Ioannis Stathopoulos

Publications (2)11.18 Total impact

• Source

  Available from: Rinat Zaynagetdinov

  Article: Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis.

  Sophia P Karabela, Ioannis Psallidas, Taylor P Sherrill, Chrysoula A Kairi, Rinat Zaynagetdinov, Dong-Sheng Cheng, Spyridoula Vassiliou, Frank McMahon, Linda A Gleaves, Wei Han, Ioannis Stathopoulos, Spyros G Zakynthinos, Fiona E Yull, Charis Roussos, Ioannis Kalomenidis, Timothy S Blackwell, Georgios T Stathopoulos
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  ABSTRACT: Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1β and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1β, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.
  Carcinogenesis 02/2012; 33(4):859-67. · 5.70 Impact Factor
• Article: Neutralization of tumor necrosis factor bioactivity ameliorates urethane-induced pulmonary oncogenesis in mice.

  Sophia P Karabela, Chrysoula A Kairi, Sophia Magkouta, Ioannis Psallidas, Charalampos Moschos, Ioannis Stathopoulos, Spyros G Zakynthinos, Charis Roussos, Ioannis Kalomenidis, Georgios T Stathopoulos
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  ABSTRACT: Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice (n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice (n = 21) received a single control or urethane injection followed by twice-weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon γ and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon γ and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane-induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically.
  Neoplasia (New York, N.Y.) 12/2011; 13(12):1143-51. · 5.48 Impact Factor