Synergistic effects of deuterium oxide and gemcitabine in human pancreatic cancer cell lines

• Published in: Cancer letters 2008-02, Vol.259 (2), p.231-239
• Main Authors: Bader, Yvonne, Hartmann, Johannes, Horvath, Zsuzsanna, Saiko, Philipp, Grusch, Michael, Madlener, Sibylle, Maier, Susanne, Oehler, Leopold, Fritzer-Szekeres, Monika, Heller, Nicole, Alken, Rudolf-Giesbert, Krupitza, Georg, Szekeres, Thomas
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; AsPC-1; Bone marrow; Bone Marrow Cells - drug effects; BxPC-3; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Colonies & territories; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Deuterium oxide (D 2O); Deuterium Oxide - pharmacology; Deuterium Oxide - therapeutic use; Dose-Response Relationship, Drug; Drug Synergism; Experiments; Gemcitabine (dFdC); Hematology, Oncology and Palliative Medicine; Hematopoietic Stem Cells - drug effects; Humans; Inhibitory Concentration 50; Neoplastic Stem Cells - drug effects; PANC-1; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Standard deviation; Studies; Tumor Stem Cell Assay
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2007.10.010

Abstract Purpose Pancreatic cancer still remains a treatment-refractory cancer. Standard therapy for metastatic cancer is gemcitabine (dFdC) chemotherapy. Since heavy water (deuterium oxide, D2 O) was shown to be active in pancreatic cancer in vitro , we examined the simultaneous or sequential cytotoxic effects of D2 O and dFdC in pancreatic cancer cell lines (AsPC-1, BxPC-3, and PANC-1). Moreover, we investigated the effect of D2 O treatment on the colony formation of peripheral blood mononuclear cells (PBMNC) as well as the apoptosis inducing activity of D2 O and dFdC and the regulation of tumor suppressor gene p21. Results Simultaneous incubation of human pancreatic carcinoma cells with D2 O and dFdC led to a decrease of IC50 values of dFdC alone in all cell lines examined. Sequential application of D2 O and dFdC caused synergistic effects. Treatment with 10–30% D2 O did not show any significant inhibition effects on the colony formation of peripheral blood mononuclear cells (PBMNC), indicating limited adverse effects of D2 O on bone marrow cells. Treatment with D2 O in combination with dFdC significantly ( p < 0.05) increased the induction of apoptosis in PANC-1 and AsPC-1 cells and led to an overexpression of p21 tumor suppressor gene compared to incubation with dFdC alone. As the combination of D2 O and dFdC might offer an additional option for the control of pancreatic cancer, this treatment should be investigated in a pancreas carcinoma animal model in order to scrutinize the in vitro data.