Dongya Zhu, Institution of Stem Cell and Neuroregeneration, School of Pharmacy, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Tel/Fax: +86-25-86868483/+86-25-86868469, E-mail: dyzhu@njmu.edu.cn
Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS) in the brain. Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders, including stroke, depression and anxiety disorders, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, chronic pain, and drug addiction. Due to critical roles of nNOS in learning and memory and synaptic plasticity, direct inhibition of nNOS may cause severe side effects. Importantly, interactions of several proteins, including post-synaptic density 95 (PSD-95), carboxy-terminal PDZ ligand of nNOS (CAPON) and serotonin transporter (SERT), with the PSD/Disc-large/ZO-1 homologous (PDZ) domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain. Therefore, it will be a preferable means to interfere with nNOS-mediated protein-protein interactions (PPIs), which do not lead to undesirable effects. Herein, we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders, and the discovery of drugs targeting the PPIs, which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.
The cancer morbidity and mortality have rapidly escalated globally, with 19.3 million new cancer cases and nearly 10 million cancer-related deaths in 2020, and an estimated 28.4 million new cases by 2040[1]. While surgery remains the primary treatment for patients with solid tumors, many patients still succumb to the disease postoperatively due to cancer recurrence and metastasis, even after chemo- and radio-thrapies.[2] Surgical injury and perioperative stress may impair immune function, which may contribute to the recurrence and metastasis.[3] Several studies suggest that certain anesthetic agents, such as volatile anesthetics and opioids, may promote cancer cell survival, angiogenesis, and metastasis.[4] In contrast, other research indicates that regional anesthesia techniques, like epidurals, may reduce the risk of cancer recurrence.[5] This reduction is attributed to the preservation of immune function and decreased need for systemic opioids. However, the lack of large-scale, randomized controlled trials in this area complicates the issue. Consequently, the effect of perioperative anesthesia-related factors on the prognosis of cancer patients remains inconclusive. Therefore, we summarized the effects of perioperative anesthesia, including analgesics, anesthesia methods, and other perioperative anesthesia factors, on the prognosis of cancer patients.
Perioperative anesthesia and analgesic medications
Intravenous anesthetics
Propofol
Propofol, a commonly used intravenous anesthetic in clinical practice, is often used for anesthesia induction and maintenance. In recent years, propofol has been found to possess not only sedative-hypnotic effects but also non-anesthetic effects, such as antitumor properties.[6] Numerous studies have reported that propofol inhibits the proliferation and metastasis of various cancer cell types, including cancers of the colon, breast, lung, liver, cervix, and esophagus.[7–12] Propofol's inhibitory effects on cancer cells growth, migration, invasion, and glycolysis are mediated through diverse signaling pathways Studies have highlighted its efficacy in suppressing cervical cancer cell viability, colony formation, invasion, and migration, while promoting apoptosis through the HOTAIR/miR129-5p/RPL14 axis.[9] Sun et al. reported that propofol inhibits lung cancer A549 cells by downregulating miR-372 and thereby inhibiting the Wnt/β-catenin and mTOR pathways.[13]
In addition to its direct effect on the biological processes of cancer cells, propofol may also affect immune function of cancer patients after surgery. It has been shown that propofol may enhance the activity of cytotoxic T cells and decrease the production of pro-inflammatory cytokines.[14,15] Furthermore, propofol has been shown to enhance the function of peripheral blood natural killer (NK) cells in patients with esophageal squamous cell carcinoma, suggesting its potential to ameliorate postoperative immunosuppression.[16]
Propofol has also been found to have some significant effects on the sensitivity of cancer cells to chemotherapy drugs, thereby affecting the prognosis of cancer patients. For example, propofol enhanced the efficacy of paclitaxel by inhibiting the expression of microtubule labile instable proteins and the transcription factor Slug.[16–18] Han et al[17] demonstrated that propofol reduced cisplatin resistance in non-small cell lung cancer by inducing ferroptosis, thereby increasing the activity of chemotherapeutic agents.
These findings suggest that propofol plays a multifaceted role in modulating the sensitivity of cancer cells to chemotherapy, with potential implications for improving cancer treatment outcomes.
