Impact of propofol on gastrointestinal cancer outcomes: A review of cellular behavior, growth, and metastasis

Abstract

Cancer is one of the most important health problems that deeply affects all humanity and will have groundbreaking consequences in human history with its elimination. Gastrointestinal cancers, including colon and rectum, stomach, liver, pancreatic, and esophageal, account for 26% of the global cancer incidence and 35% of cancer-related deaths. Unfortunately, it is estimated that today’s high incidence and mortality rates will increase by 58% and 73% by 2040, respectively. Although the treatment process includes novel options such as immunotherapy in addition to classical options with a multidisciplinary approach, surgical treatment under general anesthesia remains the leading option. Considering a long-lasting cancer process, it is quite surprising that a very short-term anesthetic administration can have various effects on cancer cell behavior. Various anesthetic approaches such as regional blocks used in pain management, the use of anesthetic adjuvants such as β-adrenoceptor antagonists, nonsteroidal anti-inflammatory drugs, and intravenous lidocaine, and the choice of anesthetic drugs seem to have potential effects on long-term cancer outcomes. Propofol is an intravenous anesthetic drug that is used for both induction and maintenance of general anesthesia. Many in vitro and clinical studies examining the effects of propofol comparatively with other anesthetic agents on tumor recurrence and metastasis revealed possible effects on tumor cell signaling, the immune response, and the modulation of the neuroendocrine stress response. However, the evidence from all these in vitro and clinical studies is different, complicated, and inconsistent. The general effects of propofol on the behavioral patterns, growth, and metastasis of gastrointestinal tumor cells, as well as the clinical features and consequences resulting from these effects, constitute the subject of this review.

Key Words: General anesthesia; Propofol; Gastrointestinal cancer; Morbidity; Survival; Outcomes

Core Tip: Gastrointestinal cancers pose a significant global health concern. Surgical resection under general anesthesia serves as the primary treatment for gastrointestinal cancers. The two main anesthesia techniques utilized in cancer surgery today are propofol-based total intravenous anesthesia and volatile agent-based inhaled anesthesia. The potential impacts of the selected anesthesia technique on cancer cells, their biological behavior, and the associated clinical outcomes are subjects of extensive experimental and clinical research. Due to the conflicting findings from these studies, it remains impossible to provide personalized anesthesia recommendations based on the type of cancer and the patient’s condition.

INTRODUCTION

Cancer, together with ischemic cardiovascular disease, are the top two most common public health problems and causes of mortality in the world. Cancers originating from the central gastrointestinal (GI) tract include esophageal cancer, gastric cancer (GC), colorectal cancer (CRC), liver cancer (LC), and pancreatic cancer (PC) with incidences of 3.2%, 5.7%, 10.2%, 4.7%, and 2.5%, respectively[1]. Although there are significant differences in the incidence and mortality rates between subtypes in different parts of the world, GI cancers (GICs) account for 1 in 4 cancer cases and 1 in 3 cancer deaths worldwide. Considering the increase in the elderly population and inequalities in cancer treatment globally, it is thought that the expected increase in cancer incidence rate may also be reflected in GIC, especially in low-income countries[2].

Although adjuvant and neoadjuvant therapies are available, repeated surgical treatments under general anesthesia, including resection of the primary lesion, metastasectomy, and palliative surgery, are the core treatment options for patients having operable GIC. These patients may, therefore, be repeatedly exposed to anesthetic procedures. In anesthesia practice, in addition to general anesthetics including various inhaled agents such as sevoflurane, desflurane, and halothane and intravenous agents such as propofol, barbiturates, and benzodiazepines, miscellaneous anesthetic adjuvants such as opioids, muscle relaxants, β-adrenoceptor antagonists, nonsteroidal anti-inflammatory drugs, steroids, and intravenous lidocaine are often used. Also, in many cancer patients, various regional anesthesia procedures are applied both in the perioperative period and within the scope of chronic pain treatments. It has been shown that the interventions applied during the anesthesia process, which is relatively very short compared to the long cancer process, and the pharmacological agents used in these interventions can have significant effects on cancer cells that can seriously affect the process[3].

Propofol was first synthesized in 1973, entered clinical use in the United Kingdom and New Zealand in 1986, and received Food and Drug Administration approval in 1989[4]. Propofol is not only one of the most commonly used anesthetic agents for induction and maintenance of general anesthesia. Still, it is also used as a procedural sedative agent for diagnostic procedures and short, painful interventions outside the operating room. For example, in the context of interventional radiology, diagnostic sampling under imagined guidance by percutaneous and needle aspiration, therapeutic applications on local cancer treatment including radiofrequency ablation or trans-arterial chemoembolization, management of cancer complications such as pain, bleeding, organ obstructions, or venous thrombosis with placement of gastrostomy or jejunostomy[5]. Propofol can also be used for the sedation of intubated and mechanically ventilated intensive care unit patients. There are some off-label uses of propofol, such as refractory status epilepticus and refractory postoperative nausea-vomiting[6]. With these diverse indications and clinical uses, propofol is on the World Health Organization’s List of Essential Medicines, a list of medicines considered the most effective and safe to meet the most important needs in a health system[7]. This review presents the general effects of propofol on the behavioral patterns, growth, and metastasis of GI tumor cells, as well as the clinical features and consequences resulting from these effects.

GENERAL PROPERTIES OF PROPOFOL

Propofol, chemically termed 2,6-diisopropylphenol, is an emulsion containing 10% soybean oil (100 mg/mL), 2.25% glycerol (22.5 mg/mL), 1.2% egg lecithin (12 mg/mL), in its classic formulation[8]. Disodium edetate (EDTA; 0.05 mg/mL) was added to this classic formulation to prevent bacterial contamination[9]. The solution is insoluble in water, isotonic, and has a neutral pH (depending on sodium hydroxide) and a pKa of 11.1 at 20 °C. It can be stored and used at room temperature due to its melting point of 18 °C[10]. Because of low oral bioavailability due to the high first-pass effect through the liver and ineffectiveness when given via intramuscular and subcutaneous routes, propofol can be used only via the intravenous route. Table 1 presents the basic data regarding the pharmacokinetic properties of propofol.

Table 1 The pharmacokinetic and pharmacodynamic properties of propofol[10].

Properties
Route of administration		Intravenous
Standard induction dose (mg/kg)		1.5-2.5
Onset of action (second)		40-60 (‘one arm brain circulation’)
Duration of action (minute)		3-10
Volume of distribution (L/kg)		5.8
Protein binding		97%-99% (mostly albumin)
Metabolism		Hepatic oxidation and conjugation to sulfate and glucuronide conjugates
Total body clearance (L/hour/kg)		3.2
Half-life	Initial (minute)	Approximately 40
	Terminal (hour)	4-7
	Context-sensitive (day)	1-3 days after a 10-day infusion. The clinical effect of propofol is much shorter
Excretion		Primarily renal

Propofol has rapid and smooth anesthesia induction characteristics without any excitation phenomena. After intravenous administration, loss of consciousness occurs quickly because of the rapidity with which it crosses the blood-brain barrier and reaches the central nervous system. After a single bolus injection or short-term infusion, a rapid return of consciousness is expected due to rapid initial distribution. Even after prolonged administration, the return of clinical effects is still fast due to high lipid solubility and distributional and re-distributional properties of the drug among different compartments[11]. Although propofol is metabolized mainly in the liver, the kidneys, small intestine, and lungs are responsible for 40% extra-hepatic metabolism. After metabolism, 88% of propofol is excreted in the urine, while less than 0.3% is excreted unchanged[12].

