title: P-glycoprotein is expressed and causes resistance to chemotherapy in EBV-positive T-cell lymphoproliferative diseases.
abstract: Epstein-Barr virus-positive T-cell lymphoproliferative diseases (EBV-T-LPDs) are rare lymphomas with poor prognosis. Although chemotherapeutic strategies such as CHOP have been often selected, they have exhibited only limited efficacy. To clarify the mechanism of chemoresistance, we examined P-glycoprotein (P-gp) expression. P-gp acts as an energy-dependent efflux pump that excretes drugs from the cytoplasm, resulting in low-intracellular drug concentrations and poor sensitivity to chemotherapy. We examined P-gp expression in EBV-positive cells by immunohistochemistry staining in three patients of EBV-T-LPDs and the expression was detected in all patients. We also examined mdr1 mRNA expression by reverse-transcriptase polymerase-chain reaction (RT-PCR) in EBV-positive tumor cells from these patients and additional three patients. The expression was detected in all examined patients. In five EBV-T-LPDs patients, P-gp function was detected by Rhodamine-123 efflux assay in these cells. The efflux was inhibited by treatment with a P-gp inhibitor, cyclosporine A (CsA). We also examined and detected P-gp expression in EBV-positive T-cell lines SNT8 and SNT16 established from EBV-T-LPDs patients, by RT-PCR and western blotting. The function was also detected by Rhodamine-123 efflux in these cell lines. Inhibition and knock down of P-gp by CsA and siRNA, respectively, enhanced etoposide- and doxorubicin-induced cell death in the EBV-positive T-cell lines. Finally, we infected the T-cell line MOLT4 with EBV, and found that mdr1 mRNA expression and Rhodamine 123 efflux were upregulated after infection. These results indicated that enhanced P-gp expression contributed to the chemoresistance of EBV-T-LPDs.
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshimori
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Takada
authors.affiliation: Division of Advanced Medicine for Virus Infections, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Imadome
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Division of Medical Science, Department of Virology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Arai
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014750:Vincristine; D004317:Doxorubicin; D016572:Cyclosporine; D003520:Cyclophosphamide; D011241:Prednisone
keywords: Drug resistance; EBV; P-glycoprotein; T-cell lymphoma; lymphoproliferative disorders