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. 1995 May;71(5):931–936. doi: 10.1038/bjc.1995.180

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

X F Hu 1, A Slater 1, D M Wall 1, P Kantharidis 1, J D Parkin 1, A Cowman 1, J R Zalcberg 1
PMCID: PMC2033794  PMID: 7734315

Abstract

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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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bates S. E., Mickley L. A., Chen Y. N., Richert N., Rudick J., Biedler J. L., Fojo A. T. 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. doi: 10.1128/mcb.9.10.4337-4344.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chan H. S., Thorner P. S., 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. doi: 10.1200/JCO.1990.8.4.689. [DOI] [PubMed] [Google Scholar]
  3. Chaudhary P. M., Roninson I. B. 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. doi: 10.1093/jnci/85.8.632. [DOI] [PubMed] [Google Scholar]
  4. Chin K. V., Chauhan S. S., Pastan I., Gottesman M. M. Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells. Cell Growth Differ. 1990 Aug;1(8):361–365. [PubMed] [Google Scholar]
  5. Chin K. V., Tanaka S., Darlington G., Pastan I., Gottesman M. M. 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] [Google Scholar]
  6. 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. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Cornwell M. M. 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] [Google Scholar]
  8. Deuchars K. L., Ling V. P-glycoprotein and multidrug resistance in cancer chemotherapy. Semin Oncol. 1989 Apr;16(2):156–165. [PubMed] [Google Scholar]
  9. FOLEY G. E., LAZARUS H., FARBER S., UZMAN B. G., BOONE B. A., MCCARTHY R. E. CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965 Apr;18:522–529. doi: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  10. Ferrandis E., Bénard J. Activation of the human MDR1 gene promoter in differentiated neuroblasts. Int J Cancer. 1993 Jul 30;54(6):987–991. doi: 10.1002/ijc.2910540621. [DOI] [PubMed] [Google Scholar]
  11. Ford J. M., Hait W. N. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev. 1990 Sep;42(3):155–199. [PubMed] [Google Scholar]
  12. Goasguen J. E., Dossot J. M., Fardel O., Le Mee F., Le Gall E., Leblay R., LePrise P. Y., 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] [Google Scholar]
  13. Goldstein L. J., Pastan I., Gottesman M. M. Multidrug resistance in human cancer. Crit Rev Oncol Hematol. 1992;12(3):243–253. doi: 10.1016/1040-8428(92)90057-w. [DOI] [PubMed] [Google Scholar]
  14. Hayes J. D., Wolf C. R. Molecular mechanisms of drug resistance. Biochem J. 1990 Dec 1;272(2):281–295. doi: 10.1042/bj2720281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hsu S. I., Lothstein L., Horwitz S. B. 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] [Google Scholar]
  16. Hu X. F., Martin T. J., Bell D. R., de Luise M., Zalcberg J. R. 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] [Google Scholar]
  17. Ikeguchi M., Teeter L. D., Eckersberg T., Ganapathi R., Kuo M. T. 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. doi: 10.1089/dna.1991.10.639. [DOI] [PubMed] [Google Scholar]
  18. 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. doi: 10.1016/0014-5793(92)80205-u. [DOI] [PubMed] [Google Scholar]
  19. 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. doi: 10.1016/0006-291x(89)92761-7. [DOI] [PubMed] [Google Scholar]
  20. Licht T., Fiebig H. H., Bross K. J., Herrmann F., Berger D. P., 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. doi: 10.1002/ijc.2910490427. [DOI] [PubMed] [Google Scholar]
  21. Mickley L. A., Bates S. E., Richert N. D., Currier S., Tanaka S., Foss F., Rosen N., Fojo A. T. 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] [Google Scholar]
  22. 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. doi: 10.1016/0006-291x(92)91248-o. [DOI] [PubMed] [Google Scholar]
  23. Slater L. M., Sweet P., Stupecky M., Wetzel M. W., Gupta S. Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer. 1986 Aug;54(2):235–238. doi: 10.1038/bjc.1986.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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. doi: 10.1016/0006-291x(92)90571-2. [DOI] [PubMed] [Google Scholar]
  25. 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] [Google Scholar]
  26. Ueda K., Pastan I., Gottesman M. M. 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] [Google Scholar]
  27. Zalcberg J. R., Hu X. F., Wall D. M., Mirski S., Cole S., Nadalin G., De Luise M., Parkin J. D., Vrazas V., Campbell L. 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. doi: 10.1002/ijc.2910570414. [DOI] [PubMed] [Google Scholar]

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