Propofol has hypnotic, amnestic, anxiolytic, analgesic, antiemetic, anticonvulsant, and antioxidant activity, and some neurophysiologic effects such as decreasing cerebral blood flow, intracranial pressure, and cerebral metabolic rate. Although the exact mechanism of action is poorly understood, the primary mechanism responsible for the hypnotic effect is thought to be the potentiation of gamma-aminobutyric acid subtype A (GABAA) receptor activity[13]. Also, antagonism of glutamatergic N-methyl-D-aspartate (NMDA) receptors, modulation of calcium influx through slow calcium-ion channels, activation of endocannabinoid system (ECS) (inhibition of endocannabinoid anandamide), and blocking of sodium channels are other suggested mechanisms of action for hypnotic effect[14-16]. Propofol’s modulation of GABAA receptor and NMDA receptor activity, and endocannabinoid pathways can have dual effects on cancer progression, depending on the cancer type, receptor expression profile, and microenvironment. Enhancing GABAergic inhibition may impact cancer cell signaling pathways associated with proliferation and apoptosis[17]. NMDA receptor inhibition may suppress cancer cell invasion and metastasis on the one hand and play a role in cancer progression on the other by contributing to survival pathways of glutamate signaling[18]. The ECS plays a role in inflammation, immune response, and cancer progression. Propofol has been shown to interact with ECS components, essentially CB1 receptors, which are involved in tumor suppression and pain modulation[19].

The recommended dose of propofol for a standard induction of general anesthesia in a healthy adult under 55 years of age is 2-2.5 mg/kg administered in 40 mg boluses every 10 seconds titrated up to the onset of hypnotic effect for induction and 6-12 mg/kg/hour for the maintenance. A dose reduction is recommended in elderly patients, patients with impaired general conditions, e.g., American Society of Anesthesiologists III and IV, and frail patients. One of the major handicaps of prolonged infusion is propofol-related infusion syndrome. Therefore, administration of propofol at a dose of > 5 mg/kg/hour for more than 48 hours is not recommended[10]. There is insufficient data on whether propofol has different dose-dependent effects on tumor cells or whether there is an optimal dose in cancer patients. Chang et al[20] used three different propofol concentrations (10, 25, and 50 μg/mL), low, medium, and high, to investigate the dose-dependent inhibition of proliferation, migration, invasion, and tumor growth of cancer cells, and they found that propofol suppressed actions of LC cells at all doses in a dose-dependent manner. In a study examining the effect of propofol dosage on 1-year mortality in patients with solid tumors, it was reported that higher propofol doses were associated with lower mortality in patients without a diagnosis of solid cancer (breast, colorectal, and hepatobiliary) but not in those with that diagnosis[21]. The tumoral effects of different doses of propofol have been frequently examined in cell culture studies, and in all of these studies, no differences in efficacy between doses were reported and it has been stated that the antitumoral effects of propofol, including inhibition of transition, migration, proliferation, invasion, and acceleration of apoptosis, occur in a dose-dependent manner, but it was not examined specifically which effects occur at which dose[22].

Characteristic side effects of propofol include transient pain at the injection site (most frequently seen side effect due to transient receptor potential ankyrin 1 receptor activation), unfavorable hemodynamic effects such as hypotension, bradycardia (due to direct vasodilation and inhibition of sympathetic nerve activity), respiratory depression, apnea, myoclonus, EKG changes such as prolongation of QT interval, and green discoloration of the urine[23-25]. The occurrence of hemodynamic and respiratory side effects depends on the rate and dose of administration of propofol as well as other concomitant sedative drugs and opioids, the age of the patient, and whether the patient is debilitated. Propofol-related infusion syndrome is a rare but serious side effect characterized by severe unexplained metabolic acidosis, arrhythmias, acute renal failure, rhabdomyolysis, hyperkalemia, and cardiovascular collapse, which can be seen due to prolonged propofol infusion for sedation, especially in mechanically ventilated intensive care patients[26]. Although propofol is generally considered a safe and effective anesthetic agent, the risk of side effects is significantly increased in some patient groups. Patients with cardiac diseases and elderly patients (> 65 years of age) are particularly at high risk for the cardiotoxic effects of propofol, while obese patients, individuals with high body mass index, and elderly patients are at high risk for respiratory depressive effects[27,28]. In some disease groups with a high risk of serious arrhythmias and related death, such as Brugada syndrome, recent analyses, and related interpretations indicate that propofol does not increase additional risk[29]. Individuals with epilepsy or neurological diseases are at higher risk for neurological complications that may occur after propofol use, such as loss of consciousness, confusion, and even seizure activity[30]. Apnea and respiratory depression can be seen, especially in young children and those with respiratory diseases such as chronic obstructive pulmonary disease and critical illness conditions[4].

One of the major handicaps in the clinical use of propofol is the variability of individual response to the drug, mainly due to genetic and non-genetic factors such as sex, weight, and height, which various studies have long investigated. Approximately 70% of propofol metabolism is mediated by the UDP-glucuronosyltransferase (UGT) gene encoded by UGT1A9. Enzymes encoded by the CYP2B6 and CYP2C9 genes and the sulfotransferase 1A and NAD(P)H:quinone oxidoreductase 1 genes are responsible for approximately 29% of propofol biotransformation[31]. While CYP2B6 A785G gene variants significantly reduce the elimination rate of propofol, especially in elderly patients, the CYP2B6 G516T variant elevated blood propofol concentrations after a single bolus dosage[32,33]. It has been reported that the UGT1A9 genotype is an independent predictor of propofol concentration 10 minutes after the end of continuous infusion in children and that the propofol distribution constant is higher in carriers of polymorphic UGT1A9 C allele[34]. Patients with UGT1A9-331C/T had increased clearance of propofol and, therefore, required a higher propofol dose for induction. In addition, the time required for loss of consciousness is longer in patients with UGT1A9-1818T/C[35]. Genetic differences in the GABAA receptor, an important target for propofol, have also been investigated as a possible source of differences in individual susceptibility. Zhong et al[36] reported that carriers of the major allele (GG) homozygous for the GABAA1 receptor are more sensitive to propofol anesthesia and that mutation of the GABAA1 receptor also contributes to the different effects of propofol on blood pressure. Although alterations in the pharmacokinetic and pharmacodynamic response to propofol due to these genetic variations have been associated with clinical events such as malignant hyperthermia, postoperative nausea and vomiting, and delayed recovery from general anesthesia, it is not yet clear how they affect the behavioral pattern of tumor cells in patients with cancer.

Given that propofol is used as an anesthetic during surgery, is only sustained intraoperatively, and is rapidly metabolized postoperatively, and considering that tumor formation is a chronic process rather than a quick event, it raises an important question: How can propofol affect tumor cells and the microenvironment during this brief period? At this point, it is helpful to remember the concept of epigenetics. The term ‘epigenetics’ defines a stable heritable phenotype resulting from chromosome changes without changes in the DNA sequence[37]. Anesthetics, including propofol, have the potential to cause epigenetic effects. This effect occurs even after relatively short exposures but is expected to be more intense after prolonged or repeated exposures[38]. In the perioperative period, anesthetics may act either on cancer cells or through changes in the host response at cellular and molecular levels [such as increasing apoptosis, decreasing tumor cell proliferation, suppressing angiogenesis-related factors such as hypoxia-inducible factor (HIF)-1α, inhibiting matrix metalloproteinases (MMPs), and decreasing invasion]. Although propofol is rapidly metabolized, its changes in intracellular signaling pathways and gene expression may be permanent. Therefore, even short-term use may have long-lasting effects on intracellular regulatory mechanisms. It is even thought that anesthetics can affect not only the person administered but also subsequent generations[39].

