Immunohistochemical Expression of Multidrug Resistance Proteins as a Predictor of Poor Response to Chemotherapy and Prognosis in Patients with Nodal Diffuse Large B-Cell Lymphoma

Ohsawa, Masahiko; Ikura, Yoshihiro; Fukushima, Hiroko; Shirai, Nobuyuki; Sugama, Yoshimi; Suekane, Takehisa; Hirayama, Michihiko; Hino, Masayuki; Ueda, Makiko

doi:10.1159/000086984

Cited by 49 publications

(38 citation statements)

References 64 publications

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“…In human medicine P-gp expression has been observed mainly in cutaneous T-cell lymphomas (Jillella et al 2000), nasal NK/T lymphomas (Saglam et al 2008), acute lymphoblastic leukemia (ALL) (Plasschaert et al 2003), chronic lymphocytic leukemia (Jamroziak et al 2004) and DLBCL (Ohsawa et al 2005). In our study positive P-gp labeling was observed in LBL, CBL, BLL and CB/CCL.…”

Section: Discussionsupporting

confidence: 59%

Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas

Sokołowska¹,

Urbańska²,

Gizinski³

et al. 2015

Polish Journal of Veterinary Sciences

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Combination chemiotherapy is the current standard of care for dogs with lymphoma. Multidrug resistance is one of the most important factors contributing to the efficacy of chemiotherapy. The major protein responsible for this phenomenon is P-glycoprotein. Little is known about P-glycoprotein expression in particular subtypes of lymphomas. The aim of the study was evaluation of P-glycoprotein expression in various subtypes of canine lymphomas. Positive reaction with P-glycoprotein was found in 12/25 cases of various morphological subtypes of lymphomas, however, in 3/11 lymphomas the percentage of positively weakly stained cells was <10% and those tumors were also considered negative. Tumors with 10-50% P-glycoprotein positive cells were found in single cases of centroblastic and centroblastic-centrocytic tumors. In 5 lymphomas P-glycoprotein expression exceeded 50% of tumor cells. Those cases were found among centroblastic, centroblastic-centrocytic, lymphoblastic and Burkitt-like subtypes. Positive reaction was observed mainly in the cell cytoplasm, however, in some cases prominent perinuclear dot-like staining pattern was found. In 2 cases focal staining pattern comprised dominant type of immunolabelling. Among all lymphomas containing P-glycoprotein positive cells intensity of imunolabelling was assessed as weak (6/25), moderate (2/25) and strong (3/25). Our results indicate that P-glycoprotein expression is present in nearly one third of newly diagnosed canine lymphomas of different morphological subtypes including those most commonly occurring, such as cenroblastic lymphomas. Hence, determination of P-glycoprotein expression at the time of diagnosis could provide valuable information for the design of treatment protocols. Moreover, our results have shown that P-glycoprotein expression in canine tumors could be located in Golgi-zone.

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Section: Discussionsupporting

confidence: 59%

Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas

Sokołowska¹,

Urbańska²,

Gizinski³

et al. 2015

Polish Journal of Veterinary Sciences

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“…MRP1 functions similarly to MDR1 in reducing tumor sensitivity to chemotherapy, and it can recognize and pump out chemotherapy drugs bound to glutathione in tumor cells. High expression of MDR1 and MRP1 in different types of B cell lymphoma tissues has been associated with poor response to chemotherapy (25). Thus, our finding, that Mda-7/IL-24 overexpression downregulated MDR1 and MRP1 expression in Raji and Daudi cells, suggests that Mda-7/IL-24 may enhance the intracellular accumulation of anticancer drugs.…”

Section: Discussionmentioning

confidence: 59%

Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs

Zhao

Sun

et al. 2016

Oncology Reports

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Abstract. ) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC 50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC 50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells. Furthermore, the activities of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells were suppressed. These results indicated that Mda-7/IL-24 enhanced the sensitivity of B lymphoma cells to chemotherapy agents by altering the expression of multidrug-resistance genes via downregulating GTP-RhoA-ERK signaling pathway, suggesting that treatment of B cell lymphomas with Mda-7/IL-24 could avoid MDR.

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“…The overexpression of major vault protein (MVP), also called lung resistance (-related) protein (LRP/LRRP), in the cured cohort was unexpected because expression of this protein on tumour cells has been associated with chemotherapy resistance in DLBCL (Ohsawa et al, 2005). However, in this study, MVP/LRRP was mainly expressed by the tumourinfiltrating reactive cells and mightin this positionhave a different function (Schroeijers et al, 2002).…”

Section: Discussionmentioning

confidence: 62%

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

et al. 2008

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SummaryIn order to identify genes associated with primary chemotherapy‐resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B‐cell lymphoma (DLBCL), stage II–IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy‐nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM‐1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin‐3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

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Immunohistochemical Expression of Multidrug Resistance Proteins as a Predictor of Poor Response to Chemotherapy and Prognosis in Patients with Nodal Diffuse Large B-Cell Lymphoma

Cited by 49 publications

References 64 publications

Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas

Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas

Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

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