Institut de Génomique Fonctionnelle

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1 Institut de Génomique Fonctionnelle
Inserm Institut national de la santé et de la recherche médicale Régulation de l’expression des enzymes du métabolisme des médicaments par les xénorécepteurs CAR et PXR et conséquences physiopathologiques. Jean Marc Pascussi Institut de Génomique Fonctionnelle Inserm U661, Montpellier

2 Xenobiotics: foreign chemicals
Inhaled Pollutants Industrial chemicals Pesticides Toxins produced by molds, plants and animals Drugs Ingested absorbed

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5 Les xénorécepteurs, sentinelles moléculaires de l’immunité métabolique
PXR Phase I Phase II métabolisme élimination AhR Phase III transporteurs CAR 5

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7 Different strategies for activating transcription factors

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10 Nuclear Hormone Receptors superfamily

11 The Nuclear Receptor Gene superfamily

12 Nuclear receptors

13 General scheme for activation of gene transcription by NRs
The paradigm … Robyr, Wolffe, Wahli Mol. Endocrinol 2000

14 Les xénorécepteurs CAR et PXR
Expression Organes de la détoxication: foie (hépatocytes) et tracus digestif (entérocytes) CAR PXR

15 CAR and PXR coordinate the “metabolic immunity” in response to xenochemicals or endogenous activators CAR and PXR are 2 master xenobiotic receptors that regulate the expression of genes involved in xenobiotic and drug metabolism and clearance. In silico screening have identified putative PXR/ RXR binding sites in the regulatory regions of f281 genes involved in encoding drug-metabolizing enzymes and 97 genes involved in encoding drug transporters

16 Nuclear Receptor PXR (NR1I2) … the master xenosensor

17 Nuclear receptor CAR (NR1I3)
Xenosensor CAR exhibits many similarities with PXR. They are both members of the same subfamily (NR1I), form heterodimers with RXR, bind to same response elements and are expressed in the same tissues. However there are several difference between PXR and CAR. First, many CAR activators such as phenobarbital and bilirubin are not ligands, but trigger the nuclear translocation of the receptor. Second, CAR has a potent constitutive activity in the absence of ligand. This is due to the fact that LBD-AF2 domain of the protein interacts with various coactivators including SRC-1 and the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) in a ligand-independent manner. Third, inactivated CAR is cytosolic in differentiated cells such as hepatocytes. Finally, CAR may be de-activated by inverse agonists such as androstane or clotrimazole (for hCAR).

18 (d’après Handschin C & Meyer UA. Pharmacol Rev, 2003; 55, 649-73)
Schéma de l’hétérodimère CAR-RXR ou PXR-RXR en présence de leurs ligands et différentes organisations des HREs. L’annotation x correspond au nombre de nucléotides entre les deux motifs (d’après Handschin C & Meyer UA. Pharmacol Rev, 2003; 55, ) CAR ou PXR RXR Acide rétinoïque 9-cis Ligand Gène cible

19 Les xénorécepteurs CAR et PXR partagent les mêmes NRE
2B6 3A4 2B6 3A4

20 CAR and PXR regulate the bodies 'garbage-disposal system.'
Phase 0 OATP2 Uptake Phase I CYP2A,2B,3A Carboxylesterases Phase II GST SULT2 UGT1A PAPSSP2 Solubilisation Phase III Transport MDR1A,1B MRP3… excretion

21 Les xénorécepteurs CAR et PXR
Ligands/activateurs PXR (Polygamic Xenobiotic Receptor ?) Médicaments: Antibiotiques (rifampicine,etc.)‏ Glucocorticoides, RU486, PCN Antifongiques (clotrimazole)‏ Anticancéreux (paclitaxel, codermolide, ixabepilone, tamoxifene, cyclophosphamide)‏ Inhibiteur de protéases virales (amprenavir, ritonavir)‏ Inhibiteurs des pompes à protons (Benzimidazoles)‏ Bloqueurs des canaux calciques (nifedipine)‏ Alimentation/Phytothérapie: Mille pertuis gluglustérone b-carotène Ginko Biloba Pesticides Contaminants environnementaux CAR Médicaments: Clotrimazole (agoniste inverse)‏ Phenobarbital, phénytoïne Phytothérapies: Artémise Pesticides CITCO (agoniste)‏ rifampicine phénobarbital CITCO g.mol-1 437 g.mol-1 823 g.mol-1

