© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 8, 632-639,
April 21, 1993
© 1993 Oxford University Press
Induction of Multidrug Resistance in Human Cells by Transient Exposure to Different Chemotherapeutic Drugs
Department of Geneties, University of Illinois at Chicago Chicago, III
Correspondence to: Igor B. Roninson, Ph.D., Department of Genetics (M/C669), University of Illinois at Chicago, 808 South Wood St., Chicago, IL 60612.
Background: The MDR1 (multidrug resistance) gene (also known as PGY1), which encodes the transmembrane efflux pump P-glycoprotein (Pgp), confers resistance to Pgp-transported cytotoxic drugs in tissue culture. The increase in MDR1 expression in tumors after chemotherapy is usually attributed to selection of pre-existing multidrug-resistant cells by Pgp-transported drugs. MDR1 expression in tissue culture can be increased by several types of stress-inducing treatment, including agents that activate protein kinase C (PKC). Previous studies, however, failed to demonstrate that short-term exposure to any chemotherapeutic drug can induce the expression of the resident MDR1 gene in drug-sensitive human cells. Purpose: This study was designed to utilize highly sensitive assays to determine if transient exposure to chemotherapeutic drugs would have an effect on MDR1 expression in human cells and to assess if PKC inhibitors would influence such an effect Methods: We analyzed the MDR1 gene expression in several human cell lines derived from leukemias or solid tumors, after treatment with different cytotoxic drugs, in the presence or absence of PKC inhibitors. Pgp function and expression were studied by flow cytometric assays, and MDR1 messenger RNA (mRNA) was assayed by polymerase chain reaction. Results: Transient exposure to chemotherapeutic drugs, including agents that are not transported by Pgp, induced Pgp and MDR1 mRNA expression in subpopulations of treated cells in most of the tested cell lines. This induction was observed along with microscopically detectable cell damage. The drug-induced MDR1 expression and the associated twofold to threefold increase in resistance to vinblastine were sustained in K562 leukemia cells for at least several weeks after the removal of the drug. Drug-mediated MDR1 induction was blocked by nonspecific protein kinase inhibitors that are active against PKC, but not by a protein kinase inhibitor ineffective against PKC. Conclusions: Expression of the human MDR1 mRNA and Pgp can be induced in response to cellular damage by cytotoxic drugs regardless of whether the drugs are transported by Pgp. This induction can be prevented by protein kinase inhibitors. Implications: Induction of MDR1 expression in response to cellular damage may account for increased MDR1 expression in treated human tumors. Protein kinase inhibitors may be useful in preventing the emergence of multidrug resistance during cancer chemotherapy. [J Natl Cancer Inst 85:632-639, 1993]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Callaghan, E. Crowley, S. Potter, and I. D. Kerr P-glycoprotein: So Many Ways to Turn It On J. Clin. Pharmacol., March 1, 2008; 48(3): 365 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Tsujimura, K Saito, M Nawata, S Nakayamada, and Y Tanaka Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis Ann Rheum Dis, March 1, 2008; 67(3): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Puhlmann, C. Ziemann, G. Ruedell, H. Vorwerk, D. Schaefer, C. Langebrake, P. Schuermann, U. Creutzig, and D. Reinhardt Impact of the Cyclooxygenase System on Doxorubicin-Induced Functional Multidrug Resistance 1 Overexpression and Doxorubicin Sensitivity in Acute Myeloid Leukemic HL-60 Cells J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsujimura, K. Saito, S. Nakayamada, K. Nakano, J. Tsukada, K. Kohno, and Y. Tanaka Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes Genes Cells, December 1, 2004; 9(12): 1265 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kuwano, Y. Oda, H. Izumi, S.-J. Yang, T. Uchiumi, Y. Iwamoto, M. Toi, T. Fujii, H. Yamana, H. Kinoshita, et al. The role of nuclear Y-box binding protein 1 as a global marker in drug resistance Mol. Cancer Ther., November 1, 2004; 3(11): 1485 - 1492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Yague, A. L. Armesilla, G. Harrison, J. Elliott, A. Sardini, C. F. Higgins, and S. Raguz P-glycoprotein (MDR1) Expression in Leukemic Cells Is Regulated at Two Distinct Steps, mRNA Stabilization and Translational Initiation J. Biol. Chem., March 14, 2003; 278(12): 10344 - 10352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Yang, A. D. Vassil, and W. N. Hait Activation of Phospholipase C Induces the Expression of the Multidrug Resistance (MDR1) Gene through the Raf-MAPK Pathway Mol. Pharmacol., October 1, 2001; 60(4): 674 