Ketamine
Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, is a non-competitive N-methyl-D-aspartate receptor antagonist. In addition to propofol, ketamine has been shown to affect cancer migration and invasion. Ketamine may inhibit the expression of vascular endothelial growth factor and cell migration, and reduce aerobic glycolysis in colorectal cancer cells, thereby inhibit cancer progression.[18,19] In lung cancer cells, ketamine-induced apoptosis by activating CD69 gene transcription.[20] However, in pancreatic cancer cells, ketamine directly inhibits cancer cell proliferation while also inhibiting apoptosis.[21] Similarly, ketamine exacerbates cancer by upregulating levels of the anti-apoptotic protein Bcl-2, which promotes the invasion and proliferation of breast cancer cells.[22] Ketamine has also been shown to induce lymphocyte apoptosis through the mitochondrial pathway and inhibit the functional maturation of dendritic cells.[23] At present, the effect of ketamine on cancer cells is still controversial, and its effect on different cancer cells may be tissue specific.
Inhalational anesthetics
Inhalation anesthetics such as sevoflurane, isoflurane, and desflurane play an important role in clinical anesthesia. Several in vitro studies have demonstrated the effects of inhaled anesthetics on the immune system.[24] A variety of immune cells play antitumor effects in the perioperative period, such as neutrophils, NK cells, B lymphocytes, and T lymphocytes. Among them, NK cells and T lymphocytes are prominent in the antitumor effects after the surgery.[25–27] For innate immunity, several studies have observed that inhaled anesthetics impairs neutrophil function.[28]As early as 1997, sevoflurane was found to reduce the number of neutrophils.[29] At the same time, isoflurane, sevoflurane, and halothane have all been shown to reduce the cytotoxicity of NK cells.[24] A combination of in vivo and in vitro studies showed that interferon-α and interferon-β stimulation of NK cell cytotoxicity were inhibited after exposure to halothane and isoflurane.[30] For adaptive immunity, sevoflurane, isoflurane, and desflurane induce T lymphocyte apoptosis both in vitro and in vivo, and upregulate HIF-1α expression to promote angiogenesis, cell proliferation, and metastasis.[31–34] In addition, inhalational anesthetics may also affect neuroendocrine response of the HPA axis and the sympathetic nervous system, and increase the secretion of immunosuppressive-related cytokines, such as vascular endothelial growth factor and transforming growth factor β (TGF-β), through immunomodulatory hormones, such as catecholamines and prostaglandins, thereby indirectly affecting the immune response.[35]
Analgesics
Opioid analgesics
Opioids play a crucial role in providing postoperative analgesia for cancer patients. Their potential effect on cancer recurrence and metastasis, however, remains largely unknown issue. Studies have revealed that opioids disrupt the functions of immune cells. For instance, fentanyl has been shown to inhibit macrophages and NK cells, while morphine is known to reversibly inhibit the cytotoxic effects of NK cells and the activation of cytotoxic T lymphocytes, particularly CD4+CD8+ cells.[36–38] Additionally, both in vitro and in vivo studies have shown that morphine at clinically relevant doses promotes angiogenesis, thereby facilitating the nutrient supply and growth of tumors, and aiding in evading host defenses.[39] Morphine has also been associated with the promotion of lymphangiogenesis, mast cell activation, and degranulation, leading to increased levels of inflammatory cytokines.[40]
In addition to numerous cell and animal studies, the effects of opioids on the prognosis of cancer patients have also been investigated in several clinical studies. Higher intraoperative opioid doses have been associated with a decreased risk of cancer recurrence in patients undergoing surgery for stage Ⅰ–Ⅲ adenocarcinoma of the colon.[41] However, Sessler et al reported that perioperative opioid use was not associated with an increased risk of breast cancer recurrence.[42] Notably, a recent study reported that intraoperative opioids were even protective against the recurrence of triple-negative breast cancer.[43] Furthermore, a randomized prospective clinical trial found no significant change in biochemical recurrence rates and biochemical recurrence-free survival in post-prostatectomy patients at moderate or high risk of biochemical recurrence due to opioid use.[44] Therefore, the effects of perioperative opioid use on the prognosis of cancer patients remain inconclusive, which requires future studies to validate.
