Effects of propofol on the development of cancer in humans

Abstract Cancer is one of most the significant threats to human health worldwide, and the primary method of treating solid tumours is surgery. Propofol, one of the most widely used intravenous anaesthetics in surgery, was found to be involved in many cancer‐related pathophysiology processes, mainly including anti‐tumour and minor cancer‐promoting effects in various types of cancer. An increasing number of studies have identified that propofol plays a role in cancer by regulating the expression of multiple signalling pathways, downstream molecules, microRNAs and long non‐coding RNAs. Emerging evidence has indicated that propofol can enhance the anti‐tumour effect of chemotherapeutic drugs or some small molecular compounds. Additionally, in vivo animal models have shown that propofol inhibits tumour growth and metastasis. Furthermore, most clinical trials indicate that propofol is associated with better survival outcomes in cancer patients after surgery. Propofol use is encouraged in cancers that appear to have a better prognosis after its use during surgery. We hope that future large and prospective multicenter studies will provide more precise answers to guide the choice of anaesthetics during cancer surgery.


| Biological behaviour of propofol in cancer cells
Propofol is a popular anaesthetic agent with potent anti-tumour activity. However, a few studies showed that propofol promoted cell proliferation and invasion in gallbladder cancer and breast cancer. 17,18 Nevertheless, a large body of literature reports that propofol inhibits the metastasis of cancer cells in colon cancer, breast cancer, lung adenocarcinoma, hepatocellular carcinoma and cervical cancer. [19][20][21][22][23] Mechanistically, a research group used atomic force microscopy and found that propofol disrupted the cellular cytoskeleton of cervical cancer, which possibly unveiled the biological mechanism of how propofol reduced migration ability. 23 A study reported that propofol exerted an inhibitory effect on tumorigenesis by promoting autophagic flux and triggering autophagosome accumulation in cervical cancer cells. 24 Propofol not only inhibited the adhesion and migration of breast cancer cells but also promoted apoptosis. 25 In oesophageal squamous cell cancer, propofol induced cell apoptosis and reduced proliferation, invasion, and angiogenesis in a dose-and time-dependent manner. 26 These laboratory data provide support for the tumour-suppressive effects of propofol in multiple cancers.
Moreover, propofol may play a pivotal role in affecting the tumour microenvironment of the serum in patients undergoing surgery. Recent data showed that in patients undergoing radical resection of non-small cell lung cancer (NSCLC), the serum of patients treated with propofol had a lower concentration of tumour angiogenesis-related factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor beta, than that in the sevoflurane group. 27 Serum of breast cancer patients who were given propofol or sevoflurane during surgery was added to oestrogen receptor (ER)-negative breast cancer cells, and it was found that more breast cancer cells treated with serum from patients who received propofol underwent apoptosis than those treated with serum from patients who received sevoflurane. 28 Similarly, serum from colon cancer patients who received propofol during surgery inhibited colon cancer cell proliferation and invasion, and promoted apoptosis in vitro when compared with cells treated using serum from patients who received sevoflurane. 29 These phenomena indicate that propofol may affect the tumour microenvironment of the serum, thereby playing an inhibitory role in the development and progression of cancer.

