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Br J Cancer. 1995 May; 71(5): 931–936.
PMCID: PMC2033794

Rapid up-regulation of mdr1 expression by anthracyclines in a classical multidrug-resistant cell line.


Studies were carried out in a variant human multidrug-resistant (MDR) cell line CEM/A7R, which expresses very low levels of mdr1 mRNA and P-glycoprotein (P-gp). The induction of mdr1 RNA expression by three anthracyclines, (doxorubicin, daunorubicin, epirubicin), VP-16 and two vinca alkaloids (vincristine, vinblastine) was semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of mdr1 expression was expressed as ratio of mdr1 to the internal RNA (actin). A significant increase (P < 0.02) in expression of mdr1 was noted within 4 hrs of exposure to 1.5 micrograms ml-1 daunorubicin or epirubicin. Neither vinblastine nor vincristine had any effect on mdr1 levels after an 8 h exposure. With increasing concentrations of daunorubicin or epirubicin in a fixed 24 h time period, mdr1 expression increased, although a biphasic response was seen. Based on MRK 16 binding, an increase in P-gp levels was seen in the CEM/A7R line after a 24 h exposure to 1 microgram ml-1 daunorubicin or epirubicin. The rapid increase in mdr1 expression after a short period of exposure to doxorubicin, daunorubicin or epirubicin suggests that induction of mdr1 expression may have an important role in the development of drug-resistant tumours.

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  • Bates SE, Mickley LA, Chen YN, Richert N, Rudick J, Biedler JL, Fojo AT. Expression of a drug resistance gene in human neuroblastoma cell lines: modulation by retinoic acid-induced differentiation. Mol Cell Biol. 1989 Oct;9(10):4337–4344. [PMC free article] [PubMed]
  • Chan HS, Thorner PS, Haddad G, Ling V. Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol. 1990 Apr;8(4):689–704. [PubMed]
  • Chaudhary PM, Roninson IB. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst. 1993 Apr 21;85(8):632–639. [PubMed]
  • Chin KV, Chauhan SS, Pastan I, Gottesman MM. Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Differ. 1990 Aug;1(8):361–365. [PubMed]
  • Chin KV, Tanaka S, Darlington G, Pastan I, Gottesman MM. Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem. 1990 Jan 5;265(1):221–226. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Cornwell MM. The human multidrug resistance gene: sequences upstream and downstream of the initiation site influence transcription. Cell Growth Differ. 1990 Dec;1(12):607–615. [PubMed]
  • Deuchars KL, Ling V. P-glycoprotein and multidrug resistance in cancer chemotherapy. Semin Oncol. 1989 Apr;16(2):156–165. [PubMed]
  • Ferrandis E, Bénard J. Activation of the human MDR1 gene promoter in differentiated neuroblasts. Int J Cancer. 1993 Jul 30;54(6):987–991. [PubMed]
  • Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev. 1990 Sep;42(3):155–199. [PubMed]
  • Goasguen JE, Dossot JM, Fardel O, Le Mee F, Le Gall E, Leblay R, LePrise PY, Chaperon J, Fauchet R. Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications. Blood. 1993 May 1;81(9):2394–2398. [PubMed]
  • Goldstein LJ, Pastan I, Gottesman MM. Multidrug resistance in human cancer. Crit Rev Oncol Hematol. 1992;12(3):243–253. [PubMed]
  • Hayes JD, Wolf CR. Molecular mechanisms of drug resistance. Biochem J. 1990 Dec 1;272(2):281–295. [PMC free article] [PubMed]
  • Hsu SI, Lothstein L, Horwitz SB. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J Biol Chem. 1989 Jul 15;264(20):12053–12062. [PubMed]
  • Hu XF, Martin TJ, Bell DR, de Luise M, Zalcberg JR. Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines. Cancer Res. 1990 May 15;50(10):2953–2957. [PubMed]
  • Ikeguchi M, Teeter LD, Eckersberg T, Ganapathi R, Kuo MT. Structural and functional analyses of the promoter of the murine multidrug resistance gene mdr3/mdr1a reveal a negative element containing the AP-1 binding site. DNA Cell Biol. 1991 Nov;10(9):639–649. [PubMed]
  • Kioka N, Yamano Y, Komano T, Ueda K. Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett. 1992 Apr 13;301(1):37–40. [PubMed]
  • Kohno K, Sato S, Takano H, Matsuo K, Kuwano M. The direct activation of human multidrug resistance gene (MDR1) by anticancer agents. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1415–1421. [PubMed]
  • Licht T, Fiebig HH, Bross KJ, Herrmann F, Berger DP, Shoemaker R, Mertelsmann R. Induction of multiple-drug resistance during anti-neoplastic chemotherapy in vitro. Int J Cancer. 1991 Oct 21;49(4):630–637. [PubMed]
  • Mickley LA, Bates SE, Richert ND, Currier S, Tanaka S, Foss F, Rosen N, Fojo AT. Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents. J Biol Chem. 1989 Oct 25;264(30):18031–18040. [PubMed]
  • Miyazaki M, Kohno K, Uchiumi T, Tanimura H, Matsuo K, Nasu M, Kuwano M. Activation of human multidrug resistance-1 gene promoter in response to heat shock stress. Biochem Biophys Res Commun. 1992 Sep 16;187(2):677–684. [PubMed]
  • Slater LM, Sweet P, Stupecky M, Wetzel MW, Gupta S. Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer. 1986 Aug;54(2):235–238. [PMC free article] [PubMed]
  • Tanimura H, Kohno K, Sato S, Uchiumi T, Miyazaki M, Kobayashi M, Kuwano M. The human multidrug resistance 1 promoter has an element that responds to serum starvation. Biochem Biophys Res Commun. 1992 Mar 16;183(2):917–924. [PubMed]
  • Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 1981 May;41(5):1967–1972. [PubMed]
  • Ueda K, Pastan I, Gottesman MM. Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. J Biol Chem. 1987 Dec 25;262(36):17432–17436. [PubMed]
  • Zalcberg JR, Hu XF, Wall DM, Mirski S, Cole S, Nadalin G, De Luise M, Parkin JD, Vrazas V, Campbell L, et al. Cellular and karyotypic characterization of two doxorubicin resistant cell lines isolated from the same parental human leukemia cell line. Int J Cancer. 1994 May 15;57(4):522–528. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK


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