Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms
Nuclear microprobe imaging of gallium nitrate in cancer cells
Introduction
Gallium is the second metal ion, after platinum, to be used in cancer treatment (for review see [1], [2]). Gallium nitrate has shown clinical efficacy in the treatment of hypercalcemia and bone cancer. Gallium compounds have also demonstrated promising antitumor chemotherapeutic activity in clinical trials for the treatment of non-Hodgkin’s lymphoma, metastatic colorectal cancer, carcinoma of the urothelium, and in combination with cisplatin against inoperable lung cancer.
The solution and coordination chemistries of Ga3+ are very similar to those of Fe3+. In vivo studies have shown that nearly all plasma gallium is tightly bound to the iron-transport protein transferrin. In cells, gallium is complexed to transferrin receptors and released from lysosomes. The mechanism of cell death may result, at least partially, from an intracellular iron deficiency that triggers apoptosis [3]. In addition, gallium inhibits the iron-dependant enzyme ribonucleotide reductase, a key enzyme for DNA synthesis and cell division. This inhibitory effect could be the result of a competition of Ga with Fe in M2 subunit of ribonucleotide reductase. However, the cellular mechanisms for gallium antitumor activity are still not fully elucidated. The aim of this study was to determine the distribution of Ga, and endogenous trace metals such as Fe, in cancer cells by use of nuclear microprobe analysis.
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Material and methods
The biochemical characteristics of human ovarian cancer cells (IGR-OV1), cell culture conditions, and sample processing for nuclear microprobe analysis were detailed elsewhere [4]. In brief, IGR-OV1 cells were maintained in RPMI medium supplemented with 10% fetal calf serum, plus penicillin and streptomycin, 100 IU/ml and 100 mg/ml, respectively. The cells were incubated at 37 °C in a humidified atmosphere of air with 5% CO2. For nuclear microprobe experiments, cells were cultured as monolayer
Results and discussion
To determine the pharmacologically relevant gallium nitrate concentrations, inhibition of cell growth has been studied (Fig. 1). Gallium nitrate inhibited 53 ± 3% of IGR-OV1 cell growth when administered at 250 μM for 48 h, and 75 ± 5% at 500 μM. These two concentrations were chosen for drug exposure prior to element microanalysis. A concentration dependant effect of gallium on IGR-OV1 cell growth was noted. The number of viable cells decreased by a factor two when drug concentration in culture
Conclusion
The quantitative and spatially resolved information obtained by use of nuclear microprobe analysis enabled to draw a better picture of gallium nitrate cellular pharmacology in cancer cells. Gallium is generally homogeneously distributed within cells. In few cases, P, Ca, Fe and Ga accumulated in round structures within the cytosol suggesting a possible role for vacuolar Ca and/or Fe retention in gallium nitrate anticancer effects.
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