ANTITUMOR EFFECTS OF PROPOFOL

The antitumor effects of propofol can be divided into two parts: Directly affecting the tumor cell itself, mainly by targeting metabolic and signaling pathways, oncogenes, and functional proteins, and indirectly affecting the biological properties of tumor cells by influencing the tumor microenvironment (TME) through its effects on neo-vascularization formation, regulation of host immunity and the inflammatory process, and remodeling of the extracellular matrix (ECM).

Direct effects

Several studies report that propofol may inhibit tumoral development due to its interaction with the expression of some minor regulatory RNA subtypes. Small non-coding RNAs are a family of non-coding RNAs with sizes ranging from about 21-34 nucleotides (nt) of which the best known are microRNAs (miRNAs), endogenous small interfering RNAs, and PIWI-interacting RNAs. They all have essential cellular functions in many regulatory processes, including transcription, post-transcription, and translation. MiRNAs are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides in length. Most miRNAs originate from DNA sequences as primary miRNAs and are converted into precursor miRNAs and mature miRNAs[40]. Numerous studies have demonstrated that miRNAs inhibit the translation and stability of messenger RNAs and control genes closely related to tumorigenesis and development associated with cellular processes such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration[41]. Since miRNA dysregulation and gain or loss of miRNA function due to deletion, amplification, or mutation have been demonstrated in various cancer types, miRNAs are thought to play a critical role in cancer development or suppression. Also, miRNAs are considered specific for cell type and cellular differentiation status. Therefore, they can be used as biological markers for diagnosing and predicting prognosis[42]. In GICs, miR-100, miR-129-5p, miR-484, miR-204, miR-338, miR-302, miR-139, miR-215-3p, miR-4766-5p, miR-197, miR-1273h-5p, miR-23a-3p, and miR-588 can exert anti-tumorigenic activity by regulating the expression of chemokines[43]. Examples of miRNAs that propofol interacts with and shows anti-tumoral effects in GICs are miR-328-3p, miR-186-5p, miR-645, miR-93, miR-155, miR-30e, miR-374a[44,45].

Another kind of functional RNA molecule is long non-coding RNA (lncRNA). LncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Although their expression levels are low, they have a transcriptional and post-transcriptional regulatory function via interactions with DNA, RNA, nucleic acids, lipids, or proteins[46]. They also regulate gene transcription and messenger RNA splicing and act as a precursor of miRNAs[47,48]. LncRNAs were reported to function as oncogenes or tumor suppressors by participating in various signaling deregulations that influence intestinal tissue homeostasis, particularly in CRCs[49]. LncRNAs and miRNAs also interact with each other and contribute to the formation of malignant biological characteristics of tumor cells. While lncRNAs can bind to miRNAs and affect their function, miRNAs may play a role in the stability of lncRNAs, and propofol has been shown to have several regulatory effects in this interaction, resulting in antitumor activity[50]. Maternally expressed gene 3, growth arrest-specific transcript 5, tumor suppressor candidate 7, BRAF-activated noncoding RNA, fetal-lethal non-coding developmental regulatory RNA, nuclear factor kappa B (NF-κB)-interacting long noncoding RNA, heart and neural crest derivatives expressed 2-antisense RNA 1, and long intergenic nonprotein coding RNA p53-induced transcript are examples of lncRNAs that show antitumor activity in GICs through immune regulation, metastasis inhibition, and chemotherapy sensitivity enhancement[51]. Propofol suppresses GIC cell growth, inhibits metastasis, and increases drug sensitivity by modulating specific lncRNAs including LINC01133, metastasis associated lung adenocarcinoma transcript 1, TMPO antisense RNA 1, homeobox A11 antisense[45,52,53].

Stem cells have the capacity for self-renewal and the ability to differentiate into various specialized cell types. Another concept, stemness, describes the ability of normal or transformed cells to self-renew and produce differentiated offspring in addition to interacting with their environment to maintain a balance between quiescence, proliferation, and regeneration[54,55]. Cancer stem cells (CSCs) are a subpopulation of stem-like cells in tumors and not only reveal characteristics of both stem cells and cancer cells but also hold stemness properties that sustain cancer progression, such as enhanced capacities for self-renewal cloning, growing, metastasizing, drug resistance, and recurrence[56,57]. CSCs have been implicated in many types of cancer, including colon and GCs[58,59]. In recent years, colorectal CSC markers such as CD133, CD44, CD24, CD29, CD144, CD166, Aldehyde dehydrogenase 1A1, ATP binding cassette proteins, and Lgr5 and gastric CSC markers such as CD44, cell adhesion molecules, intercellular adhesion molecule 1 (also known as CD54), aldehyde dehydrogenase 1, CD90 (THY1), CD133 (PROM1), transferrin receptor protein 1 (also known as CD71), signal transducer CD24 (CD24)[60,61]. Recently, studies have indicated that propofol may interact with CSCs, disrupt their function, and produce an antitumor effect. Propofol exerts anti-tumor effects by targeting CSCs through multiple pathways such as inhibition of CSC self-renewal by interfering with CSC signaling networks like Wnt/β-catenin, Notch, and Hedgehog pathways[62], suppression of epithelial-mesenchymal transition (EMT) by downregulating miR-21, which inhibits EMT activation and tumor cell invasion[63], induction of apoptosis in CSCs by activates front fork transcription factor 3, which induces apoptosis in CSCs by targeting SOX2[64], enhancement of chemotherapy sensitivity by decreasing CSC-mediated drug resistance by downregulating HIF-1α and ABC transporters, and modulation of the TME by reducing tumor-supporting microglia and immune evasion[65].

Indirect effects

A TME is a complex ecosystem surrounding tumor cells, which includes interstitial cells (such as immune cells, fibroblasts, adipocytes, and endothelial cells), ECM, blood vessels, signal molecules (such as cytokines and chemokines). Although this composition varies between tumor types, the primary function of the TME is to create a favorable environment to support the development, local invasion, and metastasis of cancer cells[66]. Cancer treatment has undergone a revolution with new therapeutic strategies targeting the components within the TME.

Propofol may indirectly affect the biological properties of tumor cells by altering TME through several mechanisms, such as anti-angiogenesis, regulation of immunity, reduction of inflammation, and remodeling of the ECM. Angiogenesis is one of the key factors in creating a favorable microenvironment in which oxygen and nutrient support are provided and metabolic wastes can be removed by preventing the formation of a hypoxic and acidic environment. Propofol has been shown to inhibit angiogenesis by targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E signaling and inhibiting the expression of VEGF[67,68]. Hypoxia is one of the key features of TME and the most crucial trigger of neovascularization. HIFs are transcriptional factors that play an adaptive role in the hypoxic microenvironment. HIF-1 is a heterodimer complex composed of alpha and beta subunits. In addition to hypoxia, non-hypoxic factors such as proinflammatory factors also play a stimulatory role in the synthesis of HIF-1α. HIF-1 regulates various genes, such as VEGF, leptin, transforming growth factor-β3, and nitric oxide synthase[69]. Propofol has been reported to promote tumor cell apoptosis and inhibit tumoral invasion and metastasis by inhibiting the upregulation of HIF-1α and VEGF[70].

