular metabolic pathways [ 63 ], and apoptosis by targeting glutathione peroxidase 4 in breast cancer cells [ 64 ] and HCCs [ 65 ]. For the induction of immunosuppression in cancer treatment, some small-scale clinical trials have reported that the pre-operative intravenous infusion of ketamine only possesses minor [ 66 ] or even slight inhibitory effects [ 67 ] on cytotoxicity of NK cells. These results suggest that ketamine may not be able to enhance NK cell cytotoxicity activity to exert its anti-cancer activity.…”

Section: Repurposing Anesthetic/sedative Drugs Into Anticancer Treatmentmentioning

confidence: 99%

Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics

Liao

Yeh

et al. 2022

Biomedicines

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Cancer is one of the leading causes of death worldwide. There are only limited treatment strategies that can be applied to treat cancer, including surgical resection, chemotherapy, and radiotherapy, but these have only limited effectiveness. Developing a new drug for cancer therapy is protracted, costly, and inefficient. Recently, drug repurposing has become a rising research field to provide new meaning for an old drug. By searching a drug repurposing database ReDO_DB, a brief list of anesthetic/sedative drugs, such as haloperidol, ketamine, lidocaine, midazolam, propofol, and valproic acid, are shown to possess anti-cancer properties. Therefore, in the current review, we will provide a general overview of the anti-cancer mechanisms of these anesthetic/sedative drugs and explore the potential underlying signaling pathways and clinical application of these drugs applied individually or in combination with other anti-cancer agents.

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The immunomodulatory effect of ketamine in colorectal cancer surgery: a randomized-controlled trial

Cited by 22 publications

References 39 publications

Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS

Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS

Anesthesia and Oncology: Friend or Foe?

Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics

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