Regulation by dexamethasone of P‐glycoprotein expression in cultured rat hepatocytes

Fardel, Olivier; Lecureur, Valérie; Guillouzo, André

doi:10.1016/0014-5793(93)80167-s

Cited by 81 publications

(48 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mrp2 expression was also increased in brain microvessels in the studies by Bauer and colleagues (4). In primary cultures of rat hepatocytes, dexamethasone treatment stimulated decreased expression of P-gp (12,37) and increased expression of Mrp2 (7). In other cell culture studies, dexamethasone was shown to increase transcription of MRP3 in human lung carcinoma A549 cells, whereas it had no effect on transcription of the MRP2 gene (33).…”

Section: Discussionmentioning

confidence: 87%

Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Narang¹,

Fraga²,

Kumar³

et al. 2008

American Journal of Physiology-Cell Physiology

134

103

View full text Add to dashboard Cite

Narang VS, Fraga C, Kumar N, Shen J, Throm S, Stewart CF, Waters CM. Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. Am J Physiol Cell Physiol 295: C440 -C450, 2008. First published June 4, 2008 doi:10.1152/ajpcell.00491.2007.-Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with antineoplastic agents to alleviate pain associated with chemotherapy and reduce intracranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multidrug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with submicromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as breast cancer resistance protein (abcg2), P-glycoprotein (P-gp; abcb1a/abcb1b), and MDR protein 2 (Mrp2; abcc2) as indicted by protein and mRNA levels as well as by functional activity. The effect of dexamethasone on transporter function was significant within 6 h of treatment, was dose dependent, and was reversible. Dexamethasone-induced upregulation of Bcrp and P-gp expression and function was partially abrogated by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the dexamethasone-induced upregulation of Mrp2, suggesting a GR-independent regulation of Mrp2, and a GR-dependent regulation of P-gp and Bcrp. In addition to the dexamethasone-induced upregulation of MDR transporters, we measured a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). Administering dexamethasone to rats caused increased expression of PXR in brain microvessels within 24 h. These results suggest that adjuvant therapy with corticosteroids such as dexamethasone in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR. multidrug resistance proteins; pregnane xenobiotic receptor; breast cancer resistance protein BRAIN TUMORS ACCOUNT for approximately 2-3% of all cancers and approximately 25-30% of solid pediatric tumors (20). Treatment of brain tumors and other central nervous system diseases is limited by the ability of therapeutic drugs to cross the blood-brain barrier (BBB). Beyond the tight physical barrier provided by the endothelial cells, drug penetration is substantially reduced by the presence of multidrug resistance (MDR) efflux transporters of the ATP-binding cassette family (28). Previous in vitro studies have identified functionally active MDR efflux transporters such as P-glycoprotein (P-gp, or abcb1a/abcb1b), breast cancer resistance protein (Bcrp, or abcg2), MDR-associated protein 2 (Mrp2, or abcc2), and Mrp4 (or abcc4) in primary cultures of human, rat, and bovine cerebral endothelial cells (19,26). These transporters...

show abstract

Section: Discussionmentioning

confidence: 87%

Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Narang¹,

Fraga²,

Kumar³

et al. 2008

American Journal of Physiology-Cell Physiology

134

103

View full text Add to dashboard Cite

show abstract

“…48 Similarly, GCs stimulated p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21 WAF1/CIP1 promoter in rat hepatoma cells. 49 Another possibility, not examined in this study, is that DEX may have upregulated some drug-detoxifying factors such as found for metallothionein, [50][51][52] O6-methylguanine-DNA methyltransferase (MGMT), 53-55 P-glycoprotein 56,57 or glutathione, 58 which may have influenced the effectiveness of chemotherapy. 59…”

Section: Effect Of Gcs On Cell Proliferation and Cell Cycle Progressionmentioning

confidence: 99%

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Mattern¹,

Büchler²,

Herr³

2007

Cancer Biology & Therapy

View full text Add to dashboard Cite

ABBrevIAtIons DEX ABstrActGlucocorticoids have been widely used as cotreatment for patients with cancer due to potent pro-apoptotic properties in lymphoid cells, reduction of nausea and diminishing acute toxicity on normal tissue. There are now data from preclinical and, to some extent, clinical studies, demonstrating that these medicaments are highly suspicious to induce therapy resistance in the majority of malignant solid tumors-irrespective of tumor origin and the nature of specific anticancer drugs or irradiation used for treatment. Despite these huge amounts of data, the underlying mechanisms of cell type-specific signaling by these steroid hormones are just beginning to be described. This review summarizes our present understanding of a relationship between glucocorticoid-induced reversible cell cycle arrest and therapy resistance in solid tumors. We give a summary of our current knowledge of decreased proliferation rates in response to glucocorticoid pre and combination treatment which are suspicious to be involved not only in protection of normal tissues, but also in protection of solid tumors from cytotoxic effects of anticancer agents. The inhibition of cell cycle progression by pretreatment with GCs may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.

show abstract

“…The intracellular concentration of doxorubicin was determined as described previously (Fardel et al, 1993).…”

Section: Measurement Of Intracellular Doxorubicin Concentrationmentioning

confidence: 99%

Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232

et al. 1999

View full text Add to dashboard Cite

Clinical resistance to chemotherapeutic drugs is an important problem in the treatment of cancer; the circumvention of resistance has become one of the basic goals of cancer therapy. The most frequent form of primary liver cancer is hepatocellular carcinoma, which is essentially refractory to chemotherapy. We earlier showed that TT-232, a new somatostatin analogue developed in our laboratory, exerted a strong antiproliferative effect both in vitro and in vivo, but no growth hormone release inhibitory or antisecretory activity. Here we report that TT-232 has a pronounced antiproliferative effect on differentiated and dedifferentiated, drug-sensitive and multidrug-resistant hepatocellular carcinoma cell lines. TT-232 induces apoptosis at comparable levels in all these hepatoma variants demonstrating that the multidrug resistance of hepatomas does not correlate with a reduced susceptibility to apoptosis induction. These results clearly reveal that the machinery involved in apoptosis is functional in both drug-sensitive and resistant hepatoma variants and can be activated by the somatostatin analogue TT-232. © 1999 Cancer Research Campaign

show abstract

Regulation by dexamethasone of P‐glycoprotein expression in cultured rat hepatocytes

Cited by 81 publications

References 31 publications

Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232

Contact Info

Product

Resources

About