Evaluation of Galectin-1 as a Target for Therapy in Neuroblastoma
(2011), 102 Bl.
Dissertation / Fach: Medizin
Medizinische Fakultät » Universitätsklinikum Essen » Zentrum für Kinder- und Jugendmedizin » Klinik für Kinderheilkunde III
Eggert, Angelika (Doktorvater, Betreuerin)
Opalka, Bertram; Lode, Hartmut (GutachterIn)
Neuroblastoma (NB) is the second most common tumour of childhood with about 40% of the cases already metastasised at diagnosis. High-risk NB is a difficult disease to treat and relapsing minimal residual disease is generally resistant to current therapeutic regiments hence the need for novel therapeutic options. Previous studies showed that galectin-1 mRNA is up-regulated in patients with invasive, relapsing NB and the protein was up-regulated in an in vitro model of aggressive, TrkB-expressing NB. Also, galectin-1 protein has been reported to be important for invasion and migration of NB cells. Furthermore, galectin-1 knock-down has been demonstrated to synergistically potentiate the proautophagic effects of the drug temozolomide (TMZ) in a melanoma in vivo model. Inhibition of H-ras/Galectin-1 interaction by small molecule inhibitors, such as farnesylthiosalicylate (FTS), has proved anticancer activity in various model systems and is now proceeding to clinical development. However, the precise role of galectin-1 in NB has not been elucidated in vivo. In this study, we analyzed the effects of galectin-1 inhibition in NB experimental models using RNA interference technology and HDAC inhibitors alone and/or in combination with the novel NB promising therapies temozolomide and farnesylthiosalicylate. Here, we first showed that though HDAC inhibitors resulted in a decreased viability of NB cells in vitro, they however increased the expression of galectin-1 in neuroblastoma. Further experiments showed that galectin-1 depletion in SK-N-BE(2) NB cell line was synergistic to the anti-proliferative effects of suberoyl hydroxamic acid (SAHA), an HDAC inhibitor, thereby suggesting that galectin-1 silencing can provide an additional benefit to HDAC inhibitor treatment in neuroblastoma. This study demonstrated that silencing galectin-1 expression in both human and mouse neuroblastoma cells by means of small interfering RNA directed against galectin-1resulted in a decreased proliferation of NB cells in vitro. Decreasing the expression of galectin-1 in a NB xenograft model reduced tumour burden and prolonged the survival of tumour-bearing mice. Furthermore, the therapeutic potential of both FTS and TMZ were elucidated. While FTS did not show anti-tumoral activity except for one NB murine cell line, NXS2, in vitro and in vivo, TMZ was effective in inhibiting growth of NB tumours and prolonging the survival of tumour-bearing mice in both syngeneic and xenograft NB models. However, there was no synergistic effect of combining TMZ and FTS or of silencing galectin-1 and treatment with either FTS or TMZ both in vitro and in vivo. Further studies on the mechanisms by which galectin-1 loss and TMZ treatment causes tumour growth inhibition showed that these treatments did not result in any reduction in proliferation or changes in cell cycle distribution as showed by Ki67 proliferation index and FACS analysis respectively. In summary, this work has demonstrated that blocking galectin-1 function reduces growth of aggressive neuroblastoma cells both in vitro and in vivo. Thus, this study suggests that targeting galectin-1 appears to be an interesting and promising therapeutic strategy in neuroblastoma.
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