Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Anesthesiology
Published in: BMC Anesthesiology 1/2015

Open Access 01-12-2015 | Research article

Effects of ketamine, s-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells

Authors: Manuela Malsy, Kristina Gebhardt, Michael Gruber, Christoph Wiese, Bernhard Graf, Anika Bundscherer

Published in: BMC Anesthesiology | Issue 1/2015

Login to get access

Abstract

Background

Adenocarcinoma of the pancreas is one of the most aggressive cancer diseases affecting the human body. The oncogenic potential of this type of cancer is mainly characterized by its extreme growth rate triggered by the activation of signaling cascades. Modern oncological treatment strategies aim at efficiently modulating specific signaling and transcriptional pathways. Recently, anti-tumoral potential has been proven for several substances that are not primarily used in cancer treatment. In some tumor entities, for example, administration of glutamate antagonists inhibits cell proliferation, cell cycle arrest, and finally cell death.
To attain endogenic proof of NMDA receptor type expression in the pancreatic cancer cell lines PaTu8988t and Panc-1 and to investigate the impact of ketamine, s-ketamine, and the NMDA receptor antagonist MK 801 on proliferation, apoptosis, and necrosis in pancreatic carcinoma.

Methods

Cell proliferation was measured by means of the ELISA BrdU assay, and the apoptosis rate was analyzed by annexin V staining. Immunoblotting were also used.

Results

The NMDA receptor type R2a was expressed in both pancreatic carcinoma cell lines. Furthermore, ketamine, s-ketamine, and MK 801 significantly inhibited proliferation and apoptosis.

