Metronomic topotecan impedes tumor growth of MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy induced senescence
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Sabine Taschner-Mandl1, Magdalena Schwarz1, Johanna Blaha1, Maximilian Kauer1, Florian Kromp1, Nelli Frank1, Fikret Rifatbegovic1, Tamara Weiss1, Ruth Ladenstein1,2, Martin Hohenegger3, Inge M. Ambros1, Peter F. Ambros1,2
1CCRI, Chlidren's Cancer Research Institute, Vienna, Austria
2Department of Pediatrics, Medical University of Vienna, Vienna, Austria
3Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Sabine Taschner-Mandl, e-mail: firstname.lastname@example.org
Keywords: senescence-associated-secretory-phenotype, metronomic, topotecan, MYCN-amplified neuroblastoma, NFKB1
Received: November 04, 2015 Accepted: November 17, 2015 Published: December 09, 2015
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, p21WAF/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.
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