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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Neuroblastoma | Research article

Effects of novel pyrrolomycin MP1 in MYCN amplified chemoresistant neuroblastoma cell lines alone and combined with temsirolimus

Authors: Timothy R. McGuire, Don W. Coulter, Dachang Bai, Jason A. Sughroue, Jerry Li, Zunhua Yang, Zhen Qiao, Yan Liu, Daryl J. Murry, Yashpal S. Chhonker, Erin M. McIntyre, Gracey Alexander, John G. Sharp, Rongshi Li

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

The activity of MP1, a pyrrolomycin, was studied in MYCN amplified neuroblastoma (NB) alone and combined with temsirolimus (TEM).

Methods

Activity of MP1 was tested in MYCN amplified (BE-2c, IMR) and non amplified (SKN-AS) NB cells. The effect of MP1 on MYCN, MCL-1, cleaved PARP, LC3II/LC3I, bcl-2, BAX, and BRD-4 were determined by western blot and RNAseq. The effect of MP1 on metabolism, mitochondrial morphology, and cell cycle was determined. Toxicology and efficacy of MP1 plus TEM were evaluated.

Results

The IC50 of MP1 was 0.096 μM in BE-2c cells compared to 0.89 μM in IMR, and >50 μM in SKN-AS. The IC50 of MP1 plus TEM in BE-2c cells was 0.023 μM. MP1 inhibited metabolism leading to quiescence and produced a decline in cell cycle S-phase. Electron microscopy showed cristae loss and rounding up of mitochondria. Gene and protein expression for MYCN and MCL-1 declined while LCII and cleaved PARP increased. Protein expression of BAX, bcl-2, and BRD-4 were not significantly changed after MP1 treatment. The in-vivo concentrations of MP1 in blood and tumor were sufficient to produce the biologic effects seen in-vitro. MP1 plus TEM produced a complete response in 3 out of 5 tumor bearing mice. In a second mouse study, the combination of MP1 and TEM slowed tumor growth compared to control.

Conclusions

MP1 has a potent inhibitory effect on the viability of MYCN amplified NB. Inhibition of metabolism by MP1 induced quiescence and autophagy with a favorable toxicology and drug distribution profile. When combined with TEM anti-tumor activity was potentiated in-vitro and in-vivo.
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Metadata
Title
Effects of novel pyrrolomycin MP1 in MYCN amplified chemoresistant neuroblastoma cell lines alone and combined with temsirolimus
Authors
Timothy R. McGuire
Don W. Coulter
Dachang Bai
Jason A. Sughroue
Jerry Li
Zunhua Yang
Zhen Qiao
Yan Liu
Daryl J. Murry
Yashpal S. Chhonker
Erin M. McIntyre
Gracey Alexander
John G. Sharp
Rongshi Li
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6033-2

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