title: Inhibition of prostate cancer proliferation by Deferiprone.
abstract: Cancer growth and proliferation rely on intracellular iron availability. We studied the effects of Deferiprone (DFP), a chelator of intracellular iron, on three prostate cancer cell lines: murine, metastatic TRAMP-C2; murine, non-metastatic Myc-CaP; and human, non-metastatic 22rv1. The effects of DFP were evaluated at different cellular levels: cell culture proliferation and migration; metabolism of live cells (time-course multi-nuclear magnetic resonance spectroscopy cell perfusion studies, with 1-13C-glucose, and extracellular flux analysis); and expression (Western blot) and activity of mitochondrial aconitase, an iron-dependent enzyme. The 50% and 90% inhibitory concentrations (IC50and IC90, respectively) of DFP for the three cell lines after 48 h of incubation were within the ranges 51-67 μM and 81-186 μM, respectively. Exposure to 100 μM DFP led to: (i) significant inhibition of cell migration after different exposure times, ranging from 12 h (TRAMP-C2) to 48 h (22rv1), in agreement with the respective cell doubling times; (ii) significantly decreased glucose consumption and glucose-driven tricarboxylic acid cycle activity in metastatic TRAMP-C2 cells, during the first 10 h of exposure, and impaired cellular bioenergetics and membrane phospholipid turnover after 23 h of exposure, consistent with a cytostatic effect of DFP. At this time point, all cell lines studied showed: (iii) significant decreases in mitochondrial functional parameters associated with the oxygen consumption rate, and (iv) significantly lower mitochondrial aconitase expression and activity. Our results indicate the potential of DFP to inhibit prostate cancer proliferation at clinically relevant doses and plasma concentrations.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rui V
authors.identifier: http://orcid.org/0000-0001-7574-4723
authors.initials: RV
authors.lastname: Simões
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Veeraperumal
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Inna S
authors.identifier: http://orcid.org/0000-0003-3561-8663
authors.initials: IS
authors.lastname: Serganova
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kruchevsky
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Varshavsky
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ellen
authors.identifier: http://orcid.org/0000-0003-4454-7481
authors.initials: E
authors.lastname: Ackerstaff
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Weill Cornell Medical College, Cornell University, New York, NY, USA.
authors.forename: Jason A
authors.identifier: http://orcid.org/0000-0002-1399-5065
authors.initials: JA
authors.lastname: Koutcher
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077543:Deferiprone; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011728:Pyridones / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D011728:Pyridones; D000077543:Deferiprone; D000154:Aconitate Hydratase
keywords: Deferiprone; aconitase; cell metabolism; inhibition of proliferation; prostate cancer