Article

Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma.

Abramson Cancer Center, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Blood (Impact Factor: 9.78). 04/2007; 109(8):3409-16. DOI: 10.1182/blood-2006-09-047621
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
62 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multidrug resistance (MDR) is a major obstacle to the successful chemotherapy of cancer. MDR is often the result of overexpression of ATP-binding cassette (ABC) transporters following chemotherapy. A common ABC transporter that is over-expressed in MDR cancer cells is P-glycoprotein (P-gp), which actively effluxes drugs against a concentration gradient, producing an MDR phenotype. Collateral sensitivity (CS), a phenomenon of drug hypersensitivity, is defined as the ability of certain compounds to selectively target MDR cells, but not the drug-sensitive parent cells from which they were derived. The drug tiopronin has been previously shown to elicit CS. However, unlike other CS agents, the mechanism of action was not dependent on the expression of P-gp in MDR cells. We have determined that the CS activity of tiopronin is mediated by the generation of reactive oxygen species (ROS), and that CS can be reversed by a variety of ROS-scavenging compounds. Specifically, selective toxicity of tiopronin towards MDR cells is achieved by inhibition of glutathione peroxidase (GPx), and the mode of inhibition of GPx1 by tiopronin is shown in this report. Why MDR cells are particularly sensitive to ROS is discussed, as is the difficulty in exploiting this hypersensitivity to tiopronin in the clinic.
    Journal of Biological Chemistry 06/2014; · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.
    Biochemical Society Transactions 08/2014; 42(4):939-44. · 3.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Comparative Clinical Pathology 01/2013;

Full-text (2 Sources)

Download
9 Downloads
Available from
Sep 17, 2014