The TME consists of different kinds of inflammatory cells, including leukocytes (neutrophils, monocytes, eosinophils, and basophils) and lymphocytes [T cells, B cells, and natural killer (NK) cells], and inflammatory mediators including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and prostaglandin E2. Besides, it has also been shown that cancer can develop at the surgical site due to inflammation and damage due to surgery[71]. One of the three main mechanisms for the recurrence and metastasis of cancer is the proliferation of surviving cancer cells at the surgical resection site with the help of various proinflammatory cytokines, pro-oncogenes, and angiogenic factors[72]. In addition to its anesthetic properties, propofol has been shown to inhibit the production of proinflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8, and IL-10 and reduce the inflammation in TME[73]. The high mobility group box B1 (HMGB1) protein, which differs from early-onset rapid inflammatory factors such as TNF and IL-1, is secreted actively from activated macrophages and monocytes as a cytokine mediator in the late stages of inflammation. It is also released passively in the early stages of inflammation from apoptotic or necrotic cells[74]. HMGB1 promotes tumor development by increasing inflammation and angiogenesis and promoting tumoral metastasis, while it plays a tumor suppressor role by promoting DNA repair and genome stability, supporting autophagy, and enhancing the immune response, thus having a dual effect[74]. So, while it may initially trigger an immune response, it may later promote chronic inflammation, promoting conditions such as autoimmune diseases and cancer. Although, propofol was found to decrease HMGB1 expression and serve to improve the tumor inflammatory microenvironment, current studies seem insufficient to determine the net effect of propofol on tumor cells after interaction with HMGB1[75]. Another target that propofol has been shown to interact with while exhibiting anti-inflammatory properties is the cyclooxygenase (COX) enzyme. COX, an enzyme in the arachidonic acid cascade, is responsible for the conversion of arachidonic acid to prostaglandin H2, which is afterward converted to prostanoids, including prostacyclin, thromboxane A2, prostaglandin D2, prostaglandin F2alpha, and prostaglandin E2[76]. The COX inhibition effect of propofol may result in the suppression of tumor cell growth, survival, invasiveness, and inhibition of angiogenesis. It has been proposed as one of the mechanisms of antitumoral action of propofol[77]. Considering all these data, propofol’s anti-inflammatory properties may make a difference and deserve special attention, particularly in patients with cancer.

During the cancer process, different immune cells play various roles. The first step defense mechanism against the invasion of tumoral cells is the host’s immune system, constituted by epithelial barriers, granulocytes, macrophages, NK cells, and dendritic cells. Lymphocytes exhibit direct cytotoxicity for tumor cells, while monocytes and macrophages combine to enhance endogenous immunity through antigen presentation and play a lethal role for tumor cells. However, the TME is often under immunosuppressant effects, which support tumoral growth and proliferation[78]. The primary mechanism of action of propofol is the inhibition of GABAergic neurotransmission in the central nervous system[79]. Immune cells, including neutrophils, monocytes, and macrophages, incorporate GABAergic receptors; thus, propofol has anti-inflammatory and antioxidant properties with its regulatory effects on lymphocytes, neutrophils, NK cells, and macrophages in the TME[80-82]. For example, propofol may inhibit the secretion of proinflammatory cytokines by activating GABAA receptors on the surface of macrophages while, on the other hand, inhibiting Toll-like receptor 4 (TLR4) and eliciting immunomodulatory effects[83].

Two types of tumor-infiltrating macrophages, M1 and M2, have been identified according to their functionality and characteristics. While M1 is prominent in the type 1 helper T cell (Th1)-type immune response in which foreign pathogens and endogenous tumor cells are killed, M2 plays a role in the Th2-type immune response by promoting tumor formation and development[84]. With GABA receptor activation, propofol has been reported to be involved in several macrophage functions such as phagocytosis, polarization, secretion of inflammatory cytokines, antimicrobial responses, and autophagic activation mediated by Ca²⁺, protein kinase B (AKT)/mTOR, or autophagy-related genes[85-87].

As the central part of innate immunity, NK cells function as the first-line warriors against the occurrence and metastases of tumors. NK cells are essential in inhibiting tumor development and controlling tumor growth and metastases. Evidence shows NK cells reduce CRC progression in the perioperative period[88]. Although NK cells increase in number in the peripheral blood of patients with tumors, they are functionally ineffective, and similarly, inadequate killing functions of NK cells have been found in TME[89]. The performance-enhancing effects of propofol on NK cells may play a role in enhancing immunity in TME.

Cancer cell metabolism is associated with marked changes in metabolic pathways compared to normal cells. In a cancer cell, glucose is used mainly for energy supply, while glutamine feeds mitochondrial intermediates for biosynthetic precursor supply. Aerobic glycolysis, or the Warburg effect, is the specific metabolic process that is characterized by the increased rate of glucose uptake and lactate production even under aerobic conditions, bypassing normal functioning mitochondria[62]. Propofol has been reported to undermine tumoral development by influencing metabolic pathways and inhibiting glycolysis, such as downregulating glucose transporter type 1 and mitochondrial pyruvate carrier expression, reducing intracellular Ca²⁺ concentration, inhibiting NMDA receptors, and regulating circular RNA expression[90-92].

THE INTERACTION OF PROPOFOL WITH CHEMOTHERAPY AND RADIOTHERAPY

Clinical and preclinical studies have investigated the interaction of propofol with chemotherapy and radiotherapy during cancer treatment. Propofol affects chemotherapeutic activity via different mechanisms. It increases sensitivity to chemotherapy and inhibits the EMT process, especially by suppressing the Slug transcription factor, a major EMT component that contributes to chemoresistance in cancer cells[93]. Propofol was shown to inhibit Slug expression in ovarian cancer cells after paclitaxel treatment and enhances paclitaxel-induced apoptosis[94]. NF-κB activation is indicative of high tolerance to chemotherapy and poor prognosis for cancer patients, and propofol may abolish the gemcitabine-induced DNA-binding activity of NF-κB in pancreatic tumors, leading to increased sensitivity to gemcitabine[95]. Propofol pretreatment followed by cisplatin treatment abolishes the expression level of epidermal growth factor receptor and its downstream targets Janus kinase 2 and signal transducer and activator of transcription 3 (STAT3), which regulate essential cell functions such as proliferation, chemotactic migration, invasion, and apoptosis avoidance, revealing the role of epidermal growth factor receptor/Janus kinase 2/STAT3 on propofol and cisplatin-induced anti-cancer activities[96]. There are also reports that propofol may reduce the efficacy of chemotherapeutics mainly through inhibiting gap junctions (GJs) function, which may act as tumor suppressors through connexins, structural proteins within them[97].

Propofol by infusion is a popular choice for sedation in radiotherapy processes of all uncooperative patients, especially pediatric patients, with the benefits of rapid recovery and antiemetic properties. In clinical evaluations, it was found to be safe to use in children with a low rate of tolerance development, especially in repeated use[98]. However, studies evaluating how propofol affects the efficacy of radiotherapy are extremely limited. In a cell culture study, propofol was found to significantly inhibit the function of the GJ formed by connexins 32 and reduced the cytotoxicity of radiograph irradiation by inhibition of GJ intercellular communication[99]. Further studies are needed to provide more satisfactory information on the interaction of propofol and radiotherapy in cancer patients.

AN OVERVIEW OF EXPERIMENTAL AND CLINICAL TRIALS IN GICS

Experimental studies

Various published experimental studies explore propofol’s effects on the proliferation, stemness, invasion, migration, metastasis, and growth capacities of CRC cells. In a study examining the impact of propofol on the invasion ability of human colon cancer cells using the LoVo colon cancer cell line, propofol decreased MMP-2 and MMP-9 expression (also known as type IV collagenases or gelatinases that can degrade most ECM components forming the basal membrane) via extracellular signal-regulated kinase 1 and 2 pathway activation with the possible involvement of GABAA receptor pathway and thus inhibited cancer cell invasion. GABAA receptor is the major mediator of rapid synaptic inhibition in signal transmission. Propofol initiates chlorine flow into the cell with its agonistic effect on this receptor, and the cell becomes unresponsive to external stimuli with the associated hyperpolarization[100]. This study is noteworthy in evaluating the direct impact of propofol’s basic action mechanism on colon cancer cell invasion ability.

