Klin Padiatr 2010; 222 - A44
DOI: 10.1055/s-0030-1254495

Hydroxyurea induces a senescent, non-malignant, immunogenic state in neuroblastoma cells – a new therapeutic strategy?

S Taschner-Mandl 1, A Kowalska 1, H Binder 1, D Rieder 2, Z Trajanoski 2, J Khan 3, F Speleman 4, I Ambros 1, P Ambros 1
  • 1Children's Cancer Research Institute, Vienna, Austria
  • 2 Medical University of Innsbruck, Innsbruck, Austria
  • 3 NCI, NIH, Washington DC, USA
  • 4 Ghent University Hospital, Ghent, Belgium

Oncogene inactivation can cause cellular senescence, a permanent state of proliferative arrest, resulting in tumor “regression“. In MYCN-amplified (MNA) neuroblastoma (NB) long-term hydroxyurea (HU) treatment leads to the elimination of episomal MNA and senescence induction in vitro. The aim was to characterize senescent NB cells and describe their functional role. MLPA and arrayCGH confirmed that MNA is the only chromosomal aberration that changes between non-senescent and senescent NB-cell lines. Gene expression profiling revealed that senescent NB cells down-regulate unfavorable (e.g. survivin) and up-regulate favorable tumor markers (e.g. NTRK1, CD44). Furthermore, inhibitors of the cell cycle (p21, p15, p16), tumor growth- and angiogenesis (e.g. TIMP1, IGFBPs) were increased. In functional in vitro analyses senescent tumor cells reduced cell growth of non-senescent tumor cells and – in line with increased expression of MHCI and other immune-response-related molecules – senescent NB cells allowed T-cell and NKT-cell activation. Thus, HU induces a senescent, non-malignant, immunogenic state providing the basis for future studies using HU in NB patients to prevent tumor relapse.

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