Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

Abstract

Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a "two-sided effect" in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent.

Iron alters Ca2+ homeostasis in doxorubicin‐resistant K562 cells

“…In our present study, the elevation of Ca 2+ in K562D cells was determined at the lowest dose of 2.5 µmol/L iron. We had determined that Ca 2+ elevation was observed above 40 µmol/L iron concentration in parental K562 cells in our previous study, 23 therefore, K562D cells in calcium elevations appeared to be approximately 16‐fold more sensitive in their response to iron.…”

“…Flow cytometry analysis was used for measuring the iron uptake. Figure 2 depicts fluorescence intensity histograms of a representative experiment where K562D cells were first treated with iron for 1 hour, and then loaded with calcein‐AM (CA‐AM) 23 . A fluorescent dye, calcein, was used to determine the intracellular iron.…”

“…Our group also showed that iron is essential to elicit a Ca 2+ signal, and that intracellular iron concentrations determine the Ca 2+ response. K562 cells with DFO causes [Ca 2+ ] to rise with much smaller doses following the administration of iron 23 …”

The protective role of Deferoxamine in the prevention of hepatic fibrosis in children treated with Doxorubicin: a randomized controlled clinical trial

“…Chelation of excess iron prevents its deposition and damage to several organs and tissues including liver [10]. It also prevents collagen accumulation and hepatic satellite cell activity, thus decreases liver injury [11]. In addition, DFO was shown to have antiproliferative effect which may ultimately lead to cell cycle arrest and apoptosis [12].…”

“…Furthermore, DFO maintains the activity of the liver enzyme glucose-6-phosphatase [13]. It can also serve as an antioxidant, and reduces liver brosis which is manifested as a decreasing trend in serum markers of liver brosis including liver hydroxyproline and liver -smooth muscle actin (α-SMA).Therefore, DFO through different mechanisms decreases pro brogenic factors, and inhibits in ammatory cascade [9][10][11][12].…”