Zhang et al[101] investigated the effects of propofol on colon cancer metastasis through STAT3/HOX antisense intergenic RNA (HOTAIR) axis by activating Wnt-inhibitory factor-1 and suppressing the Wnt pathway. HOTAIR is a lncRNA that plays a role as an oncogenic molecule in different cancer cells, and high HOTAIR levels also indicate poor prognosis in patients with colon cancer[101]. HOTAIR was shown to activate the Wnt pathway through inhibition of Wnt-inhibitory factor-1 expression in esophageal squamous cell carcinoma[102]. STAT3 regulates the activity of HOTAIR and also promotes EMT and metastasis in colon cancer[103]. EMT defines the conversion of polar epithelial cells into mesenchymal cells that increase the invasion capacity for a tumor cell. In their study, after exposing human colon cancer lines to 8 μg/mL propofol, the authors found that propofol promoted cell apoptosis, inhibited cell invasion in colon cancer cells, and negatively modulated HOTAIR expression, which STAT3 positively modulated. Similarly, Bai et al[104] aimed to determine whether propofol can regulate its target gene STAT3 expression by the hsa-miR-328-3p pathway and inhibit the proliferation of GC. They found propofol significantly inhibited GC cell proliferation, upregulated has-miR-328-3p, down-regulated STAT3, and downstream proliferation-related target gene expression[104].

Wang et al[105] investigated the relationship between propofol and the stem cell-like characteristics of colon cancer cells using sirtuin 1 (SIRT1) and components of the Wnt/β-catenin pathway and phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathways. Of the seven sirtuins encoded in the mammalian genome, SIRT1 is a nuclear protein expressed in all tissues and involved in various cellular processes, including apoptosis, autophagy, cell motility, genome stability, chromatin structure, and epigenetic regulation[105]. Wnt/β-catenin signaling regulates key cellular functions, including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal, and is also involved in several malignancies, including CRCs and non-colorectal GICs[106]. PI3K/AKT/mTOR is a major intracellular signaling pathway that responds to the availability of nutrients, hormones, and growth factor stimulation and is involved in tumor cell growth and proliferation[107]. The authors found that propofol inhibited the stemness and EMT of LoVo and SW480 cells. In addition, propofol downregulated SIRT1 in cancer and inhibited tumor proliferation by inhibiting the Wnt/β-catenin pathway and PI3K/AKT/mTOR pathway[108]. Zhan et al[109] investigated the underlying mechanism of propofol inhibition of the growth and invasion of GC cells. Similarly, they found that propofol-induced miR-493-3p decreased GC cell development via targeting dickkopf-1, inhibiting Wnt/β-catenin signaling.

In another study examining the effects of propofol and sevoflurane on proliferation, apoptosis, and gene expression in colon cancer cells, HCT 116 cells were exposed to blood samples from 60 patients. As a result, it was concluded that although the use of propofol or sevoflurane did not cause significant effects on apoptosis, migration, and cell cycle, cancer cell viability was significantly increased in the sevoflurane group, and TP53 gene expression (plays a role in p53 synthesis and DNA signaling damage) was increased dramatically in the propofol group[110]. On the contrary, a similar in vitro study showed that propofol and lidocaine had both dose- and time-dependent antiproliferative tumor effects without affecting the TME on colon cancer cells (HCT-116 and RKO cells)[111]. The difference in the results was attributed to the difference in the doses of the study drugs, which was lower in the former study.

Xu et al[112] examined the effects of propofol on cell proliferation and invasion through in vitro approaches, investigating the impact on EMT and the underlying molecular mechanisms after interaction with IL-13. IL-13 suppresses cell-cell adhesion, reduces carcinoembryonic antigen expression, and is thought to be a key mediator in EMT for CRC cells[112]. The authors found that propofol can effectively suppress cell proliferation in colorectal cell lines RKO and SW480 cells, can inhibit EMT induced by IL-13, and also propofol treatment causes up-regulation of miR-361 and miR-135b, which suppresses the expression of STAT6 and thereafter leads to the inhibition of IL-13/STAT6/zinc finger E-box binding homeobox 1 signaling pathway. Similarly, Liu et al[113] studied the effects of propofol on GC development. They found propofol could inhibit EMT, invasion, and migration of GC cells by promoting miR-195-5p expression and suppressing Snail expression.

Zhao and Liu[114] assessed the levels of circular RNA poly(A) binding protein nuclear 1 (circ-PABPN1, hsa_ circ_0031288), miRNA-638, and serine and arginine-rich factor 1 to question the effects of propofol on cell viability, colony formation, apoptosis, invasion, and migration of CRC cells. The expression of circ-PABPN1, which was previously known to be a progenitor in cervical cancer cells, was upregulated in CRC cells, and the knockdown of circ-PABPN1 enhanced the suppressive effect of propofol on tumor growth in vivo. The upregulation of miR-638, which was directly targeted by circ-PABPN1, was the propofol mechanism to regulate cell viability, colony formation, invasion, migration, and apoptosis in vitro. In addition, propofol downregulated serine and arginine-rich factor 1 expression by the circ-PABPN1/miR-638 axis in CRC cells[114]. Wu et al[115] reported that propofol reduced cell viability, migration, and invasion and upregulated caspase 3 in CRC cells. Propofol is also reported to have inhibitory effects on the glycolytic pathway, suppressing lactate dehydrogenase expression, an essential enzyme in the glycolytic pathway[115]. Li et al[116] investigated the possible mechanisms of propofol’s antitumor effects by measuring the expression levels of miR-124-3p.1 and AKT3 in CRC cells. They found that propofol suppresses CRC cells’ proliferation, invasion, and metastasis by upregulating the abundance of miR-124-3p.1 and downregulating AKT3 expression[116]. Yao et al[117] focused on LINC01133 expression in CRC cells after propofol treatment, which FOXO1 mediates. LINC01133, as an RNA molecule, can affect cancer metastasis by regulating EMT in several types of tumors. The authors found that propofol exerts an inhibitory effect on CRC progression by regulating FOXO1-mediated transcription of LINC01133, which, in turn, promotes nuclear receptor subfamily 3 group C member 2 expression through miR-186-5p sponging[117]. Ye et al[118] evaluated the effects of propofol on cell proliferation and apoptosis of CRC in SW620 and HCT15 cell lines. They measured the correlation between propofol and miR-1-3p/insulin-like growth factor 1 (IGF-1) axis to elaborate the mechanism of action. MiR-1-3p, which has a tumor suppressive effect, was previously found in circulating vesicles of CRC patients who received propofol anesthesia for tumor resection[118]. IGF-1, an anti-apoptotic factor that regulates the proliferation and survival of various cell types, was identified as a predictive marker of CRC[119]. This in vivo study showed propofol suppressed CRC progression by promoting miR-1-3p, inhibiting IGF-1 expression through interacting with its 3’-untranslated region, thus inactivating AKT/mTOR signals. Xian et al[120] explored the effect of propofol at 10 μg/mL and 20 μg/mL concentrations on the biological behaviors of stomach cancer cells. They analyzed the relationship between propofol and miR-205. The results suggested propofol inhibited stomach cancer cell growth and promoted apoptosis via overexpressing miR-205 and inhibiting the Yes-associated protein 1 axis. Yes-associated protein 1 is a transcriptional co-activator with prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance and essential functions in normal tissue homeostasis and regeneration[120]. Iwasaki et al[121] investigated the effects of sevoflurane and propofol on cancer cell biology and their respective effects on lipopolysaccharide (LPS)-induced tumor immunity in a non-surgical nude mice xenograft model. After cultured colon cancer cell (Caco-2) was injected subcutaneously into mice on day 1, mice were exposed to either 1.5% sevoflurane for 1.5 hours or propofol (20 μg/g; intraperitoneal injection) with or without LPS (4 μg/g; intraperitoneal injection) from days 15 to 17 and compared with controls. The authors reported that propofol reduced tumor size, decreased HIF-1α, IL-1β, and hepatocyte growth factor gene expressions, and increased tissue inhibitor of metalloproteinases 2 gene and protein expression in comparison to sevoflurane in the tumor tissue and none of the anesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development[121]. Chen et al[122] investigated the effect of propofol on glucose metabolism in HT29 and SW480 CRC cells in an in vivo xenograft model. Propofol caused a dose-dependent decrease in aerobic glycolysis, known as the Warburg effect, through depression of the NMDA receptor/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase pathway and consequent inhibition of HIF1α. HIF1α is a stimulant factor for aerobic glycolysis that induces the expression of glucose transporters and directly targets the regulatory enzymes of glycolysis, including hexokinase 2, phosphoglycerate kinase 1, lactate dehydrogenase A, monocarboxylate transporter 4, and pyruvate dehydrogenase lipoamide kinase isozyme 1. Propofol inhibits the NMDA receptor and modulates calcium influx through slow calcium-ion channels. Ca²⁺/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca²⁺/calmodulin complex, which is involved in many signaling cascades and is thought to be an essential mediator not only for learning and memory but also for cancer progression. The authors concluded that propofol inhibited the expression of main enzymes in the glycolytic pathway, including glucose transporter type 1, hexokinase 2, phosphoglycerate kinase 1, and lactate dehydrogenase A, in the CRC cells but not in normal cells.

