title: The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells.
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.
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Waye
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Naeem
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Muhammad Umer
authors.initials: MU
authors.lastname: Choudhry
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Parasido
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Tricoli
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Angiela
authors.initials: A
authors.lastname: Sivakumar
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Mikhaiel
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yenugonda
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.affiliation: Department of Radiation Oncology, University of Colorado, Denver, CO 80208, USA.
authors.forename: Sana D
authors.initials: SD
authors.lastname: Karam
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20057, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rood
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
authors.affiliation: Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.|Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003619:Dansyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: C557984:2-chloro-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-4-(2-(1-hydroxy-3-methylbutan-2-ylamino)-9-isopropyl-9H-purin-6-ylamino)benzamide; D000970:Antineoplastic Agents; D003619:Dansyl Compounds; D016159:Tumor Suppressor Protein p53; D000225:Adenine
keywords: BIK; Endonuclease G; apoptosis; autophagy; medulloblastoma; p53; p63; p73