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Metronomic topotecan impedes tumor growth of MYCN -amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence

Taschner-Mandl, Sabine ; Schwarz, Magdalena ; Blaha, Johanna ; Kauer, Maximilian ; Kromp, Florian ; Frank, Nelli ; Rifatbegovic, Fikret ; Weiss, Tamara ; Ladenstein, Ruth ; Hohenegger, Martin ; Ambros, Inge M ; Ambros, Peter F

Oncotarget, 2015, Vol.7(3), p.3571-3586 [Peer Reviewed Journal]

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  • Title:
    Metronomic topotecan impedes tumor growth of MYCN -amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence
  • Author/Creator: Taschner-Mandl, Sabine ; Schwarz, Magdalena ; Blaha, Johanna ; Kauer, Maximilian ; Kromp, Florian ; Frank, Nelli ; Rifatbegovic, Fikret ; Weiss, Tamara ; Ladenstein, Ruth ; Hohenegger, Martin ; Ambros, Inge M ; Ambros, Peter F
  • Subjects: Research Paper ; Senescence-Associated-Secretory-Phenotype ; Metronomic ; Topotecan ; Mycn-Amplified Neuroblastoma ; Nfkb1
  • Is Part Of: Oncotarget, 2015, Vol.7(3), p.3571-3586
  • Description: Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth-arrest and act immune-stimulatory, while others are tumor-promoting. We evaluated whether metronomic, i.e. long-term, repetitive low-dose, drug treatment induces senescence in vitro and in vivo . And importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified. We demonstrate that metronomic application of chemotherapeutic drugs induces therapy-induced senescence, characterized by cell cycle arrest, p21 WAF/CIP1 up-regulation and DNA double-strand breaks selectively in MYCN -amplified NB. Low-dose topotecan (TPT) was identified as an inducer of a favorable SASP while lacking NFKB1/p50 activation. In contrast, Bromo-deoxy-uridine induced senescent NB-cells secret a tumor-promoting SASP in a NFKB1/p50-dependent manner. Importantly, TPT-treated senescent tumor cells act growth-inhibitory in a dose-dependent manner on non-senescent tumor cells and MYCN expression is significantly reduced in vitro and in vivo . Furthermore, in a mouse xenotransplant-model for MYCN -amplified NB metronomic TPT leads to senescence selectively in tumor cells, complete or partial remission, prolonged survival and a favorable SASP. This new mode-of-action of metronomic TPT treatment, i.e. promoting a tumor-inhibiting type of senescence in MYCN-amplified tumors, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles.
  • Identifier: E-ISSN: 1949-2553 ; DOI: 10.18632/oncotarget.6527 ; PMCID: 4823128 ; PMID: 26657295