Non-opioid analgesics
Non-opioid analgesics commonly used perioperatively include non-selective cyclooxygenase (COX) inhibitors and selective COX-2 inhibitors. Numerous studies have shown that non-selective COX inhibitors, such as non-steroidal anti-inflammatory drugs (NSAIDs), reduce the risk and mortality rate in patients with cancer. [45] COX-2 is widely expressed in various types of cancers, playing a versatile and multifaceted role in carcinogenesis, cancer progression, and resistance to chemotherapy and radiotherapy.[46] NSAIDs inhibit the COX activity, thereby blocking the conversion of arachidonic acid to prostaglandins, or indirectly affect cancer progression and metastasis through their analgesic effects, thereby benefiting patients. Similarly, selective COX-2 inhibitors affect the long-term prognosis of cancer patients. Interestingly, research indicates that selective COX-2 inhibitors help control chronic postoperative pain in esophageal cancer patients and may prolong patient survival.[47] Celecoxib has been shown to reduce the incidence of colorectal adenomas and colorectal cancer.[48] However, in a recent randomized clinical trial involving 2526 patients with stage Ⅲ colon cancer, the addition of celecoxib to standard adjuvant chemotherapy did not significantly improve disease-free survival (DFS), compared with placebo.[49] In conclusion, further large patient cohort studies are needed to investigate the effect of non-opioid analgesics on the prognosis of cancer patients.
Local anesthetics
Lidocaine, a widely used amide local anesthetic, is used for both systemic intravenous infusion and nerve blocks. It acts on cancer cells and the tumor microenvironment both in vivo and in vitro in ways similar to other anesthetics. Lidocaine may reinforce the function of NK cells by modulating the release of lytic granules, essential components of the antitumor immune response.[50] Moreover, perioperative lidocaine has been found to impede immune cell infiltration into the premetastatic microenvironment and prevent the release of pro-metastatic inflammatory cytokines, thereby reducing the risk of future metastases.[51] Furthermore, lidocaine has been shown to enhance the tumor-killing effect of traditional chemotherapy drugs. For example, Xing et al[52] demonstrated that lidocaine inhibited tumor growth and increased tumor sensitivity to cisplatin treatment in a xenograft model. Lidocaine not only inhibits cancer progression, but also alleviates pain, reduces surgical irritation, and mitigates stress responses in various cancers, effectively reducing postoperative pain and the inflammatory response in cancer.[53] These findings indicate the potential of lidocaine as an adjuvant drug for cancer treatment.
Recent clinical studies have investigated potential benefits of intraoperative lidocaine use in long-term survival of cancer patients. A study on clinical efficacy of lidocaine in the treatment of pancreatic cancer recurrence found that patients treated with intravenous lidocaine had better survival rates in one and three years, although there was no difference in DFS.[54] Another multicenter randomized controlled trial found that intraoperative lidocaine infusion did not improve OS or DFS in patients undergoing pancreatectomy for pancreatic cancer; however, it did reduce the formation of circulating neutrophil extracellular traps, which are associated with poor a prognosis, in pancreatic cancer tissue.[55] Similarly, intraoperative intravenous lidocaine infusion was correlated with an improved OS or DFS in patients undergoing primary cytoreductive surgery of ovarian cancer, as well as a reduction in intraoperative opioid use.[56] Furthermore, a prospective randomized controlled trial of patients undergoing ovarian tumor resection found that intraoperative and 72-hour intraperitoneal injection of ropivacaine shortened the time to chemotherapy administration.[57] Despite these positive effects, the use of lidocaine as an adjuvant drug still requires large-scale and scientifically rigorous prospective randomized controlled trials to thoroughly investigate its safety and efficacy.
