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 (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 08, 2017
- Source ID
- 10.1002/nbm.3712
Entities
People
- Ellen Ackerstaff
- Inna Serganova
- Jason A Koutcher
- Joseph Varshavsky
- Natalia Kruchevsky
- Ronald G. Blasberg
- Rui V Simoes
- Suresh Veeraperumal
Organizations
- Cornell University
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- United States Department of Defense