Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 2, pp 217–227 | Cite as

Role of pregnane X receptor in chemotherapeutic treatment

  • Wei Zhuo
  • Lei Hu
  • Jinfeng Lv
  • Hongbing Wang
  • Honghao Zhou
  • Lan FanEmail author
Review Article


Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that differently expresses not only in human normal tissues but also in numerous types of human cancers. PXR can be activated by many endogenous substances and exogenous chemicals, and thus affects chemotherapeutic effects and intervenes drug–drug interactions by regulating its target genes involving drug metabolism and transportation, cell proliferation and apoptosis, and modulating endobiotic homeostasis. Tissue and context-specific regulation of PXR contributes to diverse effects in the treatment for numerous cancers. Genetic variants of PXR lead to intra- and inter-individual differences in the expression and inducibility of PXR, resulting in different responses to chemotherapy in PXR-positive cancers. The purpose of this review is to summarize and discuss the role of PXR in the metabolism and clearance of anticancer drugs. It is also expected that this review will provide insights into PXR-mediated enhancement for chemotherapeutic treatment, prediction of drug–drug interactions and personalized medicine.


PXR Pharmacogenomics Chemotherapeutic drugs Metabolism 


  1. 1.
    Blumberg B, Kang H, Bolado J Jr, Chen H, Craig AG, Moreno TA, Umesono K, Perlmann T, De Robertis EM, Evans RM (1998) BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Genes Dev 12:1269–1277PubMedCentralPubMedGoogle Scholar
  2. 2.
    Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205PubMedCentralPubMedGoogle Scholar
  3. 3.
    Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterström RH, Perlmann T, Lehmann JM (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82PubMedGoogle Scholar
  4. 4.
    Nishimura M, Naito S, Yokoi T (2004) Tissue-specific mRNA expression profiles of human nuclear receptor subfamilies. Drug Metab Pharmacokinet 19:135–149PubMedGoogle Scholar
  5. 5.
    Pondugula SR, Mani S (2013) Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response. Cancer Lett 328:1–9PubMedCentralPubMedGoogle Scholar
  6. 6.
    Hu M, Fan L, Zhou HH, Tomlinson B (2012) Theranostics meets traditional Chinese medicine: rational prediction of drug-herb interactions. Expert Rev Mol Diagn 12:815–830PubMedGoogle Scholar
  7. 7.
    Zhang B, Xie W, Krasowski MD (2008) PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics 9:1695–1709PubMedCentralPubMedGoogle Scholar
  8. 8.
    Orans J, Teotico DG, Redinbo MR (2005) The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 19:2891–2900PubMedGoogle Scholar
  9. 9.
    Squires EJ, Sueyoshi T, Negishi M (2004) Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem 279:49307–49314PubMedGoogle Scholar
  10. 10.
    Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L (1996) Nuclear receptor coactivators and corepressors. Mol Endocrinol 10:1167–1177PubMedGoogle Scholar
  11. 11.
    Chen Y, Nie D (2009) Pregnane X receptor and its potential role in drug resistance in cancer treatment. Recent Pat Anticancer Drug Discov 4:19–27PubMedGoogle Scholar
  12. 12.
    McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344PubMedGoogle Scholar
  13. 13.
    Zhou C, Verma S, Blumberg B (2009) The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl Recept Signal 7:e001PubMedCentralPubMedGoogle Scholar
  14. 14.
    Chai X, Zeng S, Xie W (2013) Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert Opin Drug Metab Toxicol 9:253–266PubMedGoogle Scholar
  15. 15.
    Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D (2012) Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol 83:1112–1126PubMedCentralPubMedGoogle Scholar
  16. 16.
    Rosenfeld JM, Vargas R Jr, Xie W, Evans RM (2003) Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol Endocrinol 17:1268–1282PubMedGoogle Scholar
  17. 17.
    Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646PubMedGoogle Scholar
  18. 18.
    Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, Evans RM (2003) Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 100:4150–4155PubMedCentralPubMedGoogle Scholar
  19. 19.
    Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T, Ishida T, Ohuchi N, Blumberg B, Sasano H (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66:535–542PubMedGoogle Scholar
  20. 20.
    Guzelian J, Barwick JL, Hunter L, Phang TL, Quattrochi LC, Guzelian PS (2006) Identification of genes controlled by the pregnane X receptor by microarray analysis of mRNAs from pregnenolone 16alpha-carbonitrile-treated rats. Toxicol Sci 94:379–387PubMedCentralPubMedGoogle Scholar
  21. 21.
