P-glycoprotein expression is induced in human pancreatic cancer xenografts during treatment with a cell cycle regulator, mimosine.

Abstract

Application of several cell cycle checkpoint regulators seem to be promising in various experimental models including pancreatic cancer, and they are being evaluated in Phase I-II clinical trials. Among these compounds, mimosine, a plant-derived amino acid has shown an antineoplastic effect on human lung or pancreatic cancer xenografts in addition to cell cycle arrest in the late G1 phase. In the present study, immunosuppressed CBA mice bearing subcutaneously growing human ductal pancreatic adenocarcinomas were treated with 30 mg/kg L-mimosine for 34 days. The treatment resulted in retardation of tumor growth, accompanied by a significantly diminished proliferative activity (22.6%+/-1.7% Ki-67 positivity vs. 29.9%+/-1.1% in controls, mean+/-SEM, P<0.007) and an increased apoptotic rate (14.5+/-1.1 apoptotic cells/mm2 vs. 3.8+/-0.4/mm2 in the controls, P<0.0001). The immunohistochemical expression of the multidrug resistance gene (MDR1)-encoded P glycoprotein (p 170) was studied. The parental and the untreated tumors did not express p 170 protein, but in the mimosine-treated samples 30 to 60% of the carcinoma cells displayed a linear, membrane bound positivity. The results indicate that P-glycoprotein is inducible by a cell cycle regulator, creating an acquired resistant phenotype.