22 Watkins et al. Science 2001; Chrencik et al. Mol Endocrinol 2005
hPXR LBD crystal structure (2.6 A resolution) Large and flexible ligand-binding pocket Presence of 2 additional strands of b-sheet Hydrophobic ligand-binding pocket Can accommodates a single hydrophobic ligand in multiple conformation Absence of a highly constrained pocket allows for molecular flexibility and plasticity in ligand recognition Bound ligand= SR12813 Watkins et al. Science 2001; Chrencik et al. Mol Endocrinol 2005 22

23 Plasticity in the PXR Binding Pocket
SR12813 hyperforin 1280 Å 1544 Å Receptor Volume of ligand pocket (A3) ER 476 VDR 871 PXR CAR 1120

24 hCAR/RXR LBD heterodimer crystal structure
(2.6 A resolution) RXR CAR Bound ligand: CITCO SRC-1 peptide Vol= A Xu et al. Mol Cell 2004

25 CAR activators provoke CAR nuclear translocation
CAR-GFP in human hepatocytes In vivo in mice NT PB CITCO

26 Mécanismes d’activation des xénorécepteurs CAR et PXR
Citco AMPc/AMP AICAR OA CAR AMPK LKB1 Thr-38 PB ? PP2A CAR cofactors Thr-38-P CCRP PKC CAR PXR RXR HSP PXR RIF cytoplasme noyau 26

27 Complementary roles of CAR and PXR toward xenobiotics recognition ?
PXR, CAR

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30 Species differences in CAR and PXR activation

31 Variation in LBD consistent with in vivo species differences in response to inducers
(CYP3A1 DR3)2-tk-CAT

32 CAR and PXR humanized mice
Wolf et al. J Clin Invest. 2008

33 Ying and Yang of CAR and PXR
Xenosensors that protect the body from a multitude of foreign chemicals (xenobiotics) and endogenous toxic compounds xenobiotic RXR CAR/PXR Drug-drug and food-drug interactions Interindividual variability in drug response Endocrine disruption VitD3, T3 and lipids metabolism

34 Major Cytochrome P450s involved in the metabolism of
clinically used drugs ... ... are PXR and CAR target genes

35 Nuclear receptor Activating drugs
CAR and PXR are activated by widely used drugs and top selling phytochemicals Nuclear receptor Activating drugs PXR amprenavir, avasimibe, bosentan, carbamazepine, ciglitazone, clotrimazole, cortisone, corticosterone, cyclophosphamide, dexamethasone, efavirenz, exemestane, hydrocortisone, hyperforin, lovastatin, mifepristone, nelfinavir, nifedipine, omeprazole, paclitaxel, phenobarbital, phenytoin, rifabutin, rifampicin, ritonavir, simvastatin, spironolactone, tamoxifen, 4-hydroxytamoxifen, troglitazone, troleandomycin, St John’s wort, Kava, Sophora flavescens CAR CITCO, phenobarbital, phenytoin Garlic, Ginkgo

36 CAR and PXR xenosensors are involved in drug-drug interactions
CYPs CYP enzymes XeR RXR Drug A OH Drug B Inactivation activation

37 Xenosensors and drug-drug interactions
«Fatal paracetamol poisoning in an epileptic (phenytoin)» Minton et al Hum Toxicol «Loss of analgesic effect of morphine due to coadministration of rifampin » Fromm et al Pain

38 Xenosensors and diet-drug interactions
«Profound drop of cyclosporin A whole blood through levels caused by St. John’s wort (Hypericum perforatum)» Breidenbach et al Transplantation

39 Role of CAR and PXR in drugs-induced osteomalacia and osteopenia ?
«Rifampicin induced osteomalacia» Shah et al Tubercle «Calcium metabolism during rifampicin and isoniazid therapy for tuberculosis» Brodie et al J R Soc Med. «Osteomalacia associated with carbamazepine/valproate» Karaaslan et al Ann Pharmacother «Antiretroviral therapy and the prevalence of osteopenia and osteoporosis : a meta-analytic review» Brown et al AIDS.

