The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma

Autor: Shannon Kelly, Jeffrey P. Bond, Austin Goodyke, Abhinav Nagulapally, Tyler Maser, Anna Ostrander, Giselle Saulnier Sholler, Joseph Zagorski, Yeonhee Park
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
p53
Cancer Research
Apoptosis
MYC
Piperazines
Mice
Neuroblastoma
0302 clinical medicine
MYCN
Antineoplastic Combined Chemotherapy Protocols
Oncogene MYCN
Cytotoxic T cell
Original Research
Cancer Biology
Caspase 7
medicine.diagnostic_test
biology
Chemistry
Caspase 3
Drug Synergism
Proto-Oncogene Proteins c-mdm2
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Oncology
030220 oncology & carcinogenesis
Mdm2
Female
Heterocyclic Compounds
3-Ring
Signal Transduction
Programmed cell death
Cell Survival
lcsh:RC254-282
Flow cytometry
BET inhibitor
Proto-Oncogene Proteins c-myc
03 medical and health sciences
MDM2
Cell Line
Tumor
medicine
Animals
Humans
Radiology
Nuclear Medicine and imaging
neoplasms
Cell Proliferation
Proteins
medicine.disease
BET
Isoquinolines
G1 Phase Cell Cycle Checkpoints
Enzyme Activation
030104 developmental biology
Cancer research
biology.protein
Acetanilides
Tumor Suppressor Protein p53
Neoplasm Transplantation
Zdroj: Cancer Medicine
Cancer Medicine, Vol 9, Iss 21, Pp 8144-8158 (2020)
ISSN: 2045-7634
Popis: Background Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high‐risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra‐Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma. Methods Two p53 wild‐type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host. Results The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death. Conclusion This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.
Recent literature suggests that targeting MYC family genes as well as MDM2, the negative regulator of p53, may be a viable approach to the treatment of NB. We targeted these endpoints using the BET inhibitor OTX015 and the MDM2 inhibitor CGM097 and demonstrated a synergistic increase in cell death, activation of the p53 pathway, and a significant increase in time to event in vivo, further implicating these pathways in the biology and treatment of NB.
Databáze: OpenAIRE
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