0. Multi Drug Resistance (MDR)

Author: Gianpiero Pescarmona
Date: 29/05/2009



in Bacteria

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C-reactive protein inhibits cholesterol efflux from human macrophage-derived foam cells. 2008

Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. 2007

Mol Genet Metab. 2011 Jan;102(1):91-8. Epub 2010 Sep 19.
Functional analysis of genetic variations in the 5'-flanking region of the human MDR1 gene. 2011

  • P-glycoprotein (P-gp), the product of the MDR1 gene, shows large interindividual variations in expression, which leads to differences in the pharmacokinetics of the substrate drugs. The functions of single nucleotide polymorphisms located in the nuclear receptor-responsive element of the 5'-flanking region in the human MDR1 gene were analyzed in order to clarify the mechanism underlying the interindividual variation in P-gp expression. Electrophoretic mobility shift assays revealed that the -7833C>T substitution in the nuclear receptor-responsive region of MDR1 decreases the binding affinities of four nuclear receptors to their responsive elements: * vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR)* . A reporter gene assay revealed that the C-to-T substitution at -7833 also reduces the transcriptional activation of MDR1 by VDR, TRβ, CAR, and PXR. However, another SNP (-1211T>C substitution), which results in the formation of a xenobiotic responsive element-like sequence and a hypoxia responsive element-like sequence, failed to affect the aryl hydrocarbon receptor-dependent and hypoxia-induced transcriptional a ctivation of MDR1. Although the frequency of the -7833C>T substitution in MDR1 is relatively low, the SNP is crucial because it may alter the pharmacokinetics of P-gp substrates in a small subset of the population.

Clin Pharmacol Ther. 2010 Nov;88(5):685-94. Epub 2010 Sep 15.
The impact of thyroid disease on the regulation, expression, and function of ABCB1 (MDR1/P glycoprotein) and consequences for the disposition of digoxin. 2010

  • The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56 cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein.

Lanthionine synthetase components C-like 2 increases cellular sensitivity to adriamycin by decreasing the expression of P-glycoprotein through a transcription-mediated mechanism. 2003

Although the coincidental amplification and accompanying overexpression of bystander genes that neighbor oncogene targets occur frequently during the development of human tumors, little has been done to investigate the functional or biological consequences of amplified bystander gene overexpression. LANCL2 (LANC-like 2) is a bystander gene that is coamplified and overexpressed with epidermal growth factor receptor in approximately 20% of all glioblastomas. This gene has also been designated as Testis Adriamycin Sensitivity Protein because it is most highly expressed in testis and its expression has been noted to increase cellular sensitivity to Adriamycin. Because of the latter association, we have examined potential relationships between LANCL2 and the expression of multidrug-resistance (MDR)1, as well as its cognate protein, P-glycoprotein (P-gp), because elevated expression of P-gp is known to increase cell resistance to many cytotoxic drugs, including Adriamycin. Using the Dx5 derivative of MES-SA cells in which P-gp is overexpressed, we show that the level of endogenous P-gp decreases with increased expression of exogenous LanCl-2 and that cells with reduced P-gp show increased sensitivity to Adriamycin. Results from reverse transcription-PCR and MDR1 promoter activity analyses suggest that LanCl-2 transcriptionally suppresses MDR1, and this interpretation of LanCl-2 function is consistent with results from immunofluorescence analysis, which shows that LanCl-2 resides in the nucleus, as well as at the plasma membrane. With respect to this study, our data indicate that LanCl-2 increases cellular sensitivity to Adriamycin by decreasing the expression of P-gp, but more generally, these results indicate that the identification of bystander gene amplification in human tumors can have clinical implications.

Ruolo della PgP. Tesi Ivana Campia 2007

2009-07-01T19:17:43 - CINZIA BOFFA

Multidrug resistance describes the phenomenon of simultaneous resistance to unrelated drugs (Multidrug resistance: molecular mechanisms and clinical relevance. 1997).
Multidrug resistance is the major obstacle limiting the effectiveness of chemotherapy in clinical; it depends on a variety of pharmacokinetic factors including tumor microenvironment and tumor cell specific. The drug resistance due to cell-specific factors may occur for various reasons:

  1. increased efflux or decreased influx of the drug;
  2. increased inactivation or decreased activation;
  3. changes in quality and quantitative of its targets;
  4. increased repair of DNA damage induced by drug;
  5. escape by apoptotic processes.

The drug resistance can be divided into (Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. 2008):

  1. "intrinsic": when the tumor cells are proving resistant to drug treatment;
  2. "acquired": when cells become insensitive after a period more or less short therapy.

Biochemical mechanisms through which the cell acts to reduce the damaging effects of chemotherapy are:

  1. impaired transport through the membrane with the consequent decrease of drugs or increase their output (Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. 2006);
  2. altered expression of target enzymes and proteins such as topoisomerase I;
  3. modified activation or degradation of the drug;
  4. increase of DNA repair;
  5. failure of the physiological mechanism of the apoptosis.

Two forms of MDR have been identified:

  1. Classical MDR and non-classical MDR (not Pgp MDR) (Human multidrug resistance ABCB and ABCG transporters: participation in a chemioimmunity defense system. 2006) characterized by a carrier-mediated transport of drugs with lack of specificity of substrate that causes a decrease capacity in accumulation of chemotherapeutics in cancer cells; classical MDR is expressed by P-glycoprotein (Pgp, P-170 or Pd-170), non-Pgp MDR by multidrug-resistance-associated protein (MRP).
  2. Atypical MDR (atypical MDR or at-MDR, altered topoisomerase) caused by failure of the training stable ternary complex DNA topoisomerase II-drug, due to qualitative and quantitative changes of the enzyme topoisomerase II (Multidrug resistance. 1988).

Boffa-Fazzone (II°anno Patologia Clinica) 18/06/09

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