40 Déficits en vitamine D et ostéomalacies consécutives à la prise prolongée de médicaments… sur la piste de CAR et PXR 25(OH)D3 1,25(OH)D3 1,24,25(OH)D3 (inactive) 7 déhydroxycholestérol CYP27A1 CYP27B1 CYP24A1 VDR RXR PXR RXR VDR RXR RXR CAR CYP3A4 (DR3, ER6) CYP2B6 (DR4) CYP2C9 (DR4) SULT2A1 (IR0) NRE Thummel et al. Mol Pharm 2001 Drocourt et al. J Biol Chem 2002 Echchgadda et al. Mol Pharmacol 2004

41 Les activateurs de CAR et PXR augmentent l’expression et l'activité de la CYP24 dans l’hépatocyte humain Pascussi , 2005, JCI Lambert 2008 TAP

42 CYP24 : nouveau gène cible de CAR et PXR

43 CAR et PXR transactivent les VDREs du gène CYP24
Konno 2008 Mol. Pharmacology HepG2 HuH7 HuH7

44 The VDR-PXR cross-talk
CYP3A4 CYP24 XeR Drocourt 2002 JBC, Xu 2006 Mol P, Pascussi 2005 JCI, Moreau 2007 BBRC, K onno 2008 MP, Lambert 2008 TAP

45 CAR, PXR et la stéatose hépatique non alcoolique induite par certains
médicaments. Rifampicine traitement contre la tuberculose Stéatose hépatique Morere 1975 Sem Hop Carbamazepine traitement antiépileptique Stéatose hépatique Oscarson 2006 CPT Phenobarbital Stéatose hépatique Calandre 1991 ANS Nifedipine traitement contre l’hypertension Stéatose hépatique Babary 1989 J Hep Nakamura 2007 JBC

46 Culture primaire d’hépatocytes humains
Etudes comparatives de transcriptomes d’hépatocytes humains ... sur la piste d’un acteur peu connu de la lipogénese : Spot14 Culture primaire d’hépatocytes humains Extraction ARN Traitements (8 & 40h): DMSO 0.1% Phénobarbital (0.5mM) Rifampicine (10M) CITCO (100nM) Protocole double couleur - ARN de cultures traitées - ARN de référence Spot14, THRSP (Chr. 11q13.5/14.1) 143AA, 17kDa, Pi=4.75

47 Les activateurs de PXR augmentent l’expression de Spot14 dans
l’hépatocyte humain. 5 10 15 20 25 30 Actin CYP3A4 CYP2B6 S14 CTRL Rif 0,3 (PXR) Rif 3 (PXR) Rif 30 (PXR) SR12813 (PXR) PAX (LXR) T09 (PXR + LXR) T3 (T3R) FT285 mRNA fold induction

48 Spot14 est un gène cible de PXR
SFN

49 L’élément TRE de promoteur du gène Spot14 est nécessaire à l’action de CAR et PXR

50 Les activateurs de PXR augmentent l’expression de la FASN dans
l’hépatocyte humain.

51 L’expression de Spot14 est nécessaire à l’induction de la FASN par PXR

52 L’activation de PXR provoque une accumulation d’acides gras
dans l’hépatocyte humain. Analyses lipidomiques: Quantification des acides gras dans les hépatocytes humains chromatographie liquide à ultra haute performance (UPLC) et spectrométrie de masse (Q-TRAP) +/- RIF (72h) nmoles/g protéines nmoles/g protéines

53 L’activation de PXR provoque une augmentation de la lipogenèse de novo
Michel Beylot INSERM ERI22 Mesure de la lipogenèse de novo : Quantification de l’incorporation de deutérium dans C16:0 par chromatographie en phase gazeuse et spectrométrie de masse +/- RIF (72h) Palmitate IE MPE 3% D2O (6h)

54 Ectopic overexpression of S14 increases lipogenesis in HepaRG cells
De novo lipogenesis FG12 hS14 Palmitate IE MPE 27mM Glucose FG12 hS14 FG12 6mM Glucose FA quantifications

55 En conclusion: L’activation des xénorécepteurs induit une forte perturbation du métabolisme lipidique provoquant une accumulation des acides gras et des triglycérides hépatiques.

56 Role of CAR and PXR in interindividual variability in response to cancer therapy ?
XS Narrow therapeutic index Toxicity Efficacy The clinical efficacy of anticancer therapy is severely limited by an inability to accurately predict outcome for the patient in terms of both tumor response and toxicity. The lack of prediction is of even greater clinical significance with these agents given their narrow therapeutic index. Drug metabolizing and transporters play a key role in the activation and inactivation of cytotoxics and can therefore influence the suceptibility of organs and tissues to their therapeutic or toxic effects. These genes are subject to significant inter-and intra-individual variability displaying both genetic polymorphism and inducibility. CAR and PXR regulate the expression of many important drug-metabolizing enzyme and transporters.

