Because of the different effects of medications given in the context of anesthesia and postoperative pain therapy of pancreatic carcinoma, such as ketamine, sketamine, metamizole, and paracetamol but also sufentanil, ropicavaine, and lidocaine, the administration of such medications requires careful consideration. The purpose of this study was to use drug concentrations in clinically achievable dosages to facilitate the transfer of experimental data to clinical practice.
As an NMDA receptor antagonist, ketamine in narcotic dosages causes profound analgesia; thus, this drug is not only successfully used for the management of cancer pain and opioid-refractory pain but also in preventive pain therapy [12,13]. Plasma concentrations achievable in clinical settings range between 0.1 and 0.42µg/ml (≈2.3–9.5µM) [14]. The main impact of ketamine and s-ketamine is based on the non-competitive blockade of the NMDA receptor complex. In the process, ketamine as well as its race mate s-ketamine bind to the binding site of phencyclidine (PCP) inside the NMDA channel, thus inhibiting the effect of NMDA antagonists [15]. This process results in the inhibition of the intracellular calcium concentration and in the inactivation of Ca2+-dependent cytosolic guanylate cyclase [16]. Several studies have described the influx of calcium into the cell as a key trigger factor or a regulator of cellular processes relevant to tumor progression including proliferation and apoptosis [17]. Interestingly, 24h and 48h stimulation with ketamine and s-ketamine initially reduced NFAT transcription factors in the nucleus of pancreatic carcinoma cells PaTu8988t; at the same time, stimulation with ketamine increased NFATc2 in cytoplasm.
In dormant inactive cells, NFATc2 proteins are present in the cytoplasm in a phosphorylated form. The proteins have only a low affinity for DNA [18] and are activated by stimulation with FCS. The resulting intracellular increase in calcium activates the protein serine/threonine phosphatase calcineurin, which can thus bind to the PxIxIT motifs located at the N-terminal of NFAT proteins. This way, NFAT proteins are dephosphorylated on 13 serine residues [19]. Due to the resulting conformational change, NFAT proteins are translocated into the nucleus and bind to specific DNA-binding sequences (GGAAA) [20]. NFAT proteins eventually interact with other transcription factors and exert their carcinogenic effect [21]. Both 24h and 48h stimulation with ketamine or s-ketamine seem to be able to inhibit this protein activation cascade. NFAT translocate into cytoplasm in a dormant stage, and cell proliferation decreases after stimulation for 48h.
The pyrazolone derivative metamizole (dipyrone) and the aminophenol derivative paracetamol (acetaminophen) are non-acidic, non-opioid analgesics [22,23]. The administration of these drugs is a key element of the WHO’s cancer pain ladder [24] and an important part of postoperative analgesia [25]. Oral administration of 1g metamizole results in a maximum plasma concentration of 17.3+/–7.5mg/l (≈50–75µM metamizole) and the intravenous injection of 1g paracetamol in a plasma concentration of 95+/–36µM [26,27]. According to the literature, metamizole and paracetamol primarily inhibit cyclooxygenase activity (COX), thus influencing prostaglandin synthesis as the central regulator of inflammation and inhibiting the transformation of arachidonic acid into endoperoxide, the preliminary stage of prostaglandin, thromboxane A2, and prostacyclin [28,29].
In this study, cell proliferation in PaTu8988t pancreatic carcinoma cells was inhibited by the administration of metamizole. Paracetamol had already shown a slight but significant anti-proliferative effect also in PaTu8988t and Panc–1 pancreatic carcinoma cells in an earlier study [30]. Stimulation with metamizole and paracetamol did not change the level of expression of NFATc2 or Sp1.
Recent study results have shown that COX–2 inhibitors increase Sp1 protein degradation [31]. Tolfenaminic acid is a non-steroidal anti-inflammatory drug (NSAID) that additionally activates the degradation of Sp1, Sp3, and Sp4 and decreases the expression of several Spregulated growth-promoting, angiogenic, survival, and inflammatory gene products [32]. These characteristics are of particular significance given the long existing assumption that Sp1 expression is a key factor in tumor development, growth, and metastasis. In some types of cancers, Sp1 overexpression is associated with poor survival [33].
Ropivacaine and lidocaine are amide local anesthetics [34] that block the voltage-gated sodium channels of neuronal axons. Here, the local anesthetic binds to the inside of the inactivated sodium channel, thus impeding the fast sodium influx into the cell that is important for depolarization [35]. The conduction of stimuli in the nerve is inhibited, thus stopping the transmission of pain [36]. Several studies have shown that plasma concentrations of 0.61–4µg/ml (≈1.6–10.9µM) are achievable with ropivacaine and 1–5µg/ml (≈2.3–11.5µM) with lidocaine. [37,38]. In peridural anesthesia, ropivacaine is often combined with the opioid sufentanil [39]. As a pure agonist, sufentanil binds to the opioid receptors of the nervous system [40] and has been proven to improve the quality of analgesia. In peridural anesthesia, the addition of opioids to local anesthetics results in a faster onset of effects and reduces the dosage of the individual drugs [41]. Plasma concentrations achievable with sufentanil are 0.40+/–0.14ng/ml (≈1.5nM) [42]. This phenomenon can also be observed in the case of intravenous injections of lidocaine in large abdominal surgical interventions in contrast to singular general anesthesia. The reduction in peri- and postoperative pain significantly decreases the requirement of anesthetics and opioid analgesics [43]. In our study, the administration of lidocaine decreased proliferation after 48h, but ropivacaine, sufentanil, and lidocaine had no effect on the expression of the transcription factors NFATc2 and Sp1 in pancreatic carcinoma cells.