Ist durch eine hochselektive Cyclooxigenase-2-Inhibition mit Parecoxib eine Induktion der Apoptose und Nekrotisierung beim Pankreaskarzinom möglich? Does the high-selective Cyclooxygenase-2-Inhibitior Parecoxib induce apoptosis and necrosis in pancreatic cancer?

Background: Cyclooxygenase-2 (COX-2) is directly linked to carcinogenesis and frequently overexpressed in pancreatic cancer. Since non-steroidal anti-inflammatory drugs (NSAID) are supposed to have antiproliferative and antineoplastic effects, they also might be suitable in the complex treatment of rapidly progressing pancreatic cancer. Thus we investigated the impact of COX-2 inhibitor Parecoxib (PC) on induction of apoptosis and necrosis in pancreatic cancer cells. Methods: 3 different cell lines (BxPC-3, DSL6AC1 and MIAPaCa-2) were exposed to different doses (20–3000 μg) of Parecoxib. Apoptosis was triggered by DNA topoisomerase I inhibitor Camptothecin. Activation of caspases was analysed by fluorochrome-labeled inhibitor (FLICA) method, while plasma membrane integrity was determined by flow cytometry excluding propidium iodide. Results: Parecoxib caused dose-dependent reduction of number of vital tumor cells in BxPC-3 pancreatic cancer cells (100 μg PC: 73.86 %; 1000 μg PC: 18.13 %; 3000 μg PC: 2.42 %). Furthermore we observed a linear decrease of vital DSL6A/C1- (100 μg PC: 61.03 %; 1000 μg PC: 12.80 %; 3000 μg PC: 0.21 %) and MIAPaCa-2cells (100 μg PC: 75.46 %; 1000 μg PC: 27.49 %; 3000 μg PC: 2.78 %) by Parecoxib. The decrease of tumor cells was caused by induction of necrosis by low-dose Parecoxib therapy, while apoptosis was induced by high-dose of Parecoxib (3000 μg). Conclusion: Treatment with COX-2 inhibitor Parecoxib significantly decreased number of vital tumor cells of all three pancreatic cancer cell lines in dose dependent manner. This was caused by induction of apoptosis by high-dose therapy while necrosis was caused by low-dose therapy with Parecoxib. Einleitung Das Enzym Cyclooxigenase-2 (COX-2) ist unmittelbar in die Karzinogenese beim Pankreaskarzinom involviert und im Pankreaskarzinom haufig uberexpremiert. Da nicht-steroidale anti-inflammatorische Medikamente (NSAID) antiproliferative und antineoplastische Wirkungen haben, konnten sie auch fur die Therapie schnell wachsender Karzinome geeignet sein. Daher haben wir den Einfluss des COX-2-Inhibitors Parecoxib auf die Induktion der Apoptose und Nekrose beim Pankreaskarzinom evaluiert. Methodik