Regulation of Multidrug Resistance by Pro-Inflammatory Cytokines

Ho, Emmanuel A.; Piquette-Miller, Micheline

doi:10.2174/156800906777441753

Cited by 84 publications

(54 citation statements)

References 123 publications

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“…Currently, there is convincing evidence that disease processes (e.g., inflammation) can influence the expression of multiple hepatic ABC transporters, including P-glycoprotein (McRae et al, 2003;Ho and Piquette-Miller, 2006). At the blood-brain barrier emerging evidence shows that P-glycoprotein expression is also changed during disease, e.g., in epilepsy and stroke (see below).…”

Section: A In the Peripherymentioning

confidence: 99%

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Miller

Bauer²,

Hartz³

2008

Pharmacol Rev

337

275

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Section: A In the Peripherymentioning

confidence: 99%

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Miller

Bauer²,

Hartz³

2008

Pharmacol Rev

337

275

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“…For instance, acute renal and acute hepatic failure (Murakami et al, 2002), as well as local and systemic inflammatory reactions (Ho and Piquette-Miller, 2006), reduces the expression of P-glycoprotein.…”

mentioning

confidence: 99%

Animal Models of Acute Moderate Hypoxia Are Associated with a Down-Regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and Up-Regulation of CYP3A6 and P-glycoprotein in Liver

Fradette¹,

Batonga²,

Teng³

et al. 2007

Drug Metab Dispos

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ABSTRACT:In humans, indirect evidence suggests that hypoxia reduces the rate of biotransformation of drugs cleared by cytochrome P450 (P450) subfamilies CYP1A, 2B, and 2C. The aim of this study was to assess whether acute moderate hypoxia modulates the expression of CYP2B4, 2C5, and 2C16 in vivo, and to determine whether the changes in hepatic P450 are conveyed by serum mediators. Moreover, because hypoxia increases the expression of P-glycoprotein in vitro, we examined whether in vivo acute moderate hypoxia modulates the expression of several membrane transporters in the liver. Rabbits and rats were exposed to a fractional concentration of oxygen of 8% for 48 h to generate a stable arterial partial pressure of O 2 of 34 ؎ 1 mm Hg. Compared with rabbits breathing room air, hypoxia in rabbits reduced the amount of CYP1A1, 1A2, 2B4, 2C5, and 2C16 proteins and increased the expression of CYP3A6. Sera of rabbits with hypoxia were fractionated by size exclusion chromatography, the fractions were tested for their ability to modify the expression of P450 isoforms, and serum mediators were identified through neutralization experiments. The serum mediators responsible for the downregulation of P450 isoforms were interferon-␥, interleukin-1␤ (IL-1␤), and IL-2. In vivo, in rats, hypoxia increased the mRNA and protein expression of P-glycoprotein but did not affect the mRNA of breast cancer resistance protein and organic anion-transporting polypeptide 2. It is concluded that in vivo, hypoxia down-regulates rabbit hepatic CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulates CYP3A6. CYP3A11 and P-glycoprotein were up-regulated in the livers of hypoxic rats.In patients with cardiorespiratory diseases, acute hypoxemia appears to reduce the ability of cytochrome P450 isoforms to catalyze the biotransformation of xenobiotics. Patients with pulmonary insufficiency who show an impairment of their general state present an increased incidence of adverse effects, e.g., grand mal seizures, associated with the administration of "usual" doses of theophylline. Theophylline clearance is significantly reduced in patients with acute cardiogenic pulmonary edema (Piafsky et al., 1977) and in patients with worsening airway obstruction, severe bronchial obstruction, congestive heart failure, and pneumonia (Vozeh et al., 1978).In humans, at therapeutic concentrations, the biotransformation of theophylline is primarily catalyzed by CYP1A2, whereas CYP2D6, 2E1, and 3A4 exhibit low affinity and variable capacity (Ha et al., 1995). Rabbits exposed to a fractional concentration of inspired O 2 (FiO 2 ) of 10% for 24 h demonstrate a reduced clearance of theophylline and decreased expression of CYP1A1 and 1A2, although the expression of CYP3A6 is increased (Kurdi et al., 1999). In rabbits subjected to acute moderate hypoxia, hepatic down-regulation of CYP1A1 and 1A2 is triggered by serum mediators, e.g., interferon-␥ (IFN-␥), interleukin 2 (IL-2), and IL-1␤; the up-regulation of CYP3A6 is, at least in part, associated with erythropoietin (Epo) (Fradette et ...

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“…Our findings suggest that protein-mediated MDR in paediatric STS is a complex phenomenon that deserves further investigation in order to better understand how the expression of MDR proteins might predict tumour response to chemotherapeutic agents and, consequently the prognosis of the disease. Furthermore, approaches aimed at overcoming drug resistance of tumour cells through down-regulation of MDR proteins with small interfering RNA and pro-inflammatory cytokines (39,40) could be explored in the future and lead to the development of novel treatment strategies of paediatric STS.…”

Section: Discussionmentioning

confidence: 99%

Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

et al. 2012

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Abstract. Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/ clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/ PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.

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Regulation of Multidrug Resistance by Pro-Inflammatory Cytokines

Cited by 84 publications

References 123 publications

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Animal Models of Acute Moderate Hypoxia Are Associated with a Down-Regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and Up-Regulation of CYP3A6 and P-glycoprotein in Liver

Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

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