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Membrane drug transporters and chemoresistance in human pancreatic carcinoma.

Hagmann W, Faissner R, Schnölzer M, Löhr M, Jesnowski R - Cancers (Basel) (2010)

Bottom Line: Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations.In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance.These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Clinical Cooperation Unit of Molecular Gastroenterology, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. w.hagmann@dkfz.de.

ABSTRACT
Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

No MeSH data available.


Related in: MedlinePlus

Gemcitabine cytotoxicity in parental and MRP5-silenced PANC-1 cells. PANC-1 cells containing doxycycline-inducible shRNA targeting MRP5 mRNA (PANC-1/shMRP5 cells) were treated with doxycycline (100 ng/mL; open columns) or vehicle (filled columns) for 6 days and exposed to indicated gemcitabine concentrations for another 6 days before determination of cell viability. Mean values are from triplicate samples; bars indicate SD (adapted from [27]).
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f6-cancers-03-00106: Gemcitabine cytotoxicity in parental and MRP5-silenced PANC-1 cells. PANC-1 cells containing doxycycline-inducible shRNA targeting MRP5 mRNA (PANC-1/shMRP5 cells) were treated with doxycycline (100 ng/mL; open columns) or vehicle (filled columns) for 6 days and exposed to indicated gemcitabine concentrations for another 6 days before determination of cell viability. Mean values are from triplicate samples; bars indicate SD (adapted from [27]).

Mentions: Various chemotherapy regimens using gemcitabine together with other drugs have been developed, some combining gemcitabine with 5-FU and resulting in improved benefit [81-83]. In addition, studies with human pancreatic cancer cells in vitro [39] or in a murine xenograft model [84] showed a better therapeutic effect when 5-FU was administered before gemcitabine. Furthermore, chemotherapeutic drug treatment of cells can alter the expression of nucleoside and ABC transporters [39,85], and drug export via MRP transporters contributes to cellular resistance against various chemotherapeutic compounds [23,25,26,28,30-32]. Indeed, gemcitabine alone or in combination with 5-FU treatment has been demonstrated to alter the expression of various MRPs, but also of uptake transporters of the CNT and ENT families [27]: While 5-FU or gemcitabine alone also elicited the enhanced expression of MRP5 and ENT1 mRNA, this upregulation was highest in all investigated pancreatic cancer cells after combined drug administration and was most prominent in Capan-1 and PANC-1 cells, with MRP5 increasing 33-fold, and ENT1 increasing 52-fold in Capan-1 cells [27]. Interestingly, the expression of the nucleoside transporter CNT3 increased more than 100-fold in 5-FU/gemcitabine-treated Capan-1 cells [27]. In addition, MRP5 had been suggested to affect chemoresistance against gemcitabine [32,86], and this role of MRP5 in chemoresistance, which we earlier demonstrated for 5-FU [23], is evident also from results obtained with stably MRP5-silenced pancreatic cancer cells. In these experiments, MRP5 mRNA expression was down to about 50% of controls as determined by QRT-PCR, and the cells possessed a markedly increased sensitivity to gemcitabine (Figure 6) [27].


Membrane drug transporters and chemoresistance in human pancreatic carcinoma.

Hagmann W, Faissner R, Schnölzer M, Löhr M, Jesnowski R - Cancers (Basel) (2010)

Gemcitabine cytotoxicity in parental and MRP5-silenced PANC-1 cells. PANC-1 cells containing doxycycline-inducible shRNA targeting MRP5 mRNA (PANC-1/shMRP5 cells) were treated with doxycycline (100 ng/mL; open columns) or vehicle (filled columns) for 6 days and exposed to indicated gemcitabine concentrations for another 6 days before determination of cell viability. Mean values are from triplicate samples; bars indicate SD (adapted from [27]).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756352&req=5

f6-cancers-03-00106: Gemcitabine cytotoxicity in parental and MRP5-silenced PANC-1 cells. PANC-1 cells containing doxycycline-inducible shRNA targeting MRP5 mRNA (PANC-1/shMRP5 cells) were treated with doxycycline (100 ng/mL; open columns) or vehicle (filled columns) for 6 days and exposed to indicated gemcitabine concentrations for another 6 days before determination of cell viability. Mean values are from triplicate samples; bars indicate SD (adapted from [27]).
Mentions: Various chemotherapy regimens using gemcitabine together with other drugs have been developed, some combining gemcitabine with 5-FU and resulting in improved benefit [81-83]. In addition, studies with human pancreatic cancer cells in vitro [39] or in a murine xenograft model [84] showed a better therapeutic effect when 5-FU was administered before gemcitabine. Furthermore, chemotherapeutic drug treatment of cells can alter the expression of nucleoside and ABC transporters [39,85], and drug export via MRP transporters contributes to cellular resistance against various chemotherapeutic compounds [23,25,26,28,30-32]. Indeed, gemcitabine alone or in combination with 5-FU treatment has been demonstrated to alter the expression of various MRPs, but also of uptake transporters of the CNT and ENT families [27]: While 5-FU or gemcitabine alone also elicited the enhanced expression of MRP5 and ENT1 mRNA, this upregulation was highest in all investigated pancreatic cancer cells after combined drug administration and was most prominent in Capan-1 and PANC-1 cells, with MRP5 increasing 33-fold, and ENT1 increasing 52-fold in Capan-1 cells [27]. Interestingly, the expression of the nucleoside transporter CNT3 increased more than 100-fold in 5-FU/gemcitabine-treated Capan-1 cells [27]. In addition, MRP5 had been suggested to affect chemoresistance against gemcitabine [32,86], and this role of MRP5 in chemoresistance, which we earlier demonstrated for 5-FU [23], is evident also from results obtained with stably MRP5-silenced pancreatic cancer cells. In these experiments, MRP5 mRNA expression was down to about 50% of controls as determined by QRT-PCR, and the cells possessed a markedly increased sensitivity to gemcitabine (Figure 6) [27].

Bottom Line: Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations.In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance.These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Clinical Cooperation Unit of Molecular Gastroenterology, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. w.hagmann@dkfz.de.

ABSTRACT
Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.

No MeSH data available.


Related in: MedlinePlus