    Cheng J, Shah YM, Gonzalez FJ (2012) Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci 33:323–330PubMedCentralPubMedGoogle Scholar
  22. 22.
    Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y (2007) Down-regulation of pregnane X receptor contributes to cell growth inhibition and apoptosis by anticancer agents in endometrial cancer cells. Mol Pharmacol 72:1045–1053PubMedGoogle Scholar
  23. 23.
    Zucchini N, de Sousa G, Bailly-Maitre B, Gugenheim J, Bars R, Lemaire G, Rahmani R (2005) Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes. Biochim Biophys Acta 1745:48–58PubMedGoogle Scholar
  24. 24.
    Gupta D, Venkatesh M, Wang H, Kim S, Sinz M, Goldberg GL, Whitney K, Longley C, Mani S (2008) Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer. Clin Cancer Res 14:5332–5340PubMedGoogle Scholar
  25. 25.
    Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR Jr, Schuetz EG, Boguski MS (2001) The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11:555–572PubMedGoogle Scholar
  26. 26.
    King CR, Xiao M, Yu J, Minton MR, Addleman NJ, Van Booven DJ, Kwok PY, McLeod HL, Marsh S (2007) Identification of NR1I2 genetic variation using resequencing. Eur J Clin Pharmacol 63:547–554PubMedGoogle Scholar
  27. 27.
    Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E (2008) Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos 36:169–181PubMedGoogle Scholar
  28. 28.
    Koyano S, Kurose K, Ozawa S, Saeki M, Nakajima Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Nakajima T, Saito H, Kimura H, Goto Y, Saitoh O, Katoh M, Ohnuma T, Kawai M, Sugai K, Ohtsuki T, Suzuki C, Minami N, Saito Y, Sawada J (2002) Eleven novel single nucleotide polymorphisms in the NR1I2 (PXR) gene, four of which induce non-synonymous amino acid alterations. Drug Metab Pharmacokinet 17:561–565PubMedGoogle Scholar
  29. 29.
    Koyano S, Kurose K, Saito Y, Ozawa S, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Nakajima T, Matsumoto K, Akasawa A, Saito H, Sawada J (2004) Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region. Drug Metab Dispos 32:149–154PubMedGoogle Scholar
  30. 30.
    Lim YP, Liu CH, Shyu LJ, Huang JD (2005) Functional characterization of a novel polymorphism of pregnane X receptor, Q158 K, in Chinese subjects. Pharmacogenet Genomics 15:337–341PubMedGoogle Scholar
  31. 31.
    Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O (2001) Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 29:1454–1459PubMedGoogle Scholar
  32. 32.
    Uno Y, Sakamoto Y, Yoshida K, Hasegawa T, Hasegawa Y, Koshino T, Inoue I (2003) Characterization of six base pair deletion in the putative HNF1-binding site of human PXR promoter. J Hum Genet 48:594–597PubMedGoogle Scholar
  33. 33.
    Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, Schuetz EG (2004) PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol 199:251–265PubMedGoogle Scholar
  34. 34.
    Keightley MC (1998) Steroid receptor isoforms: exception or rule? Mol Cell Endocrinol 137:1–5PubMedGoogle Scholar
  35. 35.
    Gardner-Stephen D, Heydel JM, Goyal A, Lu Y, Xie W, Lindblom T, Mackenzie P, Radominska-Pandya A (2004) Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression. Drug Metab Dispos 32:340–347PubMedCentralPubMedGoogle Scholar
  36. 36.
    Fukuen S, Fukuda T, Matsuda H, Sumida A, Yamamoto I, Inaba T, Azuma J (2002) Identification of the novel splicing variants for the hPXR in human livers. Biochem Biophys Res Commun 298:433–438PubMedGoogle Scholar
  37. 37.
    Mensah-Osman EJ, Thomas DG, Tabb MM, Larios JM, Hughes DP, Giordano TJ, Lizyness ML, Rae JM, Blumberg B, Hollenberg PF, Baker LH (2007) Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer 109:957–965PubMedCentralPubMedGoogle Scholar
  38. 38.
    Lin YS, Yasuda K, Assem M, Cline C, Barber J, Li CW, Kholodovych V, Ai N, Chen JD, Welsh WJ, Ekins S, Schuetz EG (2009) The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation. Drug Metab Dispos 37:1295–1304PubMedCentralPubMedGoogle Scholar
  39. 39.
