Targeting pheochromocytoma/paraganglioma with polyamine inhibitors.
DENSPM
DESPM
Paraganglioma (PGL)
Pheochromocytoma (PCC)
Polyamine
SDHB
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
03
04
2020
revised:
12
06
2020
accepted:
17
06
2020
pubmed:
21
6
2020
medline:
9
10
2020
entrez:
21
6
2020
Statut:
ppublish
Résumé
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting. Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts. This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
Sections du résumé
BACKGROUND
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.
METHODS
Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N
RESULTS
Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.
CONCLUSIONS
This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.
Identifiants
pubmed: 32562798
pii: S0026-0495(20)30161-X
doi: 10.1016/j.metabol.2020.154297
pmc: PMC7482423
mid: NIHMS1624433
pii:
doi:
Substances chimiques
Biogenic Polyamines
0
SDHB protein, human
EC 1.3.5.1
Succinate Dehydrogenase
EC 1.3.99.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
154297Subventions
Organisme : RRD VA
ID : I01 RX003123
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205224
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 HD999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA HD008735
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest R.B. invented the polyamine drug platforms and holds a number of patents in polyamine drug development. H.K.G. received royalties from the University of Texas Southwestern Medical Center at Dallas.
Références
J Nutr. 2002 Aug;132(8 Suppl):2345S-2349S
pubmed: 12163690
Cell. 2015 Jul 30;162(3):540-51
pubmed: 26232224
Exp Clin Endocrinol Diabetes. 2019 Feb;127(2-03):117-128
pubmed: 30235495
J Clin Oncol. 2005 Dec 1;23(34):8812-8
pubmed: 16314641
J Clin Endocrinol Metab. 2018 May 1;103(5):1779-1789
pubmed: 29409060
Cancer Res. 1985 May;45(5):2050-7
pubmed: 3921235
BMC Res Notes. 2015 Jun 24;8:257
pubmed: 26104921
Nat Cell Biol. 2015 Oct;17(10):1317-26
pubmed: 26302408
Horm Metab Res. 2012 May;44(5):328-33
pubmed: 22328163
J Proteomics Bioinform. 2015 Jun;8(6):126-132
pubmed: 26401069
Metabolites. 2017 May 04;7(2):
pubmed: 28471419
Mol Cell Proteomics. 2014 Feb;13(2):397-406
pubmed: 24309898
Int J Cancer. 2010 May 1;126(9):2012-24
pubmed: 19960435
Curr Protoc Bioinformatics. 2012 Mar;Chapter 14:Unit14.11
pubmed: 22389014
J Clin Endocrinol Metab. 2006 Mar;91(3):827-36
pubmed: 16317055
Science. 1984 Jun 8;224(4653):1121-4
pubmed: 6719137
Nucleic Acids Res. 2016 Jul 8;44(W1):W194-200
pubmed: 27098040
Nucleic Acids Res. 2012 May;40(10):4288-97
pubmed: 22287627
Clin Chem. 2018 Nov;64(11):1646-1656
pubmed: 30097498
Drug Metab Dispos. 1995 Oct;23(10):1117-25
pubmed: 8654201
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7804-8
pubmed: 8356088
Results Probl Cell Differ. 2008;44:201-21
pubmed: 17579816
Cancers (Basel). 2019 Apr 28;11(5):
pubmed: 31035382
PLoS One. 2013 Jun 13;8(6):e65624
pubmed: 23785438
Virchows Arch. 2017 Oct;471(4):553-557
pubmed: 28864906
Clin Cancer Res. 1995 Aug;1(8):847-57
pubmed: 9816054
J Clin Endocrinol Metab. 2014 Oct;99(10):3903-11
pubmed: 25014000
Curr Opin Endocrinol Diabetes Obes. 2019 Jun;26(3):146-154
pubmed: 30893083
Oncogene. 1989 Sep;4(9):1117-21
pubmed: 2780050
J Histochem Cytochem. 1999 Nov;47(11):1395-404
pubmed: 10544213
Nat Rev Cancer. 2018 Nov;18(11):681-695
pubmed: 30181570
Endocr Pract. 2016 Mar;22(3):302-14
pubmed: 26523625
Br J Cancer. 2004 Jan 26;90(2):535-41
pubmed: 14735205
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19190-5
pubmed: 23091029
Biochem J. 1988 Apr 15;251(2):559-62
pubmed: 3135801
Clin Cancer Res. 2009 Oct 1;15(19):5956-61
pubmed: 19789308
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Cancer Res. 2009 Jan 15;69(2):547-53
pubmed: 19147568
Cancer Cell. 2013 Jun 10;23(6):739-52
pubmed: 23707781
Hum Mol Genet. 2011 Oct 15;20(20):3974-85
pubmed: 21784903
J Biol Chem. 2018 Nov 30;293(48):18757-18769
pubmed: 30404920
Clin Cancer Res. 2016 Sep 1;22(17):4391-404
pubmed: 27012811
Anal Chem. 2000 Mar 15;72(6):1236-41
pubmed: 10740865
Sci Transl Med. 2019 Jan 30;11(477):
pubmed: 30700572
Nat Commun. 2015 Nov 02;6:8784
pubmed: 26522426
J Pharmacol Exp Ther. 1996 Jul;278(1):185-92
pubmed: 8764350
Cancer Cell. 2017 Feb 13;31(2):181-193
pubmed: 28162975
Int Med Case Rep J. 2016 Mar 17;9:65-7
pubmed: 27051319
Eur J Endocrinol. 2014 Sep;171(3):R111-22
pubmed: 24891137
Methods Mol Biol. 2018;1694:469-488
pubmed: 29080189
Lancet. 2007 Jun 23;369(9579):2106-20
pubmed: 17586306
Genet Med. 2019 Mar;21(3):705-717
pubmed: 30050099
PLoS Genet. 2005 Jul;1(1):72-80
pubmed: 16103922
J Proteome Res. 2014 Jun 6;13(6):3114-20
pubmed: 24766612
Cancer Res. 1992 May 1;52(9):2424-30
pubmed: 1568212
Clin Auton Res. 2018 Jun;28(3):301-314
pubmed: 29594605
Biol Neonate. 1987;51(5):260-7
pubmed: 3593807
Lancet. 2005 Aug 20-26;366(9486):665-75
pubmed: 16112304
Anticancer Res. 1992 Mar-Apr;12(2):457-66
pubmed: 1580563
J Vis Exp. 2010 Aug 24;(42):
pubmed: 20811329
Methods Mol Biol. 2017;1550:339-368
pubmed: 28188540
Cancer Res. 2008 Dec 1;68(23):9735-45
pubmed: 19047152
J Proteome Res. 2003 Sep-Oct;2(5):488-94
pubmed: 14582645
Endocr Relat Cancer. 2019 May;26(5):539-550
pubmed: 30893643
Metabolomics. 2010 Mar;6(1):78-95
pubmed: 20300169
Cancers (Basel). 2019 Jun 11;11(6):
pubmed: 31212687
Nat Genet. 2018 Aug;50(8):1086-1092
pubmed: 30013182
Anal Chem. 2011 May 1;83(9):3406-14
pubmed: 21456517
PLoS One. 2013 Nov 27;8(11):e80539
pubmed: 24312232