Membrane Drug Transporters and Chemoresistance in Human Pancreatic Carcinoma

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.

Failure of Pancreatic Cancer Chemotherapy: Consequences of Drug Resistance Mechanisms

“…The expression levels of the enzyme DCK determines the patient survival and the sensitivity of a tumor to gemcitabine (Hagmann, et al, 2010a;Plunkett, et al, 1995). HuR is a RNAbinding protein that modulates the translation of DCK mRNA and multiple other protooncogenic proteins in cancer cells (Williams, et al, 2010).…”

“…Evidences in support of the role of MRP3, MRP4 and MRP5 in the efflux of etoposide, 5FU and gemcitabine suggest that these MRP's are directly linked with the resistance phenotype (Hagmann, et al, 2010a;Hagmann, et al, 2010b). Transcriptional regulation of MRP's by nuclear factor like 2 protein (Nrf2) is an important target to overcome resistance because overexpression of Nrf2 is associated with increased resistance of cells towards chemotherapy-induced cell death (Hagmann, et al, 2010a).…”

Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells

“…The alteration of influx and efflux protein expression may lead to a significant reduction in the intracellular concentration of chemotherapeutic agents, which ultimately results in poor response to treatment and development of multiple drug resistance (MDR) against several structurally unrelated anticancer agents (13)(14)(15)(16)(17)(18). Gemcitabine is taken up into the cells by various concentrative nucleoside transporter (CNT) and equilibrative nucleoside transporter (ENT) isoforms (19)(20)(21). In human pancreatic adenocarcinoma cells including capan-2 cells, the expression of members of the CNT family is negligible (19)(20)(21)(22)(23).…”

“…Gemcitabine is taken up into the cells by various concentrative nucleoside transporter (CNT) and equilibrative nucleoside transporter (ENT) isoforms (19)(20)(21). In human pancreatic adenocarcinoma cells including capan-2 cells, the expression of members of the CNT family is negligible (19)(20)(21)(22)(23). Therefore, gemcitabine is mostly taken up via the hENT1 transporter, a member of the equilibrative nucleoside transporter efflux proteins family, which is abundantly expressed.…”

“…Additionally, it has been reported that the sensitivity of pancreatic cancer cell lines to gemcitabine is significantly influenced by MRP5 (ABCC5) efflux protein (20,24) and to a lesser extent by MRP1 (ABCC1) (25) and P-gp (ABCB1) (25,26). Therefore, chemicals that can modulate expression of influx and efflux proteins have the potential to substantially alter therapeutic outcomes of chemotherapy.…”