Targeting pheochromocytoma/paraganglioma with polyamine inhibitors

Autor: Felix Beuschlein, David Taïeb, Sergei G. Tevosian, Raymond J. Bergeron, Laura Shelton, Kenneth Cusi, Srilaxmi Kalavalapalli, Karel Pacak, Arthur S. Tischler, Abhishek Jha, Soumya Luthra, James A. Bibb, Shashank Jatav, Chris Beecher, Jose G. Trevino, Kimi Kong, Fernando Bril, Prodip Bose, Arielle Click, Susan Richter, Matthias Kroiss, Priyanka Gupta, Robert Hromas, Douglas P. Lee, Austin Kirby, Katharina Langton, Yiling Xu, Mercedes Robledo, Timothy J. Garrett, Kriti Kriti, James F. Powers, Daniel Plant, Henri J L M Timmers, Bruna Calsina, Joy Guingab-Cagmat, Graeme Eisenhofer, Hans K. Ghayee, Heather M. Hatch, Sudhir K. Rai
Přispěvatelé: University of Florida [Gainesville] (UF), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
Polyamine
SDHB
Endocrinology
Diabetes and Metabolism
Pheochromocytoma (PCC)
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Adrenal Gland Neoplasms
Spermine
030209 endocrinology & metabolism
[SDV.CAN]Life Sciences [q-bio]/Cancer
Pheochromocytoma
DESPM
Article
Paraganglioma
03 medical and health sciences
chemistry.chemical_compound
Mice
All institutes and research themes of the Radboud University Medical Center
0302 clinical medicine
Endocrinology
Internal medicine
Cell Line
Tumor
medicine
Animals
Humans
Metabolomics
Paraganglioma (PGL)
DENSPM
Cell growth
Biogenic Polyamines
Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16]
medicine.disease
Xenograft Model Antitumor Assays
3. Good health
Spermidine
Succinate Dehydrogenase
030104 developmental biology
Polyamine Analogue
chemistry
Cell culture
Mutation
Cancer research
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Zdroj: Metabolism
Metabolism, Elsevier, 2020, 110, pp.154297. ⟨10.1016/j.metabol.2020.154297⟩
Metabolism-Clinical and Experimental, 110
Metabolism, 2020, 110, pp.154297. ⟨10.1016/j.metabol.2020.154297⟩
ISSN: 0026-0495
DOI: 10.1016/j.metabol.2020.154297⟩
Popis: 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 N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts. 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. Precis 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.
Databáze: OpenAIRE
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