![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY
Department of Pediatric Hematology and Oncology, University of Muenster, Muenster, Germany (U.P., H.V., C.L., U.C., D.R.); Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany (C.Z.); Department of Toxicology, University of Goettingen, Goettingen, Germany (C.Z., G.R.); and Competence Center for Environmental Health, Clinic for Ear, Nose, and Throat, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany (D.S.)
Multidrug resistance (MDR), a challenge in treating childhood acute myeloid leukemia (AML), is frequently associated with decreased drug accumulation caused by multidrug transporter MDR1. Doxorubicin, an important anti-AML drug, is a known MDR1 substrate and inducer. Its cytostatic efficacy is thus limited by MDR1 overexpression. A recent study demonstrated cyclooxygenase-2-dependent, prostaglandin E2 (PGE2)-mediated regulation of mdr1b expression in primary rat hepatocyte cultures. Cyclooxygenase-2 expression is increased in several malignancies and considered a negative prognostic factor. Our study focused on cyclooxygenase system's impact on drug-induced MDR1 overexpression in AML cells. As a prerequisite, coexpression of MDR1 and cyclooxygenase-2 mRNA in HL-60 cells and primary AML blasts was demonstrated by Northern blot. Interestingly, incubation of AML cells with doxorubicin not only induced functionally active MDR1 overexpression but also mediated increased cyclooxygenase-2 mRNA and protein expressions with subsequent PGE2 release (determined by flow cytometry, rhodamine123 efflux assay, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay). After preincubation and subsequent parallel treatment with the cyclooxygenase-2-preferential inhibitor meloxicam, doxorubicin-induced MDR1 overexpression and function were reduced (maximally at 0.1-0.5 µM meloxicam), whereas cytostatic efficacy of doxorubicin in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays was significantly increased by up to 78 (HL-60) and 30% (AML blasts) after 72 h of doxorubicin treatment. In HL-60 cells, meloxicam-dependent effect on doxorubicin cytotoxicity was neutralized by PGE2 preincubation. In conclusion, the cyclooxygenase system, especially the cyclooxygenase-2 isoform, might be involved in regulating doxorubicin-induced MDR1 overexpression in AML cells, with PGE2 seeming to be a mediating factor. Cyclooxygenase inhibitors thus bear promise to overcome MDR in AML and improve therapy.
Address correspondence to: Dr. Ulrike Puhlmann, AML-BFM Study, Pediatric Hematology/Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Str. 33, 48129 Muenster, Germany. E-mail: ulrike{at}puhlmann.de
This article has been cited by other articles:
|
|
 |
|
  L. Yu, W. K. K. Wu, Z. J. Li, Q. C. Liu, H. T. Li, Y. C. Wu, and C. H. Cho Enhancement of Doxorubicin Cytotoxicity on Human Esophageal Squamous Cell Carcinoma Cells by Indomethacin and 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via Inhibiting P-Glycoprotein Activity Mol. Pharmacol., June 1, 2009; 75(6): 1364 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lupertz, Y. Chovolou, K. Unfried, A. Kampkotter, W. Watjen, and R. Kahl The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity Carcinogenesis, November 1, 2008; 29(11): 2045 - 2052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Manov, Y. Bashenko, A. Eliaz-Wolkowicz, M. Mizrahi, O. Liran, and T. C. Iancu High-Dose Acetaminophen Inhibits the Lethal Effect of Doxorubicin in HepG2 Cells: The Role of P-glycoprotein and Mitogen-Activated Protein Kinase p44/42 Pathway J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1013 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]
|
|
|
|
|
|
C. Ziemann, A. Riecke, G. Rudell, E. Oetjen, H. J. Steinfelder, C. Lass, G. F. Kahl, and K. I. Hirsch-Ernst The Role of Prostaglandin E Receptor-Dependent Signaling via cAMP in Mdr1b Gene Activation in Primary Rat Hepatocyte Cultures J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 378 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Miller, V. A. Patel, and A. Sorokin Cyclooxygenase-2 Rescues Rat Mesangial Cells from Apoptosis Induced by Adriamycin via Upregulation of Multidrug Resistance Protein 1 (P-Glycoprotein) J. Am. Soc. Nephrol., April 1, 2006; 17(4): 977 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gega, H. Yanagi, R. Yoshikawa, M. Noda, H. Ikeuchi, K. Tsukamoto, T. Oshima, Y. Fujiwara, N. Gondo, K. Tamura, et al. Successful Chemotherapeutic Modality of Doxorubicin Plus Dacarbazine for the Treatment of Desmoid Tumors in Association With Familial Adenomatous Polyposis J. Clin. Oncol., January 1, 2006; 24(1): 102 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Zatelli, A. Luchin, D. Piccin, F. Tagliati, A. Bottoni, C. Vignali, M. Bondanelli, and E. C. degli Uberti Cyclooxygenase-2 Inhibitors Reverse Chemoresistance Phenotype in Medullary Thyroid Carcinoma by a Permeability Glycoprotein-Mediated Mechanism J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5754 - 5760. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