    Tompkins LM, Sit TL, Wallace AD (2008) Unique transcription start sites and distinct promoter regions differentiate the pregnane X receptor (PXR) isoforms PXR 1 and PXR 2. Drug Metab Dispos 36:923–929PubMedGoogle Scholar
  40. 40.
    di Masi A, De Marinis E, Ascenzi P, Marino M (2009) Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Mol Aspects Med 30:297–343PubMedGoogle Scholar
  41. 41.
    Koutsounas I, Patsouris E, Theocharis S (2013) Pregnane X receptor and human malignancy. Histol Histopathol 28:405–420PubMedGoogle Scholar
  42. 42.
    Ma X, Idle JR, Gonzalez FJ (2008) The pregnane X receptor: from bench to bedside. Expert Opin Drug Metab Toxicol 4:895–908PubMedCentralPubMedGoogle Scholar
  43. 43.
    Chen T (2010) Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev 62:1257–1264PubMedCentralPubMedGoogle Scholar
  44. 44.
    Koutsounas I, Theocharis S, Patsouris E, Giaginis C (2013) Pregnane X receptor (PXR) at the crossroads of human metabolism and disease. Curr Drug Metab 14:341–350PubMedGoogle Scholar
  45. 45.
    Qiao E, Ji M, Wu J, Ma R, Zhang X, He Y, Zha Q, Song X, Zhu LW, Tang J (2013) Expression of the PXR gene in various types of cancer and drug resistance. Oncol Lett 5:1093–1100PubMedCentralPubMedGoogle Scholar
  46. 46.
    Handschin C, Meyer UA (2003) Induction of drug metabolism: the role of nuclear receptors. Pharmacol Rev 55:649–673PubMedGoogle Scholar
  47. 47.
    Gollamudi R, Gupta D, Goel S, Mani S (2008) Novel orphan nuclear receptors–coregulator interactions controlling anti-cancer drug metabolism. Curr Drug Metab 9:611–613PubMedGoogle Scholar
  48. 48.
    Lamba J, Lamba V, Schuetz E (2005) Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 6:369–383PubMedGoogle Scholar
  49. 49.
    Willson TM, Kliewer SA (2002) PXR, CAR and drug metabolism. Nat Rev Drug Discov 1:259–266PubMedGoogle Scholar
  50. 50.
    Verma S, Tabb MM, Blumberg B (2009) Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells. BMC Cancer 9:3PubMedCentralPubMedGoogle Scholar
  51. 51.
    Wang H, Venkatesh M, Li H, Goetz R, Mukherjee S, Biswas A, Zhu L, Kaubisch A, Wang L, Pullman J, Whitney K, Kuro-o M, Roig AI, Shay JW, Mohammadi M, Mani S (2011) Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J Clin Invest 121:3220–3232PubMedCentralPubMedGoogle Scholar
  52. 52.
    Zhou J, Liu M, Zhai Y, Xie W (2008) The antiapoptotic role of pregnane X receptor in human colon cancer cells. Mol Endocrinol 22:868–880PubMedCentralPubMedGoogle Scholar
  53. 53.
    Ouyang N, Ke S, Eagleton N, Xie Y, Chen G, Laffins B, Yao H, Zhou B, Tian Y (2010) Pregnane X receptor suppresses proliferation and tumorigenicity of colon cancer cells. Br J Cancer 102:1753–1761PubMedCentralPubMedGoogle Scholar
  54. 54.
    Elias A, Wu J, Chen T (2013) Tumor suppressor protein p53 negatively regulates human pregnane X receptor activity. Mol Pharmacol 83:1229–1236PubMedCentralPubMedGoogle Scholar
  55. 55.
    Swinnen JV, Brusselmans K, Verhoeven G (2006) Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 9:358–365PubMedGoogle Scholar
  56. 56.
    Zhou J, Zhai Y, Mu Y, Gong H, Uppal H, Toma D, Ren S, Evans RM, Xie W (2006) A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 281:15013–15020PubMedCentralPubMedGoogle Scholar
  57. 57.
    Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W (2008) Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134:556–567PubMedGoogle Scholar
  58. 58.
