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 1-13 C-glucose, and extracellular flux analysis); and expression (Western blot) and activity of mitochondrial aconitase, an iron-dependent enzyme. The 50% and 90% inhibitory concentrations (IC50 and 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: Rui V Simões, Suresh Veeraperumal, Inna S Serganova, Natalia Kruchevsky, Joseph Varshavsky, Ronald G Blasberg, Ellen Ackerstaff, Jason A Koutcher
• Journal: NMR in biomedicine (NMR Biomed) Vol. 30 Issue 6 (Jun 2017) ISSN: 1099-1492 [Electronic] England
• PMID: 28272795 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 John Wiley & Sons, Ltd.

Chemical References

• Pyridones
• Deferiprone
• Aconitate Hydratase

Topics

• Aconitate Hydratase (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Deferiprone
• Humans
• Male
• Mitochondria (drug effects, metabolism)
• Oxygen Consumption (drug effects)
• Prostatic Neoplasms (metabolism, pathology)
• Pyridones (pharmacology)
• Time Factors