Influence of clinically relevant chemotherapeutics on the expression of multidrug-resistance family members in human pancreatic carcinoma cell lines
Sven Eisold1, Dirk Nauheimer2, Jan Schmidt2, Thomas Giese3, Ernst Klar1, Michael Linnebacher1; 1Surgery, University of Rostock, Rostock, Germany; 2Surgery, University of Heidelberg, Heidelberg, Germany; 3Immunology, University of Heidelberg, Heidelberg, Germany
Treatment of pancreatic carcinomas by chemotherapy in an adjuvant, neoadjuvant or palliative setting is often impeded by an intrinsic multidrug resistance (MDR) of these tumor cells. An important mechanism causing the MDR phenotype is the ATP-dependent export of drugs across the plasma membrane mediated by transporters of the P-glycoprotein family (ABCB) or of the multidrug resistance related protein (MRP) family (ABCC). To elucidate the contribution of ABCB and ABCC family members for the MDR phenotype of pancreatic carcinomas, we analyzed the mRNA expression of MDR-1, MDR-3, MRP1, MRP3 and MRP5, which have been shown before to confer resistance to chemotherapeutic drugs in several tumor entities. Quantitative RT-PCR expression analyses of 10 human pancreatic carcinoma cell lines were performed with and without in vitro chemotherapy (14 to 28 days) including gemcitabine, 5-fluorouracil, cisplatin or a combination of 5-fluorouracil with cisplatin. MDR1 and MDR3 mRNA expression was detectable in all cell lines but not significantly influenced by chemotherapeutic treatment. In the untreated pancreatic cell lines Pan-1, KCI-MOH-1, Mia-PaCa-2, PK-1, PK-8, PK-9 and ASPC-1, these analyses demonstrated high base line levels of MRP5 > MRP3 > MRP1, whereas Patu 8902, HupT4 und Fampac expressed only marginal amounts of these mRNA transkripts. Under chemotherapeutic treatment, all tested cell lines showed a significant upregulation of MRP3 > MRP1 > MRP5. Expression levels were influenced (in falling order of upregulating potency) by 5-fluorouracil and cisplatin in combination, 5-fluorouracil, cisplatin and gemcitabine. These data suggest that MRP1, MRP3 and MRP5 are likely to be involved in the multidrug resistance phenotype often seen in pancreatic carcinomas. The majority of pancreatic carcinoma cells expresses high levels of MRPs even without prior chemotherapeutic treatment. Quantification of MRP expression levels may be helpful to guide therapy decisions and to predict individual tumors responses towards chemotherapeutic treatment. Our finding of a minor MRP upregulating capacity of gemcitabine may be an explanation for the significantly better outcome of pancreatic carcinoma patients treated with gemcitabine. Eventually, the treated cell lines may be a valuable tool for future analyses of the pancreatic carcinoma MDR phenotype and its therapeutic reversal.
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