    Gong H, Singh SV, Singh SP, Mu Y, Lee JH, Saini SP, Toma D, Ren S, Kagan VE, Day BW, Zimniak P, Xie W (2006) Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells. Mol Endocrinol 20:279–290PubMedGoogle Scholar
  59. 59.
    Ma MK, McLeod HL (2003) Lessons learned from the irinotecan metabolic pathway. Curr Med Chem 10:41–49PubMedGoogle Scholar
  60. 60.
    Haaz MC, Rivory L, Riché C, Vernillet L, Robert J (1998) Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. Cancer Res 58:468–472PubMedGoogle Scholar
  61. 61.
    Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194PubMedGoogle Scholar
  62. 62.
    Chu XY, Kato Y, Sugiyama Y (1999) Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. Drug Metab Dispos 27:440–441PubMedGoogle Scholar
  63. 63.
    Chu XY, Suzuki H, Ueda K, Kato Y, Akiyama S, Sugiyama Y (1999) Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. J Pharmacol Exp Ther 288:735–741PubMedGoogle Scholar
  64. 64.
    Raynal C, Pascussi JM, Leguelinel G, Breuker C, Kantar J, Lallemant B, Poujol S, Bonnans C, Joubert D, Hollande F, Lumbroso S, Brouillet JP, Evrard A (2010) Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Mol Cancer 9:46PubMedCentralPubMedGoogle Scholar
  65. 65.
    Basseville A, Preisser L, de Carné Trécesson S, Boisdron-Celle M, Gamelin E, Coqueret O, Morel A (2011) Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells. Mol Cancer 10:80PubMedCentralPubMedGoogle Scholar
  66. 66.
    Yonemori K, Takeda Y, Toyota E, Kobayashi N, Kudo K (2004) Potential interactions between irinotecan and rifampin in a patient with small-cell lung cancer. Int J Clin Oncol 9:206–209PubMedGoogle Scholar
  67. 67.
    Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VK (2000) St John’s wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 166:R11–R16PubMedGoogle Scholar
  68. 68.
    Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A (2002) Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247–1249PubMedGoogle Scholar
  69. 69.
    Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D, Mulcahy F, Feely J (2002) St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol 53:75–82PubMedCentralPubMedGoogle Scholar
  70. 70.
    Dehal SS, Kupfer D (1997) CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 57:3402–3406PubMedGoogle Scholar
  71. 71.
    Jacolot F, Simon I, Dreano Y, Beaune P, Riche C, Berthou F (1991) Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. Biochem Pharmacol 41:1911–1919PubMedGoogle Scholar
  72. 72.
    Teft WA, Mansell SE, Kim RB (2011) Endoxifen, the active metabolite of tamoxifen, is a substrate of the efflux transporter P-glycoprotein (multidrug resistance 1). Drug Metab Dispos 39:558–562PubMedGoogle Scholar
  73. 73.
    Choi HK, Yang JW, Roh SH, Han CY, Kang KW (2007) Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer 14:293–303PubMedGoogle Scholar
  74. 74.
    Chen Y, Tang Y, Chen S, Nie D (2009) Regulation of drug resistance by human pregnane X receptor in breast cancer. Cancer Biol Ther 8:1265–1272PubMedCentralPubMedGoogle Scholar
  75. 75.
    Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB (2008) Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 68:9338–9347PubMedCentralPubMedGoogle Scholar
  76. 76.
    Desai PB, Nallani SC, Sane RS, Moore LB, Goodwin BJ, Buckley DJ, Buckley AR (2002) Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen. Drug Metab Dispos 30:608–612PubMedGoogle Scholar
  77. 77.
    Harmsen S, Meijerman I, Febus CL, Maas-Bakker RF, Beijnen JH, Schellens JH (2010) PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother Pharmacol 66:765–771PubMedCentralPubMedGoogle Scholar
  78. 78.
    Nagaoka R, Iwasaki T, Rokutanda N, Takeshita A, Koibuchi Y, Horiguchi J, Shimokawa N, Iino Y, Morishita Y, Koibuchi N (2006) Tamoxifen activates CYP3A4 and MDR1 genes through steroid and xenobiotic receptor in breast cancer cells. Endocrine 30:261–268PubMedGoogle Scholar
  79. 79.
    Sane RS, Buckley DJ, Buckley AR, Nallani SC, Desai PB (2008) Role of human pregnane X receptor in tamoxifen- and 4-hydroxytamoxifen-mediated CYP3A4 induction in primary human hepatocytes and LS174T cells. Drug Metab Dispos 36:946–954PubMedGoogle Scholar
  80. 80.