Anesthetic techniques
General anesthesia
General anesthesia plays a critical role in the process of cancer surgery, with the two main methods of the inhalation anesthesia based on volatile anesthetics and total intravenous anesthesia using propofol. Emerging evidence indicates a potential association between volatile anesthetic-based inhalation anesthesia and a worse long-term cancer prognosis, compared with propofol-based intravenous anesthesia. Preclinical studies have also revealed that anesthetics affected cellular immunity and influence cancer cell proliferation, migration, and invasion.[58] Notably, inhalation anesthetics may exert direct inhibitory effects on innate and adaptive immunity, leading to reduced neutrophil recruitment, adhesion, and macrophage phagocytosis, as well as impaired cytotoxicity of NK cells and polarization of T lymphocytes to tumorigenic Th2 cell populations.[59] In contrast, intravenous anesthetics such as propofol have been shown to positively modulate immune function in cancer patients, thereby exhibiting some antitumor effects.[60]
Current clinical studies mainly focus on comparing the effects and outcomes of inhalation anesthesia versus intravenous anesthesia in cancer patients undergoing surgery. Findings from Kwon Hui Seo et al[61] indicated that patients undergoing surgery for non-small cell lung cancer exhibited over 20% higher recurrence risk in the inhalation anesthesia group, compared with the intravenous anesthesia group. Similarly, large study including colon cancer patients demonstrated better survival outcomes with intravenous anesthesia alone across different tumor-node-metastasis stages.[62] However, conflicting results have been also reported in patients undergoing breast cancer surgery, with some studies suggesting a lower risk of cancer recurrence with the propofol-based intravenous anesthesia, and others showing no significant difference in postoperative survival outcomes.[14][63] A long-term follow-up of a multicenter randomized trial, which enrolled 1,228 patients aged 65-90 years scheduled for major cancer surgery, found no difference in recurrence-free survival and event-free survival.[64] Similarly, a retrospective cohort study investigating the effects of anesthesia type on survival outcomes in patients who underwent elective surgical resection for papillary thyroid carcinoma found that propofol anesthesia was not associated with better survival compared to desflurane anesthesia.[65] Anonther systematic review and meta-analysis highlighted the potentially better OS during cancer surgery with the propofol-based intravenous anesthesia, compared with inhaled anesthesia.[66] Nevertheless, those conflicting findings call for more prospective multicenter studies with larger sample sizes to comprehensively investigate the effects of these two main anesthesia modalities on cancer recurrence related to surgical procedures.
Regional anesthesia
Regional anesthesia techniques, such as epidural anesthesia, spinal anesthesia, and nerve blocks, temporarily block the conduction function of the spinal cord or peripheral nerves to achieve anesthesia and analgesia. It has been suggested that regional anesthesia may reduce surgical stress response and immunosuppression, decrease the need for volatile anesthesia, and reduce pain and opioid requirements, potentially mitigating perioperative tumor pathways and improving long-term oncological outcomes.[67] A randomized controlled trial found a significant reduction in NK cell and T cell activities in those who received regional anesthesia compared with those who received general anesthesia.[68]
However, due to the heterogeneity of surgical scope, cancer type, patient characteristics, and limitations of study types, clinical studies on the long-term prognosis of cancer patients yield inconsistent results. Many studies compared regional anesthesia with general anesthesia alone instead of their combined effects. For example, Xu et al[69] investigated the outcomes of adult patients undergoing thoracoscopic lung cancer resection, finding that epidural analgesia combined with thoracic epidural block did not improve recurrence-free survival or other survival outcomes, nor did it benefit patients diagnosed with lung cancer. Likewise, in a randomized controlled trial of elderly patients undergoing major thoracic and abdominal surgery, general anesthesia combined with thoracic epidural block and epidural analgesia did not enhance OS and tumor-specific survival, although it did reduce inhaled anesthetics and long-acting opioids.[70]
Conversely, previous studies examining the effect of regional analgesia on breast cancer recurrence suggest that regional block combined with general anesthesia may be an appropriate anesthetic strategy for patients with breast cancer. One case-control study revealed that paravertebral block-regional anesthesia with the propofol-based sedation reduced locoregional recurrence in breast cancer patients undergoing breast-conserving surgery.[71] Additionally, a retrospective study found that patients with non-muscle-invasive bladder cancer who underwent transurethral resection of bladder cancers under neuraxial anesthesia had significantly longer recurrence-free survival than those who received general anesthesia.[72]
In conclusion, current clinical trials do not offer any unequivocal evidence that regional anesthesia may improve the long-term prognosis of cancer patients. Therefore, the decision to use regional anesthesia in the perioperative period should be based on patient characteristics and specific surgical needs, rather than specifically for preventing cancer recurrence.
