The Multidrug Resistance‐associated Protein Gene Confers Drug Resistance in Human Gastric and Colon Cancers

Abstract

To determine the expression of multidrug resistance‐associated protein (MRP) gene and its role in gastric and colon cancers, we analyzed 10 gastric and 10 colon non‐drug‐selected cell lines and a similar number of tissue samples of these cancers. We compared the expression of MRP and mdr1 mRNA in cell lines and tissues using reverse‐transcriptase polymerase chain reaction. In mdr1‐negative cells, the relationship between the level of MRP gene expression and sensitivity to anticancer drugs was examined. The effect of verapamil, an MRP‐modulating agent, was also examined in these cells. The expression of MRP gene in gastric cancer cell lines varied from a low to a high level, but mdr1 was not detected in any of these cell lines. Colon cancer cell lines expressed low to intermediate levels of MRP gene, and half of the cells co‐expressed low to high levels of mdr1. In tissue samples, the expression pattern of the two multidrug resistance (MDR) genes was broadly similar to that described for the cell lines, except that most of the gastric cancer tissue samples did express low levels of mdr1. No significant correlation was observed between the level of MRP gene expression and sensitivity to anticancer drugs in gastric and colon cell lines. However, verapamil significantly increased the sensitivity to etoposide, doxorubicin and vincristine in cells highly expressing MRP gene. Our results indicate that MRP gene may be important in conferring MDR in gastric and colon cancer cells.

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

“…The high level of PGP in intestine and the fact that PGP inhibitors exhibit signi®cant cross-reactivity with other transporters confounds such studies in normal tissues. For example, both verapamil and quinidine have been shown to interact with MRP transporters (Tomonaga et al, 1996;Makhey et al, 1998;Vezmar & Georges, 2000). Recent studies have implicated non-PGP, non-MRP transporters as possible limiting factors for intestinal permeability (Soldner et al, 2000;Jonker et al, 2000) and there is a growing awareness that our understanding of the drug e ux systems present in the intestine is far from complete.…”

Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells

“…The two main forms of MDR are intrinsic resistance, in which the previously untreated cancer cells are inherently insensitive to chemotherapeutic drugs, and acquired resistance, in which the cancer cells become insensitive as a result of chemotherapy (11,12). The most commonly reported mechanism for the acquisition of resistance to a broad range of anticancer drugs is the expression of one or more energy-dependent transporters, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), lung resistance protein (LRP) and breast cancer resistance protein (BCRP/MXR/ABCG2) (12)(13)(14)(15)(16)(17)(18)(19). These transporters mediate drug efflux from tumor cells and may further cause cross-resistance to multiple drugs with diverse chemical structures and curative efficacies.…”

Multidrug Resistance P-Glycoprotein Is Not Involved in Cholesterol Esterification

“…Unfortunately, verapamil and progesterone show fairly poor specificity toward MDR1 when used at high concentrations. For instance, progesterone inhibits ACAT (17) and verapamil has been described as a weak inhibitor of another transporter protein related to MDR1, called MRP1 (18,19) and reduces cell glutathione content (20). Both MDR1 and MRP1 are involved in the chemoresistance of cancer cells and in the transport of xenobiotics (13,21).…”