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Antimicrobial Agents and Chemotherapy, March 2002, p. 755-761, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.755-761.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells

Katrina L. Mealey,¹ Rola Barhoumi,² Robert C. Burghardt,² Stephen Safe,¹ and Deborah T. Kochevar^1*

Department of Veterinary Physiology and Pharmacology,¹ Veterinary Anatomy and Public Health, Texas A&M University College of Veterinary Medicine, College Station, Texas 77843-4466²

Received 13 April 2001/ Returned for modification 20 September 2001/ Accepted 10 December 2001

P-glycoprotein (P-gp) overexpression by tumor cells imparts resistance to multiple antineoplastic chemotherapeutic agents (multiple drug resistance). Treatment of tumor cells with chemotherapeutic agents such as anthracyclines, epipodophyllotoxins, and Vinca alkaloids results in induction of P-gp expression. This study was performed to determine if clinically relevant antimicrobial drugs (i.e., drugs that are used to treat bacterial infections in cancer patients) other than antineoplastic agents can induce expression of P-gp in MCF-7 breast carcinoma cells. Expression of P-gp and MDR1 mRNA was determined in samples from MCF-7 cells that were treated in culture with doxorubicin (positive control) and the antimicrobial drugs doxycycline, piperacillin, and cefoperazone. The functional status of P-gp was assessed using laser cytometry to determine intracellular doxorubicin concentrations. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used to determine if the cytotoxicity of experimental drugs was related to their ability to induce P-gp expression. MCF-7 cells treated with doxycycline (MCF-7/doxy) were stimulated to overexpress P-gp, whereas cells treated with piperacillin and cefoperazone did not overexpress P-gp. MCF-7/doxy cells were compared to a positive-control subline, MCF-7/Adr, previously selected for doxorubicin resistance, and to MCF-7 cells treated with doxorubicin (MCF-7/doxo). All three sublines overexpressed P-gp and MDR1 mRNA and accumulated less intracellular doxorubicin than did control MCF-7 cells. P-gp expression was induced only by experimental drugs that were cytotoxic (doxorubicin and doxycycline). Doxycycline, a drug that has been used for treatment of bacterial infections in cancer patients, can induce functional P-gp expression in cancer cells, resulting in multidrug resistance.

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* Corresponding author. Mailing address: 4466 Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843-4466. Phone: (979) 845-5700. Fax: (979) 845-6544. E-mail: dkochevar{at}cvm.tamu.edu.

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Antimicrobial Agents and Chemotherapy, March 2002, p. 755-761, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.755-761.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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