Effects of ropivacaine, bupivacaine and sufentanil in colon and pancreatic cancer cells in vitro
Introduction
In recent years evidence is growing that, during the perioperative period, the risk of cancer dissemination is increased [1], [2]. Injury of tumor vessels and surgical manipulation enables cancer cells to enter the circulation. Enhanced levels of growth factors during the postoperative wound healing process as well as a dysbalance between pro- and antiangiogenetic factors can stimulate the growth of disseminated cancer cells and micro metastases. Furthermore, perioperative immunosuppression compromises anticancer immune surveillance. This fatal combination of released cancer cells, impairment of the immune function and high growth factor levels can enhance the risk for cancer recurrence during the perioperative period.
These findings arise the question if the choice of a special anesthesia technique could influence the risk of cancer recurrence [3], [4]. Especially the effect of regional anesthesia on cancer progression was in the focus of clinical investigation over the recent years. Results of retrospective studies showed an association between the perioperative use of regional anesthesia during cancer surgery and better oncological outcome in breast [5], ovarian [6] and prostatic [7] cancer. A metaanalysis including 14 studies demonstrated a benefit of epidural anesthesia compared to general anesthesia alone regarding overall survival. The strongest positive association was found in colorectal cancer [8].
These protective effects of regional anesthesia seem to be based on the suppression of perioperative stress response by neuroaxial blockade [3]. Inhibition of the neuroendocrine stress axis can attenuate both immunosuppression and reduce sympathical activation caused by surgery. Decreased pain levels reduce the requirement of additional analgesic drugs and allow saving anesthetic agents during surgery.
The administration of the long acting local anesthetics ropivacaine or bupivacaine via epidural catheter is a common concept for perioperative pain management for patients undergoing major abdominal surgery. To improve analgesic effects, the opioid analgesic sufentanil usually is added to the local anesthetic agent. Local anesthetics reveal their analgesic effect by inhibition of voltage activated sodium channels. These local anesthetic sensitive sodium channels are expressed in several cancer types including breast, colon and prostate cancer and were shown to be associated with cancer metastasis [9], [10]. Reduced expression of the voltage gated Nav1.5 channel suppressed cell proliferation and invasiveness and induced apoptosis in astrocytoma cells [11].
We hypothesized that the beneficial effects of regional anesthesia on cancer progression could be based on direct interaction between administered drugs and tumor cells themselves. For this reason, we investigated the effects of clinically achievable concentrations of ropivacaine, bupivacaine and sufentanil on cell proliferation, cell cycle distribution and apoptosis in colon and pancreatic cancer cell lines in vitro.
Section snippets
Reagents
Commercially available ropivacaine (Fagron, Waregem, Belgium), bupivacaine (Fluka, Buchs Switzerland) and sufentanil (Sigma–Aldrich, St. Gallen, Switzerland) were used for this study. Stock solutions of the test reagents were prepared by dissolving the drugs in the ascertained standard growth media for ropivacaine and bupivacaine and standard growth media containing DMSO for sufentanil (as described below). The final concentrations were achieved by diluting the stock solutions with standard
Cell proliferation
In all cell lines, 1000 μM bupivacaine significantly inhibited cell growth (Fig. 1a). In PaTu 8988t 0.1–100 μM bupivacaine induced a slight but significant increase of cell growth.
1000 μM ropivacaine reduced cell growth in HT 29, SW 480 and PANC 1 cell lines (Fig. 1b). Lower concentrations of ropivacaine partially led to a statistical significant reduction of cell proliferation between 24 ± 19% and 12 ± 15% compared to untreated control.
In SW 480 colon carcinoma cells, all concentrations (except 0.1
Discussion
The aim of this study was to investigate the effects of the clinically used local anesthetics ropivacaine or bupivacaine and the opioid analgesic sufentanil on cell proliferation, cell cycle distribution and apoptosis on both colon and pancreatic cancer cell lines.
Uncontrolled cell proliferation is one of the “hallmarks of cancer” [12], [13]. In healthy tissue cell growth is regulated by a variety of factors. Cancer cells escape these regulations by different mechanisms such as autocrine
Conclusion
Our study indicates that ropivacaine, bupivacaine and sufentanil do not directly affect cell cycle distribution and apoptosis in colon and pancreatic cancer cell lines in vitro. Antiproliferative effects only were detected at high concentrations which can be achieved by local infiltration but not during epidural anesthesia. These results suggest that the protective effects of epidural anesthesia which were observed in some clinical studies are not likely based on direct interaction with cancer
Conflict of interest
None declared.
Funding
Regensburger Forschungsförderung in der Medizin (ReForM), Faculty of Medicine, University of Regensburg.
Acknowledgements
We thank Renate Lange, Sigrid Bamberger, Regina Lindner, Marion Schindler, Ruth Spaeth and Daniel Potschka for excellent technical support. We thank Regensburger Forschungsförderung in der Medizin (ReForM), Faculty of Medicine, University of Regensburg for financial support.
References (37)
- et al.
Effect of anaesthetic technique and other perioperative factors on cancer recurrence
Br. J. Anaesth.
(2010) - et al.
Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: clinical potential of neonatal Nav1.5 in breast cancer
Eur. J. Pharmacol.
(2009) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
Only tetracaine and not other local anaesthetics induce apoptosis in rat cortical astrocytes
Br. J. Anaesth.
(2009) - et al.
Apoptosis induction by different local anaesthetics in a neuroblastoma cell line
Br. J. Anaesth.
(2009) - et al.
Ropivacaine plasma concentrations during 120-hour epidural infusion
Br. J. Anaesth.
(2000) - et al.
Paravertebral block with ropivacaine 0.5% versus systemic analgesia for pain relief after thoracotomy
Ann. Thorac. Surg.
(2005) - et al.
Patient-controlled analgesia with sufentanil: a comparison of two different methods of administration
J. Clin. Anesth.
(1996) - et al.
Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden
Br. J. Anaesth.
(2011)
Review article: the role of the perioperative period in recurrence after cancer surgery
Anesth. Analg.
Surgery as a risk factor for breast cancer recurrence and metastasis: mediating mechanisms and clinical prophylactic approaches
Breast Dis.
Cancer recurrence after surgery: direct and indirect effects of anesthetic agents
Int. J. Cancer
Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?
Anesthesiology
Intraoperative neuraxial anesthesia but not postoperative neuraxial analgesia is associated with increased relapse-free survival in ovarian cancer patients after primary cytoreductive surgery
Reg. Anesth. Pain Med.
Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis
Anesthesiology
The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies
PLoS One
Voltage-gated sodium channels and metastatic disease
Channels (Austin)
Cited by (44)
Effects of local anesthetics on cancer cells
2020, Pharmacology and TherapeuticsThe potential anti-tumor effect of anesthetics on cancer by regulating autophagy
2024, Frontiers in PharmacologyEffects of different concentrations of ropivacaine on growth and migration of lung cancer cells
2023, Chinese Journal of AnesthesiologySufentanil combined with parecoxib sodium inhibits proliferation and metastasis of HER2-positive breast cancer cells and regulates epithelial-mesenchymal transition
2023, Clinical and Experimental Metastasis