Year: 2016
Type: article
Abstract: Previously, we presented compelling data that gallium maltolate (GaM) has a profound antitumor effect on glioblastoma (GBM) in vitro and in vivo. We now provide evidence elucidating the mechanism of action by which GaM exerts its antineoplastic activity. Interaction of transferrin with GaM was confirmed by UV-Vis (ultraviolet visible) spectroscopy. Cellular iron proteins and the effects of GaM were evaluated by Western blot and immunohistochemistry (IHC). The action of GaM on the iron-dependent M2 subunit of ribonucleotide reductase (RRM2) was analyzed by Western blot and electron paramagnetic spectroscopy (EPR) in human U87 and D54 GBM cells. Transferrin receptor (TfR) and RRM2 IHC revealed strong expression by GBM tumors, but not by normal brain cells in both patient surgical and U87 xenograft tissues. The keen iron requirement of GBM cells was reflected by the higher proportion of H-ferritin (metabolic) vs. L-ferritin (storage) staining we observed in GBM tumors. More intense TfR staining was noted in treated vs. untreated xenograft tumors. This finding is consistent with an upregulation of TfRs secondary to tumor iron deprivation produced by GaM treatment. Cellularity counts were comparable between GaM-treated and control tumors, but the proportion of dead cells was higher in treated ones. Moreover, the number of mitotic figures was significantly lower in treated tumors (p=0.043). Further analysis of the effect of GaM on RRM2 function showed that GaM formed complexes with transferrin and inhibited the tyrosyl radical of RRM2, and consequently RRM2 activity, without reducing RRM2 protein levels. We propose that GaM exerts its antineoplastic effect by forming identifiable complexes with transferrin, enabling it to be taken up by GBM cells via transferrin receptors, where it interferes with iron-dependent processes, such as DNA synthesis, by inhibition of RRM2 activity. Thus, GaM shows great promise for new interventional strategies in GBM therapy.
Source: Neuro-Oncology
Institution: Medical College of Wisconsin
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2588921485