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

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number837
JournalBMC cancer
Issue number1
StatePublished - Aug 27 2019


  • MYCN
  • Metabolism
  • Mitochondria
  • Neuroblastoma
  • Pyrrolomycin Marinopyrrole (MP1)
  • Temsirolimus

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research


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