    Huizing MT, Misser VH, Pieters RC, ten Bokkel Huinink WW, Veenhof CH, Vermorken JB, Pinedo HM, Beijnen JH (1995) Taxanes: a new class of antitumor agents. Cancer Invest 13:381–404PubMedGoogle Scholar
  81. 81.
    Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277:665–667PubMedGoogle Scholar
  82. 82.
    Harris JW, Rahman A, Kim BR, Guengerich FP, Collins JM (1994) Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 54:4026–4035PubMedGoogle Scholar
  83. 83.
    Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, Harris JW (1994) Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 54:5543–5546PubMedGoogle Scholar
  84. 84.
    van Asperen J, van Tellingen O, Sparreboom A, Schinkel AH, Borst P, Nooijen WJ, Beijnen JH (1997) Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer 76:1181–1183PubMedCentralPubMedGoogle Scholar
  85. 85.
    Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, Borst P, Nooijen WJ, Beijnen JH, van Tellingen O (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031–2035PubMedCentralPubMedGoogle Scholar
  86. 86.
    Chen Y, Tang Y, Wang MT, Zeng S, Nie D (2007) Human pregnane X receptor and resistance to chemotherapy in prostate cancer. Cancer Res 67:10361–10367PubMedGoogle Scholar
  87. 87.
    Masuyama H, Suwaki N, Tateishi Y, Nakatsukasa H, Segawa T, Hiramatsu Y (2005) The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. Mol Endocrinol 19:1170–1180PubMedGoogle Scholar
  88. 88.
    Nallani SC, Goodwin B, Maglich JM, Buckley DJ, Buckley AR, Desai PB (2003) Induction of cytochrome P450 3A by paclitaxel in mice: pivotal role of the nuclear xenobiotic receptor, pregnane X receptor. Drug Metab Dispos 31:681–684PubMedGoogle Scholar
  89. 89.
    Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584–590PubMedGoogle Scholar
  90. 90.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedGoogle Scholar
  91. 91.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedGoogle Scholar
  92. 92.
    Lee HJ, Lee MG (1999) Effects of dexamethasone on the pharmacokinetics of adriamycin after intravenous administration to rats. Res Commun Mol Pathol Pharmacol 105:87–96PubMedGoogle Scholar
  93. 93.
    Lal S, Mahajan A, Chen WN, Chowbay B (2010) Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab 11:115–128PubMedGoogle Scholar
  94. 94.
    Mensah-Osman E, Lin H-L, Reinke D, Hollenberg P, Baker L (2005) Ecteinascidin-743 is a potent inhibitor of P450 3A4 enzyme and accumulates cytoplasmic PXR to inhibit transcription of P450 3A4 and MDR1: implications for the enhancement of cytotoxicity to chemotherapeutic agents in osteosarcoma. J Clin Oncol (Meeting Abstracts) 23(16s):9026Google Scholar
  95. 95.
    Sandanaraj E, Lal S, Selvarajan V, Ooi LL, Wong ZW, Wong NS, Ang PC, Lee EJ, Chowbay B (2008) PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients. Clin Cancer Res 14:7116–7126PubMedGoogle Scholar
  96. 96.
    Noble RL (1990) The discovery of the vinca alkaloids–chemotherapeutic agents against cancer. Biochem Cell Biol 68:1344–1351PubMedGoogle Scholar
  97. 97.
    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265PubMedGoogle Scholar
  98. 98.
    Levêque D, Wihlm J, Jehl F (1996) Pharmacology of Catharanthus alkaloids. Bull Cancer 83:176–186PubMedGoogle Scholar
  99. 99.
    Levêque D, Jehl F (2007) Molecular pharmacokinetics of catharanthus (vinca) alkaloids. J Clin Pharmacol 47:579–588PubMedGoogle Scholar
  100. 100.
    Gruol DJ, King MN, Kuehne ME (2002) Evidence for the locations of distinct steroid and Vinca alkaloid interaction domains within the murine mdr1b P-glycoprotein. Mol Pharmacol 62:1238–1248PubMedGoogle Scholar
  101. 101.
    Huang R, Murry DJ, Kolwankar D, Hall SD, Foster DR (2006) Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines. Biochem Pharmacol 71:1695–1704PubMedGoogle Scholar
  102. 102.