| Effect of propofol on cancer cells by regulating related signalling pathways or downstream molecules
To elucidate the molecular mechanism of the influence of propofol on the biological behaviours of cancer cells, we reviewed a large amount of literature about the regulation of signalling pathways or downstream molecules related to cancer cell proliferation, apoptosis, migration and invasion after propofol stimulation (Table 1; Figure 1). A few studies showed that propofol promoted cell proliferation and invasion in gallbladder cancer in a dose-dependent and time-dependent manner by activating the nuclear factor E2-related factor-2 (Nrf2) at the transcriptional and translational level. 17 In accordance with this, propofol induced cell migration by activating the Nrf2 signalling pathway and triggering cell proliferation in part via downregulation of the expression of p53 in human breast cancer MDA-MB-231 cells. 18 Nonetheless, plenty of studies have shown the opposite results. For example, an in vitro study found that propofol suppressed colon cancer cell invasion partly via extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent downregulation of matrix metalloproteinases (MMPs). 19 Additionally, to clarify the molecular mechanism in metastatic inhibitory effects of propofol in breast cancer, Li et al 20 reported that propofol reduced MMP expression via the suppression of nuclear factor-kappa B (NF-κB) pathways and inhibited the invasion and migration ability of cancer cells. In cervical cancer, propofol suppressed cell viability and induced apoptosis by inhibiting of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) pathway. 30 In glioma cells, propofol inhibited cell growth and increased cell apoptosis by downregulating wingless and proto-oncogene integration-1 (Wnt) signalling. 31 In NSCLC, cell viability was reduced and cell apoptosis was promoted by an increase the activity of the ERK1/2-dependent PUMA signalling pathway following exposure to propofol. 32 In cholangiocarcinoma cells, propofol exerted inhibitory effects on metastasis and induced apoptosis. Furthermore, the level of B-cell lymphoma-2-associated X (Bax) expression was increased and B-cell lymphoma-2 (Bcl-2) expression was decreased after adding propofol; the Wnt/β-catenin signalling pathway was inhibited as the concentration of propofol increased. 33 In Leydig cell cancer, propofol induced the apoptosis of cells via promoting the activity of caspase, as well as inhibiting the protein kinase B (Akt) pathway. 34 One study illustrated that propofol inhibited the process of glycolysis and repressed hypoxiainducible factor-1α (HIF-1α) in colorectal cancer cells via inhibition of the NMDAR-calcium/calmodulin-dependent protein kinase II-ERK pathway, which might be related to the inhibition of cancer progression. 35 Chen et al 36 found that propofol might promote cancer cell growth and metastasis via blocking the Wnt/β-catenin and NF-κB pathways in an ANRIL-dependent method in papillary thyroid cancer. Consistent with the previous findings, propofol inhibited the maintenance and self-renewal of leukaemia stem cells by suppressing Akt/mTOR and Wnt/βcatenin. 37 The growth and activity of gastric cancer cells were inhibited

| Anti-tumour effect of propofol in cancer cells via regulation of microRNAs
It has been revealed that miRNAs, endogenous non-coding small RNA molecules, play pivotal roles in affecting gene expression, signalling pathways and cellular biological effects, such as proliferation, metastasis and apoptosis. 42 Numerous studies have revealed that the effects of propofol in human cancer might be regulated by miRNA expression.
A recent study discovered that microvesicles were able to shuttle miRNAs into nearby or distant cells and then regulate the expression of target genes. 61  Taken together, these investigations revealed that propofol contributes to triggering anti-tumour activity by downregulating or upregulating miRNA expression and can be used as a treatment agent in various cancers.

| Effect of propofol on cancer cells due to the regulation of long non-coding RNAs
LncRNAs are longer than 200 nucleotides but are unable to express proteins. It was emphasized that lncRNAs play an essential role in the occurrence and progression of cancer. 64 One study revealed that propofol decreased colon cancer cell metastasis and increased F I G U R E 2 The anti-tumour effect of propofol by upregulation of miRNAs in cancer cells. AKT, protein kinase B; Bcl-2, B-cell lymphoma-2; JAK, Janus kinase; miR, microRNAs; MMP, matrix metalloproteinase; NF-κB, nuclear factorkappa B; STAT, signal transducer and activator of transcription 3; Wnt, wingless and proto-oncogene integration-1. "Arrows from propofol to → targets" means "activating targets." "Blockade from propofol to targets" means "inhibiting targets"

F I G U R E 3
The anti-tumour effect of propofol by downregulation of miRNAs or lncRNAs in cancer cells. AKT, protein kinase B; ATG5, autophagy-related genes 5; HOTAIR, HOX antisense intergenic RNA; HOXA11-AS, HOXA11 Antisense RNA; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; miR, microRNAs; mTOR, mammalian target of rapamycin; p27, cyclin-dependent kinase inhibitor 1B; PI3K, phosphoinositide 3-kinase; RAC1, Ras-related C3 botulinum toxin substrate 1; Wnt, wingless and proto-oncogene integration-1. "Arrows from propofol to → targets" means "activating targets." "Blockade from propofol to targets" means "inhibiting targets" cell apoptosis in part through the inhibition of lncRNA HOX antisense intergenic RNA expression (HOTAIR) and subsequent inactivation of the Wnt signalling pathway. 65 The potential mechanism of propofol in colorectal cancer is the suppression of tumorigenesis by downregulating a highly conserved lncRNA HOXA11 Antisense RNA (HOXA11-AS) and upregulating miR-let-7i, and then promoted cell apoptosis. 66 Additionally, propofol also plays an essential role in regulating autophagy. 67 To date, autophagy has been found to play a dual role in the development of cancer dependent on a variety of factors including the tumour microenvironment, cancer type and stage and genetic background. 68 In the early stages of tumorigenesis, autophagy acted as a tumour suppressor, which prevented tumour initiation, proliferation, invasion and metastasis. [69][70][71] However, once the tumours progress to the late stage, autophagy promoted tumorigenesis by sustaining tumour metabolism, growth, survival, and facilitating metastasis and resistance to therapeutic agents. [72][73][74] In gastric cancer cells, propofol facilitated apoptosis and reduced autophagy-related chemoresistance to cisplatin via inhibition of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Mechanically, it has been demonstrated that the level of MALAT1 was lower and miR-30e was upregulated, which caused suppression of autophagy-related genes 5 (ATG5), and subsequently inactivated autophagy-related chemoresistance in gastric cancer cells following propofol treatment. 67 These investigations have shown that propofol exerted tumour-inhibitory effects by regulating lncRNA expression (Table 2; Figure 3).

