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.
Highlights
Epstein–Barr virus (EBV) can infect B cells and rarely T or natural killer (NK) cells in EBV-p ositive T/NK-cell neoplasms, such as extranodal NK/T-cell lymphoma (ENKL), aggressive NK-cell leukemia, some peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), and EBV-positive T-cell lymphoproliferative diseases (EBV-T-LPDs)
We investigated the specimen from three EBV-negative diffuse large B-cell lymphoma (DLBCL) patients, whose disease responded to CHOP regimen
Immunochemotherapy consisting of cyclosporine A (CsA), etoposide, and prednisolone followed by chemotherapy has been the most commonly used EBV-T -LPDs treatment [5]
Summary
Epstein–Barr virus (EBV) can infect B cells and rarely T or natural killer (NK) cells in EBV-p ositive T/NK-cell neoplasms, such as extranodal NK/T-cell lymphoma (ENKL), aggressive NK-cell leukemia, some peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), and EBV-positive T-cell lymphoproliferative diseases (EBV-T-LPDs). Koyama and colleagues reported the effects of sequential chemotherapy consisting of immunochemotherapy: cyclosporine A (CsA), etoposide, and prednisolone followed by CHOP and Capizzi [5] This strategy has been widely used as an induction therapy of EBV-T-LPDs. the efficacy for the disorders was limited and EBV-positive cells could not be eradicated in most cases [6]. It was previously reported that the tumor cells of ENKL, one type of EBV-positive NK -cell neoplasms, expressed P-gp, resulting in high resistance to chemotherapy [12]. (1) clinical findings described in the previous reports, presence of characteristic clinical findings such as persistent IM-like symptoms, HMB, HV, (2) high-EBV load detected in peripheral blood mononuclear cells (PBMCs) by quantitative polymerase chain reaction (PCR) (>102.5 copies/μg of EBV DNA), and (3) EBV infection on T cells. Infection was verified by EBV–DNA quantitation, and immune fluorescence staining of EBV nuclear antigen (EBNA) staining of the cells as described using Polyclonal Rabbit Anti-Human C3c Complement/FITC antibody (Dako, Glostrup, Denmark) [24]
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