Unlike the studies mentioned above, the effects of propofol were evaluated on a different subject. Gao et al[123] investigated the effects of propofol on intestinal mucosal permeability and bacterial invasion by measuring miR-155 and TLR4/NF-κB levels in the intestinal mucosa with the determination of miR-155 location in a mouse CRC model in which the intestinal mucosal barrier was damaged by CRC surgery. The authors stated that progressive pulmonary fibrosis treatment promoted the expression of tight junction protein in the intestinal mucosa, protected the intestinal barrier, prevented the translocation of intestinal bacteria, and increased the level of beneficial bacteria Lactobacillus on the mucosal surface, in addition, it emphasized that miR-155 may inhibit TLR4/NF-κB expression and reduce inflammatory cytokine secretion by reversing the inflammatory response[123]. Liu et al[124] investigated propofol’s effect on NK cells’ function in killing colon cancer cells at the cellular level. After in vitro treatment with propofol for 24 hours, the expression of activated receptors, inhibitory receptors, killing effector molecules, and proliferation-associated markers on NK cell surfaces was examined. The results showed that the number of NK cells in peripheral blood from colon cancer patients increased compared to healthy subjects. Still, the activities and proliferation ability of the NK cells were decreased. Also, the tumor-killing effect of NK cells isolated from colon cancer patients was reduced. Propofol was found to promote NK cells’ activation and proliferation ability and have a killing effect in colon cancer patients[124]. Zhou et al[125] investigated the effects of propofol on the phenotype and cytotoxicity of NK cells derived from the peripheral blood of patients with esophageal squamous cell carcinoma. Propofol increased the expression of granzyme B and interferon-γ, which are cytotoxicity effector molecules for NK, and also promoted the proliferation and enhanced the functions of NK cells in vitro[125]. Similarly, Ai and Wang[126] compared the effects of propofol and sevoflurane on the cytotoxicity of NK cells (CD3-CD56+) in patients with GC. Propofol inhibited negative regulation of GC cells, and transforming growth factor-β1 on NK cell function increased the cytotoxicity of NK cells more than sevoflurane and also enhanced the killing functions of NK through the SMAD4 pathway by upregulating the expression of granzyme B[126]. A summary of the experimental studies given above is presented in Table 2.

Table 2 Summary of the experimental studies of the effects of propofol on various gastrointestinal cancer cells.

Ref.	Cancer cell type	Mechanism of action	Results
Miao et al[100], 2010	Colon	Inhibition of MAPKs phosphorylation including ERK1/2/JNK, P38 mainly through GABAA receptor	Inhibition of cancer cell invasion
Zhang et al[101], 2020	Colon	STAT3/HOTAIR axis by activating WIF-1; suppressing the Wnt pathway	Promotion of cell apoptosis and inhibition of cell invasion
Bai et al[104], 2021	Gastric	Up-regulation of the expression of has-miR-328-3p; down-regulation of STAT3	Inhibition of cell proliferation
Wang et al[105], 2023	Colon	Down-regulation of SIRT1; inhibition of the Wnt/β-catenin pathway and PI3K/AKT/mTOR pathway	Inhibition of stemness and cell proliferation
Zhan et al[109], 2023	Gastric	Induction of miR-493-3p via targeting DKK1; inhibition of Wnt/β-catenin signaling	Inhibition of the growth and invasion of cells
Alexa et al[110], 2023	Colon	Increased expression of TP53 gene	No influence on apoptosis, migration, and cell cycle
Xu et al[112], 2018	Colon	Induction of IL-13; suppression the expression of STAT6 and inhibition of IL-13/STAT6/ZEB1 signaling pathway through up-regulation of miR-361 and miR-135b	Inhibition of EMT, invasion and cell proliferation
Liu et al[113], 2020	Gastric	Promotion of miR-195-5p expression; suppression of Snail expression	Inhibition of EMT, invasion, and migration of cells
Zhao and Liu[114], 2021	Colon	Knockdown of circ-PABPN1; upregulation of miR-638; downregulation of SRSF1 expression	Repression in cell viability, colony formation, invasion, migration, and promotion in apoptosis
Wu et al[115], 2022	Colon	Upregulation of caspase 3; inhibition in glycolytic pathway with suppression LDH	Reduction in cell viability, migration, and invasion
Li et al[116], 2020	Colon	Upregulation of miR-124-3p.1; downregulation of AKT3 expression	Suppression of proliferation, invasion, and metastasis of cells
Yao et al[117], 2024	Colon	Regulating FOXO1-mediated transcription of LINC01133; promotion NR3C2 expression through miR-186-5p sponging	Inhibitory effect on cell progression and tumor metastases
Ye et al[118], 2021	Colon	Promoting miR-1-3p; inhibition of IGF-1 expression through interacting with its 3’-UTR; inactivating AKT/mTOR signals	Suppression of cell proliferation and promotion of apoptosis
Xian et al[120], 2020	Stomach	Overexpressing of miR-205; inhibiting the YAP1 axis	Inhibition of cell growth; promotion of apoptosis
Iwasaki et al[121], 2023	Colon	Decrease in HIF1α, IL1β, HGF gene expressions; increase in TIMP-2 gene and protein expression	Reduction in tumor size
Chen et al[122], 2018	Colon	Depression of the NMDAR-CAMKII-ERK pathway and consequent inhibition of HIF1α; inhibition of the expression of GLUT1, HK2, PGK1, and LDHA enzymes	Dose-dependent decrease in aerobic glycolysis (Warburg effect)
Gao et al[123], 2021	Colon	Inhibition of the expression of miR-155, TLR4/NF-κB	Promotion of the expression of tight junction protein in the intestinal mucosa; protection of the intestinal barrier; prevention of the translocation of intestinal bacteria; increase in the level of beneficial Lactobacillus bacteria on the mucosal surface
Liu et al[124], 2018	Colon	Positive expression of GranB and Ki67; increased release of LDH	Increase in the number of NK cells; promotion of the activation, proliferation ability, and killing effects of NK cells
Zhou et al[125], 2018	Esophagus	Increase in the expression of granzyme B and IFN-γ	Promotion of the proliferation and functional capacity of NK cells
Ai and Wang[126], 2020	Gastric	Inhibition of the negative regulation of gastric cancer cells and TGF-1; SMAD4 pathway by upregulating the expression of granzyme B	Increase the cytotoxicity and killing functions of NK cells

