Ionizing radiation, ion transports, and radioresistance of cancer cells

Abstract

The standard treatment of many tumor entities comprises fractionated radiation therapy which applies ionizing radiation to the tumor-bearing target volume. Ionizing radiation causes double-strand breaks in the DNA backbone that result in cell death if the number of DNA double-strand breaks exceeds the DNA repair capacity of the tumor cell. Ionizing radiation reportedly does not only act on the DNA in the nucleus but also on the plasma membrane. In particular, ionizing radiation-induced modifications of ion channels and transporters have been reported. Importantly, these altered transports seem to contribute to the survival of the irradiated tumor cells. The present review article summarizes our current knowledge on the underlying mechanisms and introduces strategies to radiosensitize tumor cells by targeting plasma membrane ion transports.

Keywords: DNA repair; cell cycle; ion channels; radiation therapy.

Figure 1

Cellular stress such as ionizing radiation induces the switch from “Grow” to “Go” phenotype.

Figure 2

Ionizing radiation (IR)-induced activation of BK K⁺ channels results in evasion of glioblastoma cells from radiation stress. Activation of BK channels occurs upstream of CaMKII and ClC-3 Cl⁻ channels. The Na⁺/K⁺/2Cl⁻ cotransporter accumulates Cl⁻ above its electrochemical equilibrium. Cl⁻ is used as osmolyte for volume decrease.

Figure 3

Mitochondrial ROS formation in dependence on ΔΨ_m (I, II, III, and IV, electron transport complexes I, II, III, and IV; Q: semiquinone radical; cyt C: cytochrome C). Ca²⁺ and the ATP/ADP ratio regulate the electron chain at complexes I and IV.