BACKGROUND: Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas. DESIGN AND METHODS: Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis. RESULTS: Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation. CONCLUSIONS: We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.
BACKGROUND:Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas. DESIGN AND METHODS: Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis. RESULTS: Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation. CONCLUSIONS: We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.
Authors: Joseph D Khoury; L Jeffrey Medeiros; George Z Rassidakis; Timothy J McDonnell; Lynne V Abruzzo; Raymond Lai Journal: J Pathol Date: 2003-01 Impact factor: 7.996
Authors: Izidore S Lossos; Ash A Alizadeh; Maximilian Diehn; Roger Warnke; Yvonne Thorstenson; Peter J Oefner; Patrick O Brown; David Botstein; Ronald Levy Journal: Proc Natl Acad Sci U S A Date: 2002-06-19 Impact factor: 11.205
Authors: Sven de Vos; Wolf-Karsten Hofmann; Thomas M Grogan; Utz Krug; Mathew Schrage; Thomas P Miller; Jonathan G Braun; William Wachsman; H Phillip Koeffler; Jonathan W Said Journal: Lab Invest Date: 2003-02 Impact factor: 5.662
Authors: D R Ferry; A Smith; J Malkhandi; D W Fyfe; P G deTakats; D Anderson; J Baker; D J Kerr Journal: Clin Cancer Res Date: 1996-04 Impact factor: 12.531
Authors: B N Singh; D K Upreti; B R Singh; G Pandey; S Verma; S Roy; A H Naqvi; A K S Rawat Journal: Antimicrob Agents Chemother Date: 2015-02-02 Impact factor: 5.191