Abstract
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.
Highlights
Patients with metastatic neuroblastoma (NB) frequently suffer from relapse and have a high risk of succumbing to the disease
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
We here provide evidence that metronomic, low dose topotecan treatment leads to DNA-damage, p21WAF/CIP1 up-regulation, senescence and tumor regression in vitro and in vivo selectively in MNA NB cells
Summary
Patients with metastatic neuroblastoma (NB) frequently suffer from relapse and have a high risk of succumbing to the disease. The physiological and pathophysiological role of cellular senescence includes organogenesis during embryonic development [11, 12] and organismal aging [13] as well as removal of damaged cells, as seen upon oncogeneactivation in pre-malignant lesions preventing tumor initiation [14]. Senescent stromal cells, i.e. fibroblasts, stimulate the proliferation of premalignant and malignant epithelial cells in culture, and the tumorigenicity of premalignant cells in mouse xenografts [18]. It is unclear whether TIS – affecting probably both, tumor and stroma – will have tumorpromoting or -inhibiting effects
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