Document Type

Journal Article

Publication Date

10-1-2015

Journal

Aging (Albany NY)

Volume

7

Issue

10

Inclusive Pages

854-868

DOI

10.18632/aging.100831

Keywords

Adenine--analogs & derivatives; Antineoplastic Agents--pharmacology: Dansyl Compounds-pharmacology; Medulloblastoma--drug therapy; Tumor Suppressor Protein p53--antagonists & inhibitors

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.

Comments

Reproduced with permission of Impact Journals LLC.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Open Access

1

Download

Included in

Pediatrics Commons

Share

COinS