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Cocker, N. Tiffin, K. Pritchard-Jones, C. R. Pinkerton, and L. R. Kelland In Vitro Prevention of the Emergence of Multidrug Resistance in a Pediatric Rhabdomyosarcoma Cell Line Clin. Cancer Res., October 1, 2001; 7(10): 3193 - 3198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Scotto and R. A. Johnson Transcription of MDR1: A Therapeutic Target Mol. Interv., June 1, 2001; 1(2): 117 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. van den Heuvel-Eibrink, E. A. C. Wiemer, M. J. de Boevere, B. van der Holt, P. J. M. Vossebeld, R. Pieters, and P. Sonneveld MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia Blood, June 1, 2001; 97(11): 3605 - 3611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Putman, H. W. van Veen, and W. N. Konings Molecular Properties of Bacterial Multidrug Transporters Microbiol. Mol. Biol. Rev., December 1, 2000; 64(4): 672 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Hu, S. Jin, and K. W. Scotto Transcriptional Activation of the MDR1 Gene by UV Irradiation. ROLE OF NF-Y AND Sp1 J. Biol. Chem., January 28, 2000; 275(4): 2979 - 2985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Demeule, M. Brossard, and R. Beliveau Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter Am J Physiol Renal Physiol, December 1, 1999; 277(6): F832 - F840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abolhoda, A. E. Wilson, H. Ross, P. V. Danenberg, M. Burt, and K. W. Scotto Rapid Activation of MDR1 Gene Expression in Human Metastatic Sarcoma after in Vivo Exposure to Doxorubicin Clin. Cancer Res., November 1, 1999; 5(11): 3352 - 3356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. F. Hu, A. Slater, P. Kantharidis, D. Rischin, S. Juneja, R. Rossi, G. Lee, J. D. Parkin, and J. R. Zalcberg Altered Multidrug Resistance Phenotype Caused by Anthracycline Analogues and Cytosine Arabinoside in Myeloid Leukemia Blood, June 15, 1999; 93(12): 4086 - 4095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Grkovic, M. H. Brown, N. J. Roberts, I. T. Paulsen, and R. A. Skurray QacR Is a Repressor Protein That Regulates Expression of the Staphylococcus aureus Multidrug Efflux Pump QacA J. Biol. Chem., July 17, 1998; 273(29): 18665 - 18673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zhou and M. T. Kuo Wild-type p53-mediated Induction of Rat mdr1b Expression by the Anticancer Drug Daunorubicin J. Biol. Chem., June 19, 1998; 273(25): 15387 - 15394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohga, T. Uchiumi, Y. Makino, K. Koike, M. Wada, M. Kuwano, and K. Kohno Direct Involvement of the Y-box Binding Protein YB-1 in Genotoxic Stress-induced Activation of the Human Multidrug Resistance 1 Gene J. Biol. Chem., March 13, 1998; 273(11): 5997 - 6000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Osborn and T. C. Chambers Role of the Stress-activated/c-Jun NH2-terminal Protein Kinase Pathway in the Cellular Response to Adriamycin and Other Chemotherapeutic Drugs J. Biol. Chem., November 29, 1996; 271(48): 30950 - 30955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Fine, T. C. Chambers, and C. W. Sachs P-Glycoprotein, Multidrug Resistance and Protein Kinase C Oncologist, August 1, 1996; 1(4): 261 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishikawa, J.-J. Bao, Y. Yamane, K. Akimaru, K. Frindrich, C. D. Wright, and M. T. Kuo Coordinated Induction of MRP/GS-X Pump and gamma -Glutamylcysteine Synthetase by Heavy Metals in Human Leukemia Cells J. Biol. Chem., June 21, 1996; 271(25): 14981 - 14988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Fine, T. Chambers, and C. Sachs P-glycoprotein, multidrug resistance and protein kinase C Stem Cells, January 1, 1996; 14(1): 47 - 55. [Abstract]
|
|
|
|
|
|
M. E. Goldsmith, J. M. Gudas, E. Schneider, and K. H. Cowan Wild Type p53 Stimulates Expression from the Human Multidrug Resistance Promoter in a p53-negative Cell Line J. Biol. Chem., January 27, 1995; 270(4): 1894 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Stein, K. Jurchott, W. Walther, S. Bergmann, P. M. Schlag, and H.-D. Royer Hyperthermia-induced Nuclear Translocation of Transcription Factor YB-1 Leads to Enhanced Expression of Multidrug Resistance-related ABC Transporters J. Biol. Chem., July 20, 2001; 276(30): 28562 - 28569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Vilaboa, A. Galan, A. Troyano, E. de Blas, and P. Aller Regulation of Multidrug Resistance 1 (MDR1)/P-glycoprotein Gene Expression and Activity by Heat-Shock Transcription Factor 1 (HSF1) J. Biol. Chem., August 4, 2000; 275(32): 24970 - 24976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hoffmeyer, O. Burk, O. von Richter, H. P. Arnold, J. Brockmoller, A. Johne, I. Cascorbi, T. Gerloff, I. Roots, M. Eichelbaum, et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo PNAS, March 28, 2000; 97(7): 3473 - 3478. [Abstract] [Full Text] [PDF]
|
|