Conclusions

In this study, we showed the expression of the NMDA receptor type R2a in pancreatic cancer cells. The NMDA antagonists ketamine, s-ketamine, and MK 801 inhibited cell proliferation and cell death. Further clinical studies are warranted to identify the impact of these agents on the treatment of cancer patients.
Literature
1.
2.
3.
4.
Gnoni A, Licchetta A, Scarpa A, Azzariti A, Brunett A, Simone G, et al. Carcinogenesis of pancreatic adenocarcinoma: precursor lesion. Int J Mol Sci. 2013;14:19731–62.
5.
6.
Doi R, Imamura M, Hosotani R, Imaizumi T, Hatori T, Takasaki K, et al. Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multi-institutional trial. Surg Today. 2008;38:1021–8.
7.
Egberts J, Cloosters V, Noack A, Scniewind B, Thon L, Klose S, et al. Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2008;5:1443–50.
8.
Parada-Turska J, Rzeski W, Majdan M, Kandefer-Szerszen M, Turski WA. Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synoviocytes in vitro. Eur J Pharmacol. 2006;535:95–7.
9.
Jimi N, Segawa K, Minami K, Sata T, Shigematsu A. Inhibitory effect of the intravenous anesthetic, ketamine, on rat mesangial cell proliferation. Anesth Analg. 1997;84:190–5.CrossRefPubMed
10.
Shiga Y, Minami K, Segawa K, Uezono Y, Shiraishi M, Sata T, et al. The inhibition of aortic smooth muscle cell proliferation by the intravenous anesthetic ketamine. Anesth Analg. 2004;99:1408–12.
11.
Rzeski W, Ikonomidou C, Turski L. Glutamate antagonists limit tumor growth. Biochem Pharmacol. 2002;64:1195–200.CrossRefPubMed
12.
Lee S, Wu T, Yu P, Chen R. Apoptotic insults to human Hep G2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondra-caspase protease pathway. Br J Anaesth. 2009;102:80–9.CrossRefPubMed
13.
Yamaguchi F, Hirata Y, Akram H, Kamitori K, Dong Y, Sui L, et al. FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK 801. BMC Cancer. 2013;13:468–79.
14.
15.
Craven R. Ketamine. Anaesthesia. 2013;1:48–53.
16.
Hirota K, Lambert DG. Ketamine:its mechanism(s) of action and unusual clinical uses. Br J Anaesth. 1996;77:441–4.CrossRefPubMed
17.
18.
Bredlau AL, Thakur R, Korones DN, Dworkin RH. Ketamine for Pain in Adults and Children with cancer: a systematic Review and Synthesis of the Literature. Pain Med. 2013;14:1505–7.CrossRefPubMed
19.
Szczurowska E, Mares P. Glutamate, glutamate receptors and downstream signaling pathways. Int J Biol Sci. 2013;9:948–59.CrossRef
20.
Cull-Candy S and Leszkiew D. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004;255:re16.
21.
22.
Mueller H, Meador-Woodruff J. NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr Res. 2004;71:361–70.CrossRefPubMed
23.
Luksch H, Uckermann O, Stepulak A, Hendruschk S, Marzahn J, Bastian S, et al. Silencing of selected glutamate receptor subunits modulates cancer growth. Anticancer Res. 2011;10:3181–92.
24.
Stepulak A, Luksch H, Gebhardt C, Uckermann O, Marzahn J, Sifringer M, et al. Expression of glutamate receptor subunits in human cancers. Histochem Cell Biol. 2009;132:435–45.
25.
Stepulak A, Luksch H, Uckermann O, Sifringer M, Rzeski W, Polberg K, et al. Glutamate Receptors in Laryngeal Cancer cells. Anticancer Res. 2011;31:565–73.
26.
Kalariti N, Pissimissis N, Koutsilieris M. The glutamatergic system outside the CNS and in cancer biology. Expert Opin Investig. 2005;12:1487–96.CrossRef
27.
Abdul M, Hoosein N. N-methyl-D-aspartate receptor in human prostate cancer. J Membr Biol. 2005;205:125–8.CrossRefPubMed
28.
Watanabe K, Kanno T, Oshima T, Miwa H, Tashiro C, Nishizaki T. The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells. Biochem Biophys Res Commun. 2008;367:487–90.CrossRefPubMed
29.
Kim M, Yamashita K, Baek J, Park H, Carvalho A, Osada M, et al. N-Methyl-D-aspartae receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer. Cancer Res. 2006;66:3409–18.
30.
This is Number 30Stepulak A, Sifringer M, Rzeski W, Endesfelder S, Gratopp A, Pohl E, et al. NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and supresses cancer growth. Proc Natl Acad Sci U S A. 2005;102:15605–10.
31.
This is Number 31Idvall J, Ahlgren I, Aronsen K, Stenberg P. Ketamine infusions: Pharmacokonetics and clinical effects. Br J Anaesth. 1979;51:1167–73.
32.
He H, Chen J, Xie WP, Cao S, Hu HY, Yang LQ, et al. Ketamine used as an acesodyne in human breast cancer therapy causes an undesirable side effect, upregulating anti-apoptosis protein Bcl-2 expression. Genet Mol Res. 2014;12:1907–15.
33.
34.
35.
Petroiano G, Osswald P. Ketamin. In: Anästhesie in Frage und Antwort. 3rd ed. Deutschand: Springerverlag; 2000. p. 99–102.CrossRef
36.
37.
Tavare A, Perry N, Benzonana L, Takata M, Ma D. Cancer recurrence after surgery: direct and indirect effects of anesthetic agents. Int J Cancer. 2012;130:1237–50.CrossRefPubMed
38.
Goldfarb Y, Ben-Eliyahu S. Surgery as a risk factor for breast cancer recurrence and metastasis: mediating mechanisms and clinical prophylactic approaches. Breast Dis. 2006;26:99–114.CrossRefPubMed
39.
Xuan W, Hankin J, Zhao H, Yao S and Ma D. The potential benefits of the use of regional anesthesia in cancer patients. Int J Cancer. 2014.
40.
Chen WK, Miao C. The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS One. 2013;8:56540.CrossRef
41.
Werdehausen R, Braun S, Essmann F, Schulze-Osthoff K, Walczak H, Lipfert P, et al. Lidocaine induces apoptosis via the mitochondrial pathway independently of death receptor signaling. Anesthesiology. 2007;107:136–43.
42.
Huang H, Benzonana L, Zhao H, Watts H, Perry N, Bevan C, et al. Prostate cancer cell malignancy via modulation of HIF-1 α pathway with isoflurane and propofol alone and in combination. Br J Cancer. 2014;111:1338–49.
43.
Basu G, Pathangey L, Tinder T, Gendler S, Mukherjee P. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. Breast Cancer Res. 2005;7:422–35.CrossRef
44.
Kushida A, Inada T, Shingu K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol Immunotoxicol. 2007;29:477–86.CrossRefPubMed
45.
Bidart M, Berger F, Pelletier L. Anti-angiogenetic therapie: from theory to practice. Ann Biol Clin (Paris). 2013;71:527–35.
46.
Burger J, Montserrat E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signalling. Blood. 2013;121:1501–9.CrossRefPubMedPubMedCentral
47.
Modest D, Hiddemann W, Heinemann V. Chemotherapy of metastatic colorectal cancer. Internist. 2014;55:37–42.CrossRefPubMed
48.
Roderick H, Cook S. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer. 2008;8:361–75.CrossRefPubMed
Metadata
Title
Effects of ketamine, s-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells
Authors
Manuela Malsy
Kristina Gebhardt
Michael Gruber
Christoph Wiese
Bernhard Graf
Anika Bundscherer
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Anesthesiology / Issue 1/2015
Electronic ISSN: 1471-2253
DOI
https://doi.org/10.1186/s12871-015-0076-y

Other articles of this Issue 1/2015

BMC Anesthesiology 1/2015 Go to the issue

Research article

Estimation of creatinine clearance using plasma creatinine or cystatin C: a secondary analysis of two pharmacokinetic studies in surgical ICU patients

Research article

Preoperative hypoalbuminemia and anemia as predictors of transfusion in radical nephrectomy for renal cell carcinoma: a retrospective study

Review

Perioperative lung protective ventilation in obese patients

Research article

Posterior parasagittal in-plane ultrasound-guided infraclavicular brachial plexus block–a case series

Research article

Is tracheostomy a better choice than translaryngeal intubation for critically ill patients requiring mechanical ventilation for more than 14 days? A comparison of short-term outcomes

Research article

Postoperative delirium assessed by post anesthesia care unit staff utilizing the Nursing Delirium Screening Scale: a prospective observational study of 1000 patients in a single Swiss institution