    Smith NF, Mani S, Schuetz EG, Yasuda K, Sissung TM, Bates SE, Figg WD, Sparreboom A (2010) Induction of CYP3A4 by vinblastine: role of the nuclear receptor NR1I2. Ann Pharmacother 44:1709–1717PubMedCentralPubMedGoogle Scholar
  103. 103.
    Hong WK, Itri LM (1994) Retinoids and human cancer. In: Sporn MB, Roberts AB, Goodman DS (eds) The retinoids. Biology, chemistry and medicine, 2nd edn. Raven Press Ltd, New York, pp 597–630Google Scholar
  104. 104.
    Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A et al (1992) 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 355:359–361PubMedGoogle Scholar
  105. 105.
    Nagy L, Thomázy VA, Shipley GL, Fésüs L, Lamph W, Heyman RA, Chandraratna RA, Davies PJ (1995) Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 15:3540–3551PubMedCentralPubMedGoogle Scholar
  106. 106.
    Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP (1998) Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci USA 95:8806–8811PubMedCentralPubMedGoogle Scholar
  107. 107.
    Muindi JR, Frankel SR, Huselton C, DeGrazia F, Garland WA, Young CW, Warrell RP Jr (1992) Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res 52:2138–2142PubMedGoogle Scholar
  108. 108.
    Marill J, Cresteil T, Lanotte M, Chabot GG (2000) Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol 58:1341–1348PubMedGoogle Scholar
  109. 109.
    Wang T, Ma X, Krausz KW, Idle JR, Gonzalez FJ (2008) Role of pregnane X receptor in control of all-trans retinoic acid (ATRA) metabolism and its potential contribution to ATRA resistance. J Pharmacol Exp Ther 324:674–684PubMedCentralPubMedGoogle Scholar
  110. 110.
    Moore MJ (1991) Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 20:194–208PubMedGoogle Scholar
  111. 111.
    Dechant KL, Brogden RN, Pilkington T, Faulds D (1991) Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42:428–467PubMedGoogle Scholar
  112. 112.
    Sladek NE (1988) Metabolism of oxazaphosphorines. Pharmacol Ther 37:301–355PubMedGoogle Scholar
  113. 113.
    Zhang Jing, Tian Quan, Zhou Shu-Feng (2006) Clinical pharmacology of cyclophosphamide and ifosfamide. Curr Drug Ther 1:55–84Google Scholar
  114. 114.
    Chang TK, Yu L, Maurel P, Waxman DJ (1997) Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 57:1946–1954PubMedGoogle Scholar
  115. 115.
    Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005) Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. Oncologist 10:104–111PubMedGoogle Scholar
  116. 116.
    Chabner BA, Roberts TG Jr (2005) Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72PubMedGoogle Scholar
  117. 117.
    Harmsen S, Meijerman I, Beijnen JH, Schellens JH (2007) The role of nuclear receptors in pharmacokinetic drug–drug interactions in oncology. Cancer Treat Rev 33:369–380PubMedGoogle Scholar
  118. 118.
    Meijerman I, Beijnen JH, Schellens JH (2006) Herb–drug interactions in oncology: focus on mechanisms of induction. Oncologist 11:742–752PubMedGoogle Scholar
  119. 119.
    Biswas A, Mani S, Redinbo MR, Krasowski MD, Li H, Ekins S (2009) Elucidating the ‘Jekyll and Hyde’ nature of PXR: the case for discovering antagonists or allosteric antagonists. Pharm Res 26:1807–1815PubMedCentralPubMedGoogle Scholar
  120. 120.
    Robbins D, Chen T (2014) Tissue-specific regulation of pregnane X receptor in cancer development and therapy. Cell Biosci 4:17PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Wei Zhuo
    • 1
    • 2
    • 3
  • Lei Hu
    • 1
    • 2
    • 3
  • Jinfeng Lv
    • 1
    • 2
    • 3
  • Hongbing Wang
    • 4
  • Honghao Zhou
    • 1
    • 2
    • 3
  • Lan Fan
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Clinical Pharmacology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Pharmacogenetics Research Institute, Institute of Clinical PharmacologyCentral South UniversityChangshaPeople’s Republic of China
  3. 3.Hunan Key Laboratory of PharmacogeneticsChangshaPeople’s Republic of China
  4. 4.Department of Pharmaceutical SciencesThe University of Maryland School of PharmacyBaltimoreUSA

Personalised recommendations