MAPKs: Mitogen-activated protein kinases; ERK: Extracellular signal-regulated kinase; JNK: c-Jun NH2-terminal kinase; GABAA: Gamma-aminobutyric acid subtype A; STAT3: Signal transducer and activator of transcription 3; HOTAIR: HOX antisense intergenic RNA; WIF-1: Wnt-inhibitory factor-1; PI3K: Phosphatidylinositol-3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; DKK1: Dickkopf-1; IL: Interleukin; SRSF1: Serine/arginine-rich splicing factor 1; LDH: Lactate dehydrogenase; FOXO1: Forkhead box O1; NR3C2: Nuclear receptor subfamily 3 group C member 2; IGF-1: Insulin-like growth factor 1; UTR: Untranslated region; YAP1: Yes-associated protein 1; HIF: Hypoxia-inducible factor; HGF: Hepatocyte growth factor; TIMP-2: Tissue inhibitor metalloproteinase 2; NMDAR: N-methyl-D-aspartate receptor; CAMKII: Calcium-calmodulin-dependent protein kinase II; GLUT1: Glucose transporter type 1; HK2: Hexokinase 2; PGK1: Phosphoglycerate kinase 1; LDHA: Lactate dehydrogenase A; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa B; IFN: Interferon; TGF: Transforming growth factor; EMT: Epithelial-mesenchymal transition; NK: Natural killer.

Clinical studies

Most of the clinical trials that have focused on propofol, especially in cancer surgery, have examined its effects on mortality and survival rates and yielded results accordingly. Wu et al[127] conducted a retrospective cohort study on a total of 1158 patients who had undergone elective colon cancer surgery between 2005 and 2014 under general anesthesia with propofol or desflurane. They found that propofol anesthesia for colon cancer surgery was associated with better overall survival (OS) (regardless of having a lower or higher tumor-node-metastasis stage and presence or absence of postoperative metastasis), less local (anastomotic, nodal, or mesenteric) recurrence, and less postoperative metastasis when compared with desflurane. The authors pointed out some limitations of the study, including a retrospective design without randomization, incomplete information on blood transfusion that may promote cancer cell growth, use of tumor-node-metastasis classification as opposed to the American Joint Committee on Cancer staging system, patients in the desflurane group were older, sicker, and generally at a worse stage of disease, and histological subtypes of colon cancers could not be refined due to incomplete data[127]. Zhang et al[128] compared the effects of volatile anesthetics with propofol-based total intravenous anesthesia (TIVA) through a retrospective analysis of patients who underwent elective digestive tract cancer curative surgeries, and they concluded that the selection of anesthetic agents for surgeries does not affect the survival of patients who have digestive tract cancer and has fewer effects on postoperative complications. The authors attributed the contradictory results of their study with the above study to the fact that the retrospective analyses in the above research included colonoscopies performed under propofol-based anesthesia in the early stage of colon cancer and colonoscopies performed under volatile anesthesia in older, sicker, and poorer conditioned patients[128].

Hasselager et al[129] assessed 22179 patients who had undergone CRC surgery under general anesthesia with TIVA-propofol or sevoflurane between 2004-2018 regarding medical and surgical complications within 30 days postoperatively using the Danish Colorectal Cancer Group database. After propensity score matching, they didn’t find any significant difference regarding medical complications. Still, rates of surgical complications, including wound dehiscence, anastomotic leak, ileus, wound abscess, intra-abdominal abscess, and sepsis, were statistically significantly lower in the inhalation anesthesia group[129].

Kagawa et al[130] retrospectively analyzed the association between intraoperative anesthesia methods (propofol vs inhaled anesthetics including sevoflurane, isoflurane, and desflurane) and long-term mortality in patients with GC undergoing gastrectomy. After analyzing 2671 patients from the Japanese nationwide insurance claims database, there was no significant OS between propofol and volatile anesthetics. Missing data regarding the performance status of the patients, cancer stage, and information on intra-operative fluid administration, blood transfusion, duration of surgery, preoperative frailty status, body mass index, smoking history, and alcohol consumption and follow-up interruptions due to retirement of the patients from employment that caused the age of the patients in the study to be below 70 years were noted as the limitation factors by the authors[130].

Ma et al[131] compared the effects of propofol-TIVA with sevoflurane anesthesia on the OS and disease-free survival (DFS) of 363 patients with esophageal cancer in their retrospective observational study. OS was defined as the period from the patients’ date of surgery to the time of death, and DFS was defined as the interval between the date of surgery and the date of tumor recurrence and metastasis or death. Although sevoflurane has been previously shown to induce T-lymphocyte apoptosis, reduce NK cell activity, reduce Th1/Th2 ratio, and increase tumorigenic cytokines and MMPs levels (that are key enzymes involved in basement membrane disassembly, thereby promoting tumor dissemination) to systematically damage immune function unlike propofol, there was no significant difference in OS and DFS between propofol and sevoflurane[131].

Margarit et al[132] compared the effects of TIVA-propofol and isoflurane anesthesia on plasma concentrations of interleukins IL-6 and IL-10 in patients undergoing surgery for CRC, and they didn’t find any significant difference produced by propofol or isoflurane on the IL-6 and IL-10 concentrations. In addition to the fact that IL-6 and IL-10 concentrations increase after surgery to reflect the size, duration, and type of surgical intervention, increased IL-6 concentrations in cancer patients promote tumor growth, affect tumor cell differentiation, and protect cells from apoptosis. At the same time, IL-10 suppresses proinflammatory interleukins and supports antitumor immunity[133]. This study has some possible limitations, including the type of intraoperative infusion, the antibiotic administration, and the parenteral nutrition support that can affect the patients’ immunity. Some information was missing regarding surgical techniques and medical conditions, such as tumor differentiation, disease types, and the preoperative carcinoembryonic antigen level.

Xu et al[134] evaluated the effect of serum from patients undergoing colon cancer surgery receiving thoracic epidural and propofol vs sevoflurane anesthesia on colon cancer cell biology. The colon cancer cells were cultured with patient serum from both groups, and the effects on proliferation, invasion, and apoptosis were measured. The authors found that serum taken from patients receiving propofol, compared to those from sevoflurane patients, induced a reduction in invasiveness, proliferation, and metastatic potential and enhanced apoptosis of the cancer cells. The limited sample size of the study, the fact that ropivacaine serum levels were not examined (thus it was difficult to determine whether the change in colon cell function was directly influenced by ropivacaine in the serum or by blockade of the sympathetic nervous system), and finally, the fact that patients in the propofol group also received epidural anesthesia (thus they could not determine whether the positive effect was related to the epidural, to the use of propofol, to a reduction in opioid use, or all of these) were noted as essential limitations of the study by the authors[134]. Buschmann et al[135] inspired this study and thought that one or multiple factors in serum must influence recurrence risk by modulating the inflammatory microenvironment that is downregulated by propofol. They assumed that circulating extracellular vesicles in patients undergoing tumor resection potentially represent such a factor and that these particles might mediate the long-lasting impact of propofol on CRC cells. With this background, they performed a proof-of-concept study to demonstrate that propofol and sevoflurane have differential effects on vesicle-associated miRNAs that influence signaling pathways involved in tumor progression and metastasis and found that propofol-regulated miRNAs might mediate inhibitory effects on signaling pathways involving cell proliferation, migration, and EMT of tumor cell line and enhance effects on apoptosis of carcinoma cell lines[135].

