Abstract
Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB.
Highlights
Medulloblastoma (MB) is a primitive neuroectodermal tumor that arises from granule neuron precursors in the cerebellum or from neural stem cells of the rhombic lip and is the most frequently diagnosed malignant brain tumor in children [1]
D556 cells were treated with VMY or its parent compound purvalanol B (PVB) for 18 hrs, at which point the media was changed and the cells were allowed to recover in the absence of the drugs until the control plate reached 80% confluency
Apoptosis and autophagy are activated under a variety of cell stress conditions, little is known about how these complex and partially overlapping mechanisms are induced in medulloblastoma cells
Summary
Medulloblastoma (MB) is a primitive neuroectodermal tumor that arises from granule neuron precursors in the cerebellum or from neural stem cells of the rhombic lip and is the most frequently diagnosed malignant brain tumor in children [1]. MB is seen in patients between 20 and 44 years of age, with incidences falling off significantly thereafter. A combination of surgery, radiotherapy, and chemotherapy has contributed to improved treatment outcomes, resulting in a 70-80% five-year disease-free patients with medulloblastoma remain significant and recurrence is frequently observed. Disease recurrence is nearly always fatal, and late mortality remains a serious health issue in long-term MB survivors [2]. Current therapies result in significant negative impacts on neurological, cognitive and social development, especially in the youngest affected children. Significant efforts are underway to develop more effective and less toxic MB treatments
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