| Effect of propofol in combination with chemotherapeutic drugs or molecular compounds in cancer cells
Recently, more studies have found that the combination of propofol and chemotherapeutic agents or some molecular compounds may play antitumour roles in human cancer (Table 3)

| EFFEC T OF PROP OFOL ON ANIMAL MODEL S OF C AN CER
Various investigations have discovered that propofol has essential anticancer properties not only in vitro but also in vivo. A large number of studies indicated that in nude mice models, propofol inhibited the growth of xenograft tumours in numerous cancers such as cervical cancer, lung cancer and pancreatic cancer. 30,82,83 The latter results appear to be consistent with previous studies that found propofol decreased the growth of endometrial cancer in a xenograft tumour model, but the effect was abolished by increased expression of Sox4. 40 Xu et al 31    propofol anaesthesia or sevoflurane anaesthesia was used for breast cancer resection in an orthotopic mouse model. It was found that the propofol treatment group had lesser lung metastasis than the sevoflurane group 2 weeks after surgery. 84 Another important result of the study was that the IL-6 and VEGF serum levels were significantly lower in the propofol group than in the sevoflurane group. 84 Consistent with in vitro studies, results of these explorations in vivo also suggest that propofol exerts an inhibitory effect on tumour growth and metastasis, as well as facilitates the sensitivity of tumours to cisplatin.

| EFFEC T OF PROP OFOL ON THE PROG NOS IS OF PATIENTS WITH C AN CER
A number of clinical investigations found that propofol has no effect on prognosis in several cancers ( Similarly, a retrospective study included a total of 2856 patients who received gastric cancer resection surgery and found that the OS of the patients in the propofol group was better than that of the sevoflurane group. 5 Colon cancer patients treated with propofol exhibited a favourable OS and disease-free survival (DFS) and less postoperative metastasis than those who were treated with desflurane during surgery. 6 Compared with desflurane, propofol was associated with the use of inhalational anaesthesia. 9 Additionally, another retrospective cohort study found that propofol anaesthesia was related to better OS and a lower postoperative biochemical recurrence rate than those with desflurane anaesthesia in patients undergoing robot-assisted radical prostatectomy. 85 However, these previous studies have the limitations of most retrospective investigations. Hence, a prospective trial was warranted to evaluate the effect of propofol on bladder cancer outcomes. There were 100 patients who underwent radical cystectomy, and it was found that patients treated with the combination of propofol and epidural anaesthesia had a longer DFS than patients who were treated with sevoflurane combined with opioids. 2 There is growing evidence suggesting that volatile anaesthesia may contribute to poor survival outcomes, whereas propofol seems to provide better survival outcomes in cancer patients undergoing tumour removal surgery.
A series of studies have shown that the different influences of propofol on oncogenic outcomes might depend on the primary site of cancer. However, most studies still show that propofol contributes to a better prognosis. It is encouraged to use propofol in cancers that appear to have a better prognosis after using propofol during the surgery. For cancers in which the prognosis was not influenced by propofol, prospective multicenter studies with larger sample sizes are currently underway, which are expected to provide clear answers.

| CON CLUS ION
In summary, the role of propofol in the progression of cancer pa- Therefore, it is critical to elucidate how to choose the most suitable anaesthetic agents for different types of cancer to obtain the best prognosis for cancer patients. Propofol use is encouraged in cancers that appear to have a better prognosis after its use during the surgery. For cancers in which the prognosis was not influenced by propofol, further animal trials and prospective clinical studies are needed to understand the effects that the type of anaesthesia has on the development of cancer and provide us with more precise answers to guide the choice of anaesthetics during cancer surgery.

ACK N OWLED G M ENTS
This work was supported by a grant from Gynecology and obstetrics of combined traditional Chinese and Western Medicine of Zhejiang Province (2017-XK-A42).

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

AUTH O R CO NTR I B UTI O N S
YX, WJ and XZ conceptualized and design the manuscript. YX and SP searched the literature and wrote the manuscript. FX, WJ and XZ critically viewed, edited and approved the manuscript. All authors read and approved the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.