Effect of glucose transport inhibitors on vincristine efflux in multidrug-resistant murine erythroleukaemia cells overexpressing the multidrug resistance-associated protein (MRP) and two glucose transport proteins, GLUT1 and GLUT3

Abstract

SummaryThe relationship between mammalian facilitative glucose transport proteins (GLUT) and multidrug resistance was examined in two vincristine (VCR)-selected murine erythroleukaemia (MEL) PC4 cell lines. GLUT proteins, GLUT1 and GLUT3, were constitutively coexpressed in the parental cell line and also in the VCR-selected cell lines. Increased expression of the GLUT1 isoform was noted both in the PC-V40 (a non-P-glycoprotein, mrp-overexpressing subline) and in the more resistant PC-V160 (overexpressing mrp and mdr3) cell lines.Overexpression of GLUT3 was detected only in the PC-V160 subline. An increased rate of facilitative glucose transport (Vmu) and level of plasma membrane GLUT protein expression paralleled increased VCR resistance, active VCR efflux and decreased VCR steady-state accumulation in these cell lines. Glucose transport inhibitors (GTIs), cytochalasin B (CB) and phloretin blocked the active efflux and decreased steady-state accumulation of VCR in the PC-V40 subline. GTIs did not significantly affect VCR accumulation in the parental or PC-V160 cells. A comparison of protein sequences among GLUT1, GLUT3 and MRP revealed a putative cytochalasin B binding site in MRP, which displayed 44% sequence similarity/12% identity with that previously identified in GLUT1 and GLUT3; these regions also exhibited a similar hydropathy plot pattern. The findings suggested that CB bound to MRP and directly or indirectly lowered VCR efflux and/or CB bound to one or both GLUT proteins, which acted to lower the VCR efflux mediated by MRP. This is the first report of a non-neuronal murine cell line that expressed GLUT3.

<b>VEGF secretion by adipose tissue-derived regenerative cells is impaired under hyperglycemic conditions via glucose transporter activation and ROS incr</b><b>ease </b>

“…Next, the rate of glucose uptake by ADRCs was examined in the absence and presence of the glucose transporter inhibitor phloretin under normoglycemic and hyperglycemic conditions. Phloretin has been reported to equally inhibit GLUT1, 3 and 4 (8,12,20). Phloretin significantly decreased the rate of glucose uptake by ADRCs even under hyperglycemic conditions (Fig.…”

Differential Expression of Facilitative Glucose Transporter (GLUT) Genes in Primary Lung Cancers and Their Liver Metastases

“…25) Further, Martell et al suggested that the expression level and rate of increase of GLUT paralleled increased vincristine resistance, active vincristine efflux, and decreased vincristine accumulation in murine erythroleukemia cell lines, and that GLUT inhibitors bound to multidrug-resistance-associated protein or to GLUT proteins directly or indirectly overcame drug resistance mediated by multidrug-resistance-associated protein. 26) Similarly, Vera et al suggested that GLUT plays an important role in the modulation of multidrug resistance. 27) Based on these reports, we consider that GLUT inhibitors will play an important role in cancer therapy in the future, because they may directly induce apoptosis or indirectly produce therapeutic benefits in addition to conventional chemotherapy agents by overcoming drug resistance.…”

Expression of glucose transporter 1 is associated with loss of heterozygosity of chromosome 1p in oligodendroglial tumors WHO grade II

“…The difficulty of up-regulating GLUT-1 could lead to cellular glucose scarcity especially in malignant transformation with hypoxia and therefore represents a prognostically favorable feature (Blum et al 2005;Nishioka et al 1992). In hypoxic breast and colon cancer inhibition of GLUT-1 led to improved chemosensitivity for daunorubicin (Cao et al 2007) and in an erythroblastoma cell line GLUT-1 even effects efflux of vincristine (Martell et al 1997). Further, GLUT-1 is linked to a shortened disease free survival in ovarian carcinoma (Cantuaria et al 2001), which parallels the knowledge of gliomas harboring LOH 1p (Cairncross et al 1998).…”