Preclinical Assessment of MAGMAS Inhibitor As a Potential Therapy for Pediatric Medulloblastoma

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 Oct 22

PMID 39436961

Authors

Zahra Motahari

Javier J Lepe

Malia R Bautista

Clay Hoerig

Ashley S Plant-Fox

Bhaskar Das

Christie D Fowler

Suresh N Magge

Daniela A Bota

Affiliations

Soon will be listed here.

Abstract

Methods: DAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo.

Results: BT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p<0.0001; D425, 24 hours p = 0.0001, 48 hours p = 0.02). In DAOY cells, 3 μM BT9 delayed migration and significantly reduced DAOY and D425 cell invasion (p < 0.0001). It also modified mitochondrial respiratory function in both medulloblastoma cell lines. Compared to control, however, BT9 administration did not improve survival in a D425 orthotopic xenograft mouse model.

Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

References

Jubinsky P, Short M, Ghanem M, Das B . Design, synthesis, and biological activity of novel Magmas inhibitors. Bioorg Med Chem Lett. 2011; 21(11):3479-82. DOI: 10.1016/j.bmcl.2011.03.050. View

Martin A, Raabe E, Eberhart C, Cohen K . Management of pediatric and adult patients with medulloblastoma. Curr Treat Options Oncol. 2014; 15(4):581-94. PMC: 4216607. DOI: 10.1007/s11864-014-0306-4. View

Whitfield J, Soucek L . The long journey to bring a Myc inhibitor to the clinic. J Cell Biol. 2021; 220(8). PMC: 8240852. DOI: 10.1083/jcb.202103090. View

Mokranjac D, Bourenkov G, Hell K, Neupert W, Groll M . Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor. EMBO J. 2006; 25(19):4675-85. PMC: 1590002. DOI: 10.1038/sj.emboj.7601334. View

Morrish F, Hockenbery D . MYC and mitochondrial biogenesis. Cold Spring Harb Perspect Med. 2014; 4(5). PMC: 3996374. DOI: 10.1101/cshperspect.a014225. View

Ahmed N, Kadife E, Raza A, Short M, Jubinsky P, Kannourakis G . Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods. Cells. 2020; 9(3). PMC: 7140629. DOI: 10.3390/cells9030719. View

Tagliati F, Gagliano T, Gentilin E, Minoia M, Mole D, Delgi Uberti E . Magmas overexpression inhibits staurosporine induced apoptosis in rat pituitary adenoma cell lines. PLoS One. 2013; 8(9):e75194. PMC: 3775776. DOI: 10.1371/journal.pone.0075194. View

Missiroli S, Perrone M, Genovese I, Pinton P, Giorgi C . Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours. EBioMedicine. 2020; 59:102943. PMC: 7452656. DOI: 10.1016/j.ebiom.2020.102943. View

Mookerjee S, Brand M . Measurement and Analysis of Extracellular Acid Production to Determine Glycolytic Rate. J Vis Exp. 2015; (106):e53464. PMC: 4692795. DOI: 10.3791/53464. View

10.

Hovestadt V, Smith K, Bihannic L, Filbin M, Shaw M, Baumgartner A . Resolving medulloblastoma cellular architecture by single-cell genomics. Nature. 2019; 572(7767):74-79. PMC: 6754173. DOI: 10.1038/s41586-019-1434-6. View

11.

Orr B . Pathology, diagnostics, and classification of medulloblastoma. Brain Pathol. 2020; 30(3):664-678. PMC: 7317787. DOI: 10.1111/bpa.12837. View

12.

Popay T, Wang J, Adams C, Howard G, Codreanu S, Sherrod S . MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1. Elife. 2021; 10. PMC: 7793627. DOI: 10.7554/eLife.60191. View

13.

Jubinsky P, Short M, Mutema G, Morris R, Ciraolo G, Li M . Magmas expression in neoplastic human prostate. J Mol Histol. 2005; 36(1-2):69-75. DOI: 10.1007/s10735-004-3840-8. View

14.

Yang J, Das B, Aljitawi O, Kumar A, Das S, Veldhuizen P . Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease. Cancers (Basel). 2022; 14(11). PMC: 9179500. DOI: 10.3390/cancers14112732. View

15.

Gebert N, Ryan M, Pfanner N, Wiedemann N, Stojanovski D . Mitochondrial protein import machineries and lipids: a functional connection. Biochim Biophys Acta. 2010; 1808(3):1002-11. DOI: 10.1016/j.bbamem.2010.08.003. View

16.

Sinha D, Joshi N, Chittoor B, Samji P, DSilva P . Role of Magmas in protein transport and human mitochondria biogenesis. Hum Mol Genet. 2010; 19(7):1248-62. PMC: 2838536. DOI: 10.1093/hmg/ddq002. View

17.

Mehawej C, Delahodde A, Legeai-Mallet L, Delague V, Kaci N, Desvignes J . The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. PLoS Genet. 2014; 10(5):e1004311. PMC: 4006740. DOI: 10.1371/journal.pgen.1004311. View

18.

Ghosh P, Vidal C, Dey S, Zhang L . Mitochondria Targeting as an Effective Strategy for Cancer Therapy. Int J Mol Sci. 2020; 21(9). PMC: 7247703. DOI: 10.3390/ijms21093363. View

19.

Archer T, Mahoney E, Pomeroy S . Medulloblastoma: Molecular Classification-Based Personal Therapeutics. Neurotherapeutics. 2017; 14(2):265-273. PMC: 5398996. DOI: 10.1007/s13311-017-0526-y. View

20.

Tagliati F, Gentilin E, Buratto M, Mole D, degli Uberti E, Zatelli M . Magmas, a gene newly identified as overexpressed in human and mouse ACTH-secreting pituitary adenomas, protects pituitary cells from apoptotic stimuli. Endocrinology. 2010; 151(10):4635-42. DOI: 10.1210/en.2010-0441. View