57 CAR and PXR regulate genes involved in biotransformation and clearance of widely used anticancer drugs CYP2A6 cyclophosphamide, ifosmamide, flutamine, tegafur CYP2B6 altretamine, cyclophosphamide, ifosmamide, tomoxifen CYP2C8 cyclophosphamide, docetaxel, ifosmamide, paclitaxel, tegafur, tretinoin CYP3A4/5 Bexarotene, busulfan, cisplatin, cyclophosphamide, cytarabine, dexamethasone, docetaxel, doxorubicin, erlotinib, etoposide, exemestane, flutamide,fulvestrant, gefitinib, ifosfamide, imatinib, irinotecan, letrozole, medroxyprogresterone acetate, mitoxantrone, paclitaxel, tamoxifen, targretin, teniposide, topotecan, toremifene, tretinoin, vinblastine, vincristine, vindesine, vinorelbine UGT doxorubicine, epirubicin, etoposide, irinotecan, topotecan, tamoxifen SULT tamoxifen GST busulfan, chlorambucil, cyclophosphamide, doxorubicin, ifosphamide, melphalan, nitrosurea MRP1 Arsenic trioxide, chlorambucil, daunorubicin, doxorubicin, epirubicin, etoposide, melphalan, methotrexate, mitoxantrone, paclitaxel, vinblastine, vincristine MRP2 Cisplatin, irinotecan doxorubicin, etoposide, methotrexate, SN-38, vinblastine, vincristine MRP3 Carboplatin, cisplatin, doxorubicin, epirubicin, etoposide, methotrexate, teniposide, vinblastine, vincristine BCRP Imatinib, methotrexate, mitoxantrone, SN-38, topotecan

58 Role of CAR and PXR in pharmacokinetic drug-drug interaction in oncology, some examples
Rifampicin Phenytoin Decrease cyclophosphamide and increase 4-hydroxyclyclophosphamide plasma concentrations phenobarbital Severe toxicity Therapeutic escape and risk of relapse. As shown in this slide, several CAR and PXR activators affect the pharmacokinetics of concomitantly administrad chemotherapeutic agents, leading either to and enhancement of toxicity or inhibition of toxicity For instance, activators of CAR and PXR have been shown to decrease to level of the prodrug cyclophospamide (CYP2, CYP3) and increase the plasma concentration of its active metabolite (4-hydroxycyclophosphamide), potentially leading to severa systemic toxicity. In contrast CAR and PXR activators decrease plasma concentration of irinotecan and its active metabolite SN38. The clinical consequences of these observations are far reaching, as low systemic exposure to anticancer drugs, as a result of increased clearance, has an adverse effect on the efficacy of chemotherapy and has been associated with an increased risk of relapse. Rifampicin Phenobarbital Phenytoin Decrease CPT11 & SN38 and increase SN38-G plasma concentrations St John’s wort rifampicin Increases of erlotinib clearance and reduces the AUC by 66¨%

59 Role of CAR and PXR in cyclophosphamide activation
phenytoin phenytoin Enzyme induction might also lead to toxicities, when the metabolizing enzymes are involved in the bioactivation of anticancer pro-drugs, such as the oxazaphosphorines cyclophosphamide and isofosfamide. These agents are subject to 4-hydroxylation by CYP2B6 and CYP3A4 leading to the formation of clinically active phosporamid moiety. Primary hepatocyte culture waxman In a recent case report, a patient with germ-cell cancer showed a significant strong decrease of cyclophosphamide and an increase of plasma level of its cytotoxic metabolite 4-OH cyclophosphamide in presence of phenytoin ( a CAR activator). the patient received phenytoin because of an epileptic seizure that developed 3 weeks after the first CTC course. Five days before the start of the second CTC course, the patient started with twice daily 150 mg phenytoin orally. The plasma exposure to cyclophosphamide decreased by 67% upon co-administration of phenytoin with concomitant increase in 4- hydroxycyclophosphamide AUC of 51%. The maximum concentration of 4- hydroxycyclophosphamide was 600% higher when phenytoin was co-administered. The cyclophosphamide dose was reduced from 2,835 mg day1 to 1,500 mg day De Jonge, Cancer Chemother Pharmacol. 2005 Chang, Yu, Maurel, Waxman. Cancer Res., 1997

60 Role of CAR and PXR on peripheral metabolism of irinotecan (Campto ®)
May be the best characterized example of CAR and PXR mediated interaction Irinotecan is a camptothecin derivative that result in DNA damage on interaction with topoisomerase I. It is used in the treatment of metastatic carcinoma of the colon or rectum. It is a prodrug that undergoes hydrolysis by carboxyesterase I and 2 to form the pharmacologically active compound SN38. SN38 can then be inactivated through glucuronidation by UGTs.