Oh et al[136] hypothesized that propofol-based anesthesia would have fewer harmful effects on circulating immune cells than equipotent doses of volatile anesthetics and compared the fractions of circulating NK cells, T lymphocytes, and related immune cells between propofol- and sevoflurane-based anesthesia in 153 patients undergoing CRC surgery. As a result, the fraction of circulating NK cells, the fractions of circulating Th1 and Th17 cells and cytotoxic T cells, and the fractions of CD39+ and CD73+ circulating regulatory T cells did not differ between the two groups. The increased expressions of CD39 and CD73 in regulatory T cells are essential in promoting cancer progression by suppressing Th1 and Th17 cells and impairing the tumor cell-killing effects of NK cells and cytotoxic T cells[136]. This study suggested that the general anesthetics used may minimally affect perioperative immune status among numerous perioperative factors. However, when evaluating the results of such studies, it should be kept in mind that the choice of anesthetic agent is not the only factor affecting immune status in the perioperative period. Many factors such as the type of surgical operation and associated surgical stress, the use of drugs such as opioids, local anesthetics and corticosteroids, age, nutritional status (presence of malnutrition), comorbidities, surgical bleeding and blood transfusion, the presence of immunosuppression and perioperative pain management may directly or indirectly affect immune status.

Kim et al[137] compared the effects of sevoflurane and propofol-TIVA on endothelial glycocalyx (EG) and inflammatory markers including white blood cell count, neutrophil-to-lymphocyte ratio, and C-reactive protein in patients with GC. Syndecan-1, a transmembrane (type I) heparan sulfate proteoglycan and a member of the syndecan proteoglycan family, was used to evaluate the possible EG breakdown in the study. The authors concluded that despite propofol-TIVA being superior to sevoflurane in protecting endothelial glycocalyx during the operation, both anesthetic agents have similar effects regarding perioperative EG degradation and inflammatory process[137].

Zhang et al[138] compared the effects of propofol-based or sevoflurane-based anesthesia on prognostic nutritional index (PNI) change and progression-free survival and OS in patients treated with CRC surgery. PNI, which is thought to represent a widely employed metric for evaluating cancer patients’ nutritional and immunological statuses, was determined using a mathematical expression including the parameters of albumin and total lymphocyte count. PNI change (ΔPNI) was calculated by subtracting the pre-surgery PNI from the post-surgery PNI, and patients were categorized into high and low ΔPNI groups. The authors concluded that ΔPNI reflects the dynamic changes in patients’ immune responses and nutritional statuses, which is associated with the response to immunotherapy in patients with advanced cancer. The retrospective analysis of 414 patients revealed that PNI change, rather than anesthesia methods, exhibited an independent association with an unfavorable CRC prognosis, and TIVA-propofol exhibited superior survival outcomes compared to those who received sevoflurane-based anesthesia, particularly among individuals with a high degree of PNI change[138]. A summary of the clinical studies given above is presented in Table 3.

Table 3 A summary of the clinical studies.

Ref.	Cancer type	Compared anesthetics/study type	Results
Wu et al[127], 2018	Colon	Propofol vs desflurane/retrospective cohort	Propofol anesthesia is associated with better overall survival, less local recurrence, less postoperative metastasis
Zhang et al[128], 2022	Digestive tract	Propofol vs volatile anesthetics (isoflurane, desflurane, sevoflurane)/retrospective cohort	The selection of anesthetic agents does not affect survival and postoperative complication(s)
Hasselager et al[129], 2022	Colorectal	Propofol vs sevoflurane/retrospective cohort	No difference regarding medical complications; better rates of surgical complications for the sevoflurane group
Kagawa et al[130], 2024	Gastric	Propofol vs volatile anesthetics (isoflurane, desflurane, sevoflurane)/retrospective cohort	No significant overall survival between groups
Ma et al[131], 2023	Esophageal	Propofol vs sevoflurane/retrospective observational	No significant difference in overall survival and disease-free survival between groups
Margarit et al[132], 2014	Colorectal	Propofol vs isoflurane/randomized controlled	No significant differences between groups on plasma concentrations of IL-6 and IL-10
Xu et al[134], 2016	Colon	Propofol + thoracic epidural vs sevoflurane	A reduction in invasiveness, proliferation, and metastatic potential, as well as enhanced apoptosis of the cancer cells in propofol group
Buschmann et al[135], 2020	Colorectal	Propofol vs sevoflurane/proof-of-concept	Propofol-regulated miRNAs might mediate inhibitory effects on signaling pathways involving cell proliferation, migration, and epithelial-mesenchymal transition of tumor cell lines and enhance effects on apoptosis of carcinoma cell lines
Oh et al[136], 2022	Colorectal	Propofol vs sevoflurane/randomized controlled	The type of general anesthetics used may minimally affect perioperative immune status among numerous perioperative factors
Kim et al[137], 2021	Gastric	Propofol vs sevoflurane	Propofol is superior for the protection of endothelial glycocalyx; similar effects on endothelial glycocalyx degradation and inflammatory process
Zhang et al[138], 2024	Colorectal	Propofol vs sevoflurane/retrospective observational	Propofol exhibited superior survival outcomes among individuals with a high degree of PNI change

IL: Interleukin; miRNA: MicroRNA; PNI: Prognostic nutritional index.

CONCLUSION

Studies examining the effects of anesthetics on cancer cells show that both volatile and intravenous anesthetic agents have significant effects on cell biology and host immunity. However, the fact that these studies contain contradictory results raises questions. While several experimental studies have demonstrated that volatile anesthetics increase the expression of various tumorigenic and metastatic factors that promote angiogenesis, proliferation, migration, and invasion of tumor cells, several in vitro studies, specifically on GIC cells, do not confirm these results[139,140]. The situation with propofol is slightly different compared to volatile agents. Almost all in vitro and in vivo experimental studies with propofol, some examples of which are given above, have yielded positive effects on various GIC cells, supporting clinical use. However, the positive results obtained from experimental studies are not the case when the results of clinical studies comparing propofol with sevoflurane are considered. The main factor here must be the complex process of a surgical procedure performed under general anesthesia and the complicated results that arise from it. Perioperative factors such as surgical and anesthetic neuroendocrine stress and the resulting local and systemic inflammatory response, transfusion of blood products, immunosuppression due to the nature of the disease, resistant pain response, additional chemotherapy and radiotherapy treatments, and even the surgical manipulation itself can negatively affect cancer cell behavior and the disease process, accordingly prognosis and survival. The increase in postoperative infection response due to the impairing effect of propofol on wound healing in the observational study of Hasselager et al[129] can be given as supporting evidence of this complexity. It is imperative to pay more attention to limitations and to determine experimental hypotheses more carefully in both experimental and clinical research so that the experimental laboratory environment, whose ambient conditions are precisely defined and controlled, can be exactly equivalent in real life. If this can be achieved, the discrepancy between the results of both experimental groups can be eliminated.