Andreadis C, Gimotty PA, Wahl P, Hammond R, Houldsworth J, Schuster SJ et al.. Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma. Blood 109: 3409-3416

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Blood (Impact Factor: 10.45). 04/2007; 109(8):3409-16. DOI: 10.1182/blood-2006-09-047621
Source: PubMed


Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL). Some of these failures can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based expression microarray datasets obtained prior to therapy from patients with DLBCL. Among genes in the GSH family, glutathione peroxidase 1 (GPX1) had the most significant adverse effect on disease-specific overall survival (dOS) in the primary dataset (n = 130) (HR: 1.68; 95% CI: 1.26-2.22; P < .001). This effect remained statistically significant after controlling for biologic signature, LLMPP cell-of-origin signature, and IPI score, and was confirmed in the validation dataset (n = 39) (HR: 1.7; 95% CI: 1.05-2.8; P = .033). Recursive partitioning identified a group of patients with low-level expression of GPX1 and multidrug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (P < .001). Overall, our findings suggest an important association of oxidative-stress defense and drug elimination with treatment failure in DLBCL and identify GPX1 and ABCB1 as potentially powerful biomarkers of early failure and disease-specific survival.

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Available from: Rachel S Rogers (Hammond), Sep 17, 2014
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    • "One of the most interesting previous observations, concerns the significant correlation between the concentration of antioxidant enzymes, inflammatory proteins and the clinical status of the patient, such as to attribute a prognostic role to oxidative stress parameters (Mantovani et al. 2002).The prognostic role of oxidative stress in human lymphomas has also been studied, with conflicting results. According to some authors , the worst prognosis were those with decreased expression of antioxidant enzymes, but, according to others, the conclusions were exactly the opposite (Tome et al. 2005; Andreadis et al. 2007; Peroja et al. 2012). Even the use of chemotherapeutics can significantly affect the production of radical species and therefore, the consumption of antioxidants. "
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    ABSTRACT: In the last 20 years, an increasing interest toward oxidative stress has been documented in order to investigate their direct or indirect involvement in several mechanisms regarding oncogenesis and lymphomas in particular. The aim of this paper was to evaluate oxidative stress in dogs affected by malignant lymphoma in comparison to a control group, to investigate what factors can affect this status, and to point out similarities and differences with human. Forty-eight samples from four subjects, affected by high-grade centroblastic polymorphic lymphoma and receiving a standard chemotherapy, have been processed for derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests. The obtained data show a condition of oxidative stress in dogs with lymphoma, with a significant increase in reactive oxygen species (ROS) plasma levels and a decrease in antioxidant capacity. No significant differences emerged on the basis of remission. Further results of canine studies about oxidative status in lymphomas could be a model for human, according to analogy between them.
    Full-text · Article · Jan 2013 · Comparative Clinical Pathology
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    • "Their results suggested that the group with the worst prognosis were those with decreased expression of antioxidant enzymes, including catalase, glutathione peroxidase and MnSOD, and increased expression of Trx. In a study by Andreadis et al. (2007) [24], the expression of genes in the glutathione family was examined. Their data suggested that overexpression of these genes correlated with worse prognosis. "
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    ABSTRACT: Oxidative stress and redox-regulating enzymes may have roles both in lymphomagenesis and resistance to lymphoma therapy. Previous studies from the pre-rituximab era suggest that antioxidant enzyme expression is related to prognosis in diffuse large B-cell lymphoma (DLBCL), although these results cannot be extrapolated to patient populations undergoing modern treatment modalities. In this study we assessed expression of the oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and the antioxidant enzymes thioredoxin (Trx), manganese superoxide dismutase (MnSOD) and glutamate-cysteine ligase (GCL) via immunohistochemistry in 106 patients with DLBCL. All patients were treated with CHOP-like therapy combined with rituximab. Immunostaining results were correlated with progression-free survival, disease-specific survival and traditional prognostic factors of DLBCL. Strong 8-OHdG immunostaining intensity was associated with extranodal involvement (p = 0.00002), a high International Prognostic Index (p = 0.002) and strong Trx (p = 0.011) and GCL (p = 0.0003) expression. Strong Trx staining intensity was associated with poor progression-free survival (p = 0.046) and poor disease-specific survival (p = 0.015). Strong GCL immunostaining intensity predicted poor progression-free survival (p = 0.049). Patients with either strong Trx or strong nitrotyrosine expression showed significantly poorer progression-free survival (p = 0.003) and disease-specific survival (p = 0.031) compared with the other patients. The redox state-regulating enzymes GCL and Trx are promising markers in the evaluation of DLBCL prognosis in the era of modern immunochemotherapy.
    Full-text · Article · Mar 2012
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    • "We previously reported that DLBCL patients with high ABCG2 protein expression showed significantly shorter overall survival and failure free-survival compared with patients with tumors with low or no expression of ABCG2 (Kim et al., 2009). However, Andreadis and colleagues (Andreadis et al., 2007) found no association between ABCG2 mRNA levels with outcome in a series of 130 DLBCL patients. "
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    ABSTRACT: Successful treatment of diffuse large B-cell lymphoma (DLBCL) is frequently hindered by the development of resistance to conventional chemotherapy resulting in disease relapse and high mortality. High expression of antiapoptotic and/or drug transporter proteins induced by oncogenic signaling pathways has been implicated in the development of chemoresistance in cancer. Previously, our studies showed that high expression of adenosine triphosphate-binding cassette drug transporter ABCG2 in DLBCL correlated inversely with disease- and failure-free survival. In this study, we have implicated activated hedgehog (Hh) signaling pathway as a key factor behind high ABCG2 expression in DLBCL through direct upregulation of ABCG2 gene transcription. We have identified a single binding site for GLI transcription factors in the ABCG2 promoter and established its functionality using luciferase reporter, site-directed mutagenesis and chromatin-immunoprecipitation assays. Furthermore, in DLBCL tumor samples, significantly high ABCG2 and GLI1 levels were found in DLBCL tumors with lymph node involvement in comparison with DLBCL tumor cells collected from pleural and/or peritoneal effusions. This suggests a role for the stromal microenvironment in maintaining high levels of ABCG2 and GLI1. Accordingly, in vitro co-culture of DLBCL cells with HS-5 stromal cells increased ABCG2 mRNA and protein levels by paracrine activation of Hh signaling. In addition to ABCG2, co-culture of DLBCL cells with HS-5 cells also resulted in increase expression of the antiapoptotic proteins BCL2, BCL-xL and BCL2A1 and in induced chemotolerance to doxorubicin and methotrexate, drugs routinely used for the treatment of DLBCL. Similarly, activation of Hh signaling in DLBCL cell lines with recombinant Shh N-terminal peptide resulted in increased expression of BCL2 and ABCG2 associated with increased chemotolerance. Finally, functional inhibition of ABCG2 drug efflux activity with fumitremorgin C or inhibition of Hh signaling with cyclopamine-KAAD abrogated the stroma-induced chemotolerance suggesting that targeting ABCG2 and Hh signaling may have therapeutic value in overcoming chemoresistance in DLBCL.
    Full-text · Article · May 2011 · Oncogene
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