61 CAR and PXR are expressed in several neoplastic human tissues
Neuroblastoma (PXR) Misawa , Cancer Res, 2005 Endomedrial cancer cells (PXR) Masuyama, Mol. Pharm., 2007 Hepatocarcinoma (CAR, PXR) Huang , Mol Endocrinol, 2005 Pascussi Hepatology 2007 Intestinal & colon cancer cells (CAR, PXR) Jiang, J Gastrointest Surg, 2009 Raynal, Mol.Cancer, 2010 Ouyang, Br J Cancer, 2010 Breast tissues (PXR) Dotzlaw, 1999 Miki, Cancer Res, 2006 Lung cancer cells (PXR) Miki, Mol Cell Endocrinol, 2005 Ovarian cancer tissues (PXR) Gupta, Human Cnacer Biology , 2008 Osteosarcoma (PXR) Mensah-Osman, Cancer, 2007 Prostate cancer cells (PXR) Chen, Cancer res., 2008 While CAR and PXR expression in normal tissues seems to be restricted to the detoxication organs such as liver, GI and renal epithelia, it seems that these xenoreceptors are expression in

62 Expression of PXR in Human Breast Carcinoma
LCM/RT-PCR (C) carcinoma cells (S) stromal cells PXR OATP-A PXR was detected in carcinoma tissues but not in nonneoplastic and stromal cells of breast tumors. A significant positive correlation was detected between the SXR/hPXR labeling index and both the histologic grade and the lymph node status of the carcinoma cases. Furthermore, in estrogen receptor–positive cases, hPXR expression was also positively correlated with expression of the cell proliferation marker, Ki-67. Microarray analysis showed that organic anion transporting polypeptide-A (OATP-A) was most closely correlated with SXR/hPXR gene expression, and both OATP-A mRNA and protein were significantly associated with SXR/hPXR in both breast carcinoma tissues and its cell lines. Miki et al, Cancer Res 2006; 66: (1). January 1, 2006

63 PXR expression in normal and cancerous human prostate tissues
Immunohistochemical evaluation of PXR expression in normal and cancerous human prostate tissues. A, micrographies of representative tissue samples from normal prostate tissue and prostate adenocarcinomas. Brown or dark brown, PXR staining; blue, nucleus staining with hemotoxylin; arrows, strong immunoreactivities of PXR in the basal area of the normal gland (normal) and in the nuclei of cancer cells (cancer). panoramic micrographies of PXR immunoreactivities in normal prostate tissue or tissues with different degrees of malignancy. Brown or dark brown, PXR staining; blue, nucleus staining with hemotoxylin. Original magnifications: 40× (left) and 100× (right). Chen Y et al., Cancer Res 2007;67:

64 Increased chemoresistance in PC-3 cells by PXR agonist, SR12813.
CTRL 0.2 μM SR12813 1 μM SR12813 Increased chemoresistance in PC-3 cells by PXR agonist, SR Cells were cultured in RPMI 1640 containing 5% FBS and treated with 0 μmol/L (DMSO, ○), 0.2 μmol/L (▪), or 1 μmol/L (▴) SR12813 for 12 h followed by the 72-h treatment of Taxol (A) or vinblastine (B). Chen Y et al., Cancer Res 2007;67:

65 Increased chemosensitivity of PC-3 cells with PXR expression knocked down
RT-PCR analysis of the mRNA level of PXR in wild-type or PXR non-knockdown PC-3 cells or PXR knockdown PC-3 cells. immunocytochemical staining of hPXR in wild-type or PXR non-knockdown PC-3 cells or PXR knockdown PC-3 cells. reduced promoter activities of PXR in PC-3 cells with PXR expression knocked down. sensitivity of wild-type and PXR knockdown PC-3 cells to vinblastine (0.3 μmol/L) or Taxol (0.1 μmol/L), treated with chemotherapeutics for 72 h and then the cell viability was measured by MTT Chen Y et al., Cancer Res 2007;67:

