TY - JOUR
T1 - MP-Pt(IV)
T2 - A MAOB-sensitive mitochondrial-specific prodrug for treating glioblastoma
AU - Raghavan, Sudhir
AU - Baskin, David S.
AU - Sharpe, Martyn A.
N1 - Funding Information:
This work was supported by Donna and Kenneth Peak, The Kenneth R. Peak Foundation, The John S. Dunn Foundation, The Taub Foundation, The Blanche Green Fund of the Pauline Sterne Wolff Memorial Foundation, The Kelly Kicking Cancer Foundation, The Gary and Marlee Schwarz Foundation, and The Methodist Hospital Foundation & The Veralan Foundation. The John S. Dunn Foundation also supports M.A. Sharpe’s distinguished professorship. We are grateful to the many patients and their families who have participated in our studies, and who are dedicated to joining us in our fight against brain cancer. We thank Tanvi Kumar and Sophie Lopez for their technical support. The results shown here are in whole or partly based upon data generated by TCGA Research Network (https://www.cancer.gov/tcga. CCGA), and Gravendeel databases were accessed via GlioVis (http://gliovis.bioinfo. cnio.es/).
Publisher Copyright:
© 2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - We have previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide (MP-MUS), a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme, monoamine oxidase B (MAOB), is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially targeted cationic form, methyl-pyridinium (Pþ-). Coupling this MAOB-sensitive group to a nitrogen mustard produced a prodrug that damaged GBM mitochondria and killed GBM cells. Unfortunately, the intrinsic reactivity of the nitrogen mustard group and low solubility of MP-MUS precluded clinical development. In our second-generation prodrug, MP-Pt(IV), we coupled the MP group to an unreactive cisplatin precursor. The enzymatic conversion of MP-Pt(IV) to Pþ-Pt(IV) was tested using recombinant human MAOA and rhMAOB. The generation of cisplatin from Pt(IV) by ascorbate was studied optically and using mass spectroscopy. Efficacy toward primary GBM cells and tumors was studied in vitro and in an intracranial patient-derived xenograft mice GBM model. Our studies demonstrate that MP-Pt(IV) is selectively activated by MAOB. MP-Pt(IV) is highly toxic toward GBM cells in vitro. MP-Pt(IV) toxicity against GBM is potentiated by elevating mitochondrial ascorbate and can be arrested by MAOB inhibition. In in vitro studies, sublethal MP-Pt(IV) doses elevated mitochondrial MAOB levels in surviving GBM cells. MP-Pt(IV) is a potent chemotherapeutic in intracranial patient-derived xenograft mouse models of primary GBM and potentiates both temozolomide and temozolomide–chemoradiation therapies. MP-Pt (IV) was well tolerated and is highly effective against GBM in both in vitro and in vivo models.
AB - We have previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide (MP-MUS), a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme, monoamine oxidase B (MAOB), is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially targeted cationic form, methyl-pyridinium (Pþ-). Coupling this MAOB-sensitive group to a nitrogen mustard produced a prodrug that damaged GBM mitochondria and killed GBM cells. Unfortunately, the intrinsic reactivity of the nitrogen mustard group and low solubility of MP-MUS precluded clinical development. In our second-generation prodrug, MP-Pt(IV), we coupled the MP group to an unreactive cisplatin precursor. The enzymatic conversion of MP-Pt(IV) to Pþ-Pt(IV) was tested using recombinant human MAOA and rhMAOB. The generation of cisplatin from Pt(IV) by ascorbate was studied optically and using mass spectroscopy. Efficacy toward primary GBM cells and tumors was studied in vitro and in an intracranial patient-derived xenograft mice GBM model. Our studies demonstrate that MP-Pt(IV) is selectively activated by MAOB. MP-Pt(IV) is highly toxic toward GBM cells in vitro. MP-Pt(IV) toxicity against GBM is potentiated by elevating mitochondrial ascorbate and can be arrested by MAOB inhibition. In in vitro studies, sublethal MP-Pt(IV) doses elevated mitochondrial MAOB levels in surviving GBM cells. MP-Pt(IV) is a potent chemotherapeutic in intracranial patient-derived xenograft mouse models of primary GBM and potentiates both temozolomide and temozolomide–chemoradiation therapies. MP-Pt (IV) was well tolerated and is highly effective against GBM in both in vitro and in vivo models.
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U2 - 10.1158/1535-7163.MCT-20-0420
DO - 10.1158/1535-7163.MCT-20-0420
M3 - Article
C2 - 33033175
AN - SCOPUS:85100461163
VL - 19
SP - 2445
EP - 2453
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 12
ER -