Other anesthesia-related perioperative factors
Blood pressure
Hypotension during the perioperative period may lead to inadequate perfusion of vital organs, potentially causing acute or chronic irreversible damage, thus significantly affecting the postoperative outcome of patients. Notably, perioperative blood pressure not only correlates with adverse cardiovascular events and organ damage but also affects short- and long-term mortality. Moreover, there is an emerging evidence suggesting that perioperative blood pressure may have a potential effect on cancer outcomes. Perioperative hypotension may activate the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, subsequently diminishing tissue perfusion and leading to cell hypoxia, hypoxemia, metabolic acidosis, and increased lactate in severe cases, which, in turn, may impair immune cell function and promote cancer cell proliferation and metastasis. For example, Younes et al[73] observed that the frequency of hypotensive episodes played a pivotal role in influencing cancer recurrence rates in patients who had undergone complete resection of colorectal liver metastases. Consequently, they recommended avoiding hypotensive episodes during surgery to maximize the chance of cure and extend DSF in these patients. Similarly, Park et al[74] conducted a retrospective study involving renal cell carcinoma patients and found that perioperative blood pressure in the stage 2 hypertension range (≥ 160/100 mm Hg) emerged as an independent predictor of overall mortality. Despite these findings, the potential effect of perioperative blood pressure fluctuations on cancer prognosis warrants further investigation.
Blood transfusion
The phenomenon of transfusion-related immunomodulation refers to the immunosuppressive effects of allogeneic transfusions in the perioperative period that may negatively influence cancer recurrence and metastasis. Allogeneic transfusions lead to alterations in several facets of the recipient's immune function, including a decrease in the ratio of helper T lymphocytes to suppressor T lymphocytes, diminished NK cell function, defective antigen presentation, and reduced cell-mediated immunity.[75] Furthermore, studies in various experimental animal models have indicated the potential pro-tumor growth effects of allogeneic transfusion, which may be attributed to the presence of allogeneic donor leukocytes in transfused blood products.[76]
Although there is limited evidence from randomized trials concerning the relationship between blood transfusion and cancer recurrence and prognosis, most current relevant clinical studies are retrospective. A propensity-matched analysis of patients with hepatocellular carcinoma undergoing hepatectomy revealed that red blood cell transfusion (RBCT) promoted cancer recurrence and decreased long-term survival after radical resection, while other types of transfusions, including platelets, 5% albumin, and 25% albumin, did not affect long-term survival.[77] Similar associations have also been observed in gastric cancer, non-small cell lung cancer, and head and neck cancers.[78–80] However, a retrospective, single-center cohort study of patients with stage Ⅰ–Ⅲ colorectal cancer who underwent radical surgery between 2005 and 2017 found that perioperative RBCT was significantly associated with a poorer OS.[81] The survival outcomes in the group receiving perioperative RBCT were significantly worse than those without RBCT, and perioperative RBCT was significantly associated with a poorer OS in multivariable analysis.[81] Notably, when propensity scores were used to match transfused and non-transfused cases, no difference in OS and cancer-specific survival was observed.[81] The need for intraoperative blood transfusion is influenced by factors such as surgical complexity and the patient's physical condition. Similarly, cancer recurrence and prognosis are influenced by variables such as tumor stage and postoperative adjuvant therapy. Therefore, the effect of blood transfusion on cancer prognosis remains uncertain, and there is a need for more well-designed randomized controlled trials to provide conclusive evidence.
