Involvement of the Multidrug Resistance Protein 3 in Drug Sensitivity and Its Expression in Human Glioma

Abstract

The multidrug resistance protein (MRP) family belongs to the ATP-binding cassette superfamily (ABC) of transporters, which are involved in ATP-dependent transport of hydrophobic compounds. One of the MRP family, MRP1, is partially associated with the multidrug resistance phenotype in brain tumors. In this study, we asked whether another MRP family gene, MRP3, could affect drug sensitivity to anticancer agents in human glioma cell lines and clinical glioma specimens. We first produced two antisense transfectants by introduction of antisense MRP3 cDNA into the glioma cell line NHG2, which endogenously expresses MRP3. The two MRP3 antisense transfectants showed 2-to 5-fold increases in drug sensitivity to etoposide and cisplatin compared with NHG2 cells, but their sensitivity to vincristine or nitrosourea was not changed. Two MRP3 cDNA sense transfectants of pig kidney cell lines showed 4-to 6-fold drug resistance to etoposide, but only 1.4-to 1.5-fold to cisplatin. We next compared the mRNA levels of four ABC transporters, multidrug resistance 1 (MDR1), MRP1, MRP2 and MRP3 in clinical samples, including 34 patients with gliomas, by quantitative RT-PCR analysis. In some of the clinical samples, increased expression of MRP1 and MRP3 was apparent in malignant gliomas. In situ hybridization revealed that glioma cells were stained with MRP3 probe. MRP3 may modulate drug sensitivity to certain anticancer agents in human gliomas.

Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

“…The apparent induction of MRP1 protein expression noted in late-stage tumors would seem to support this notion; i.e., 90% of tumor cells showed positive MRP1 staining in glioblastoma multiform (grade IV) versus less than 10% staining in grade II oligodendrogliomas (Benyahia et al, 2004). Likewise, significant up-regulation of MRP1 and MRP3 has also been demonstrated in malignant gliomas (anaplastic astrocytomas and glioblastomas), compared with epileptic control tissue or low-grade astrocytomas (Haga et al, 2001;Spiegl-Kreinecker et al, 2002). Interestingly, at least one immunohistochemical study failed to detect significant amounts of MRP3 protein in human glioma samples, despite the presence of high MRP3 gene levels (Bronger et al, 2005).…”

“…Mohri et al (2000) observed both MRP1 mRNA and protein expression in 50 and 90% of chemotherapy-naive grade III anaplastic astrocytomas and grade IV glioblastomas, respectively (see Kleihues et al, 1993, for a review of the World Health Organization tumor classification system). Expression of MRP1 in low-grade astrocytomas has not been consistently observed, suggesting that MRP1 expression in grade II gliomas is probably near the detection limit of the assays used (Abe et al, 1998;Mohri et al, 2000;Haga et al, 2001). The apparent induction of MRP1 protein expression noted in late-stage tumors would seem to support this notion; i.e., 90% of tumor cells showed positive MRP1 staining in glioblastoma multiform (grade IV) versus less than 10% staining in grade II oligodendrogliomas (Benyahia et al, 2004).…”

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

“…In our study, we observed that combined treatment of glioma cells with chemotherapy drug TMZ and CDK6 shRNA significantly inhibited cell growth, which is more effective than single treatment either with TMZ or CDK6 shRNA. The mechanism underlying chemotherapy-resistance of glioma has been intensively studied (18,19,21,22). Many drugresistant genes have been found, which mainly belongs to DNA repair enzymes, small-molecule transmembrane transporters and drug metabolism proteins.…”

The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

“…al. (55) investigated the expression level of members of the MRP family. They found no difference in the expression level of P-glycoprotein and MRP2 between normal brain and malignant glioma cells.…”