66 Increased chemosensitivity of endothelial HEC-1cells with PXR expression knocked down
Masuyama, Mol. Pharm., 2007

67 Increased chemoresistance in ovarian carcinoma cells by PXR agonist
SKOV-3 D. Gupta et al. Human cancer Biology, 2008

68 Role of CAR and PXR in intra-tumoral metabolism of irinotecan ?
Systemic drug clearance Cancer cells ?

69 PXR expression in normal and cancerous human colon tissues
Raynal C. et al. Mol. Cancer Res 2010

70 PXR expression level restricts SN38 chemosensibility in colon cancer cells
LS174T SW620

71 PXR expression level restricts SN38 chemosensibility in colon cancer cells

72 PXR expression level enhances SN38 glucuronidation in colon cancer cells
Intracellular metabolites profiles (HPLC

73 PXR increases UGT1As-mediated SN38 inactivation in colon cancer cells
(cytotoxic metabolite) PXR UGT1As SN38-G (inactive metabolite)

74 SN38 SN38-G CAR/PXR UGT1A1 SN38 SN38-G (cytotoxic metabolite)
(inactive metabolite)

75 Role of CAR and PXR in intra-tumoral metabolism of cyclophosphamide ?
Pro-drug activation Cancer cells ?

76 PXR regulates ALDH1A1 gene expression and Aldefluor® activity

77 CAR and PXR may increase cancer cell resistance to 4-OH-CPA while promoting severe toxicity
Hepatic cells Cancer cells

78 chemotherapy-resistance and poor clinical outcome
Aldefluor®-positive cells are associated with cancer initiation properties, chemotherapy-resistance and poor clinical outcome

79 Aldehyde Dehydrogenase 1 is a marker for normal and
malignant human colonic stem cells and have tumor initiating properties CD44 ALDH1 Nuclei

80 Aldefluor®-positive Colorectal cancer stem cells are enriched
in xenogeneic tumors following chemotherapy

81 8181 Aldefluor®-positive cells display higher expression of PXR and PXR target genes PXR ALDH1A1 ABCG2 CYP3A4 OCT4 LGR5 CD26 BMI1 NANOG PXR

82 Aldefluor®-positive cells display enhanced clonogenic,
sphere forming activity and magnétorésistance * Nb sphere / 100 cells ALDHlow ALDHbr Soft-agar (1000 cells) – 3 weeks

83 PXR knock-down decreases chemoresistance of Aldefluor®-positive cells
siRNA (sibGAL / siPXR) 100nM Cell viability (ATP content)

84 PXR knock-down decreases xenogeneic tumor recurrence
Tumor formation Treatment response Relapse Folfiri: 50mg/kg 5-FU 30mg/kg irinotecan ONCO TALK - 29/01/2013

85 PXR knock-down decreases Aldefluor®-positive cells enrichment
and tumor initiating activity after cytotoxics treatment cells 3D FOLFIRI Tumor cells dissociation reinjection 1500 cells

86 CSCs are believed to be spared from most anticancer therapies, such as chemotherapy. Inhibitors of survival pathways, along with differentiation-inducing agents, immune cells, and cytotoxic chemotherapeutics, might be used to destroy CSCs and induce complete tumor regression 8686 PXR inhibition as a new strategy for Chemoresistant and Tumor Initiating Cells (CTIC) re-sensitization to conventional therapies ? Conventional therapy PXR inhibition & conventional therapy

87 Les xénorécepteurs CAR et PXR
Gènes Cibles Enzymes et transpoteurs majeurs de la fonction de détoxication entérohépatique OATP2 CYP3A4,5,7 CYP2B6 CYP2C8,9 CYP1A2 UGT1A1,6,9 GSTs SULT2A1 MDR1 MRP2-4

88 Interactions croisées
avec d’autres voies cellulaires Perturbations endocriniennes - Vitamine D Perturbations métaboliques - Lipides CAR/PXR - Hépatite fulminante - HCC Adduit Transporteurs Métabolites CYP450 Transférases Xénobiotique inactif Molécule thérapeutique actif Interactions médicamenteuses

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91 Conclusion Cells and organisms are able to increase and adapt their capacity of detoxication in response to some xenobiotics and drugs Nuclear receptors PXR and CAR play a major part in this process by controlling a network of signaling pathways that regulate the expression of specific batteries of genes involved in the detoxication machinery Because 1) many endocrine hormones are metabolised by CAR and PXR target genes, and 2) they interfere with other signalling pathways, chronic activation of these NRs (drugs, industrial or natural contaminants) could alter endocrine physiology and disease promotion. According to their role as masters xenobiotic responsive receptors linking DME genes expression to environment stimuli, CAR and PXR might contribute to the well-known intra- and inter-subject variability in anticancer drugs response. Environmental and genetic factors affecting CAR or PXR (expression or activation levels) may affect the cytotoxic threshold of tumor cells to chemotherapy which can consequently mask or attenuate pharmacogenetic associations.