Intracellular Sequestration of²²³Ra by the Iron-Storage Protein Ferritin

Abstract

Incorporation of bone-seeking, alpha-particle-emitting, heavy-metal radionuclides dramatically increases the incidence of osteosarcoma in humans and experimental animals. The accumulation of these radionuclides within the mineral phase of the bone matrix is believed to result in local irradiation of only those proliferating cells close to the bone surface. We now present evidence for a more general pathway for the irradiation of target cells, mediated through the sequestration of heavy-metal radionuclides by the intracellular iron-storage protein ferritin. In vitro studies reveal the transfer of radionuclide from a 223Ra-transferrin complex into immunoprecipitable cytosolic ferritin. In vivo studies confirm the co-localization of incorporated 224Ra and cellular iron stores. This pathway would result in the highly localized irradiation of ferritin-containing cells. Since osteoblastic cells express large quantities of a ferritin isoform specialized in long-term metal storage, we suggest that this may represent an unrecognized source of intracellular irradiation by alpha-particle-emitting radionuclides. Such a local concentration within target cells has implications both for cellular dosimetry and for inferences of track length and target cell populations within the skeleton.

Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation

“…It is unclear whether this association is regulated by energy deposition by an a-particle produced outside of the cell or whether continuous exposure with 223 Ra allows for intracellular sequestration via exchanges with similar elements (i.e., calcium, magnesium, iron, and/or copper). For example, there is some evidence for sequestration of 223 Ra by intracellular ferritin (53).…”

Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe

“…It is unclear whether the greater efficacy of 223 Ra is the result of the different dose rates used in the analysis (1.4 mGy/min 223 Ra vs. 1.59 Gy/min external alpha particles) or by cell-type-specific intracellular uptake of 223 Ra. For example, intracellular sequestration of 223 Ra by the iron-storage protein ferritin has been demonstrated ( 14 ). In the present study, we were unable to detect any residual activity in the cells after 223 Ra removal; however, we cannot completely exclude 223 Ra cellular uptake due to sensitivity limitations.…”

Ellagic Acid and Zinc Aspartate Ameliorate Gamma Radiation Induced Biochemical Alterations in Male Rats

“…According to Hampton and Mayerson (1950), the kidney is capable of forming ferritin from iron released from haemoglobin. While in liver the oxidative stress induced by irradiation causes damage resulting in ferritin degeneration and increase in the intracellular free iron levels (Atkinson et al, 2005) and this explains why radiation increase the level of iron in liver but not in kidney. The disturbances in calcium and magnesium metabolism might be due to the insufficient renal function after irradiation (Kotb et al, 1990).…”