Hypothermia
In the perioperative period, hypothermia is a frequent complication that may lead to various adverse outcomes including postoperative infection, cardiovascular events, and an increased risk of blood transfusion.[82] Elevated temperatures generally promote the activation, function, and delivery of immune cells, while decreased temperatures inhibit these processes.[83] Zeba et al[84] conducted a single-center randomized controlled trial in 2020 to investigate the effect of intraoperative hypothermia on the cytokine profile. The study found that patients in the non-warming group had the lowest mean perioperative core body temperature and showed a sustained increase in the pro-inflammatory response. In addition, intraoperative warming to maintain normal body temperature was found to attenuate the harmful pro-inflammatory response. Furthermore, Nduka et al[85] used an animal model to investigate the effect of hypothermia on tumor growth during laparoscopic surgery. Their results showed that the tumor mass was significantly increased in the cold CO2 pneumoperitoneum group, compared with the warmed CO2 pneumoperitoneum group. However, there are still few clinical studies on the relationship between intraoperative hypothermia and cancer prognosis, and there are many factors that affect cancer prognosis, so it is difficult to explain the differences in long-term outcomes of cancer patients with intraoperative hypothermia alone. A retrospective clinical study of 124 patients with myoinvasive bladder cancer who underwent radical cystectomy from 2003 to 2016 showed no significant differences in OS and DFS between the hypothermic and normothermic groups.[86] However, in subgroup analysis based on pathologic stage, OS and DFS were significantly shorter in the hypothermic group than those in the normothermic group for stage Ⅱ patients.[86] Expanding on this, Lyon et al[87] increased the sample size to 852 patients undergoing radical cystectomy and found no significant difference in the 2-year survival rate between the hypothermic and the normothermic groups, and no significant correlation between intraoperative hypothermia and recurrence-free survival (RFS), tumor-specific survival (CSS), and OS. However, they found that a median body temperature of < 35 ℃ was an independent factor influencing OS.
Given the influence of hypothermia on tumor growth, hyperthermia has emerged as a potential cancer treatment to reduce cancer recurrence. Current evidence suggests that physiological responses to hyperthermia may enhance the ability of the microenvironment to resist tumors by regulating temperature-sensitive checkpoints in tumor vascular perfusion and metabolism.[88] However, an in vitro study reported that cancer cells were more resistant to higher temperatures than normal cells, signifying a need for further understanding of the effects of thermal stimulation on the tumor environment and antitumor immune responses.[89]
Limitation
This review examines the effects of anesthetics on tumor proliferation, apoptosis, and invasion, primarily utilizing in vitro studies. Several limitations must be acknowledged. First, some epidemiological results are inconsistent with findings from in vitro animal and cell studies. This discrepancy may be attributed to the fact that in vitro studies assess the direct effects of anesthetics on tumor cells, whereas in clinical practice, tumor tissue is typically excised, and anesthetics exert only transient effects on systemic tissues rather than directly affecting the tumor tissue itself. As a result, these in vitro findings may not accurately reflect the impact of anesthetics on tumor recurrence or metastasis in clinical settings.[42,90] Furthermore, the proficiency of the surgeon plays a critical role in influencing both the duration of the surgery and the thoroughness of tumor tissue removal. Incomplete resection of tumor tissue, often due to less meticulous surgical techniques, is a well-documented cause of cancer recurrence. Additional factors such as intraoperative blood loss, the duration of anesthesia, and the presence of tumor stem cells also significantly affect surgical outcomes and warrant further investigation. Given these considerations, we plan to undertake a more rigorous systematic review in the future, drawing on a broader range of clinical research data.
Conclusions and perspectives
In summary, the immunosuppression caused by anesthetics, surgical techniques, and other perioperative factors has been suggested to potentially facilitate metastasis and cancer recurrence (Fig. 1). However, there are conflicting findings regarding the effect of anesthesia on immune response and tumor growth (Table 1). As a result, the current evidence regarding different anesthetic strategies for perioperative cancer recurrence remains inconclusive. Therefore, to fill this knowledge gap, there is an urgent need for large, randomized multicenter prospective clinical trials to investigate the influence of different anesthetics, surgical techniques, and other relevant factors on the long-term prognosis of cancer surgery.
Figure
1.
Perioperative factors influence the prognosis of cancer patients.
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