Intercellular Communication Amplifies Stressful Effects in High-Charge, High-Energy (HZE) Particle-Irradiated Human Cells

Abstract

Understanding the mechanisms that underlay the biological effects of particulate radiations is essential for space exploration and for radiotherapy. Here, we investigated the role of gap junction intercellular communication (GJIC) in modulating harmful effects induced in confluent cultures wherein most cells are traversed by one or more radiation tracks. We focused on the effect of radiation quality (linear energy transfer; LET) on junctional propagation of DNA damage and cell death among the irradiated cells. Confluent normal human fibroblasts were exposed to graded doses of 1 GeV protons (LET ~0.2 keV/μm) or 1 GeV/u iron ions (LET ~151 keV/μm) and were assayed for clonogenic survival and for micronucleus formation, a reflection of DNA damage, shortly after irradiation and following longer incubation periods. Iron ions were ~2.7 fold more effective than protons at killing 90% of the cells in the exposed cultures when assayed within 5–10 minutes after irradiation. When cells were held in the confluent state for several hours after irradiation, substantial repair of potentially lethal damage (PLDR), coupled with a reduction in micronucleus formation, occurred in cells exposed to protons, but not in those exposed to iron ions. In fact, such confluent holding after exposure to a similarly toxic dose of iron ions enhanced the induced toxic effect. However, following iron ion irradiation, inhibition of GJIC by 18-α-glycyrrhetinic acid eliminated the enhanced toxicity and reduced micronucleus formation to levels below those detected in cells assayed shortly after irradiation. The data show that low LET radiation induces strong PLDR within hours, but that high LET radiation with similar immediate toxicity does not induce PLDR and its toxicity increases with time following irradiation. The results also show that GJIC among irradiated cells amplifies stressful effects following exposure to high, but not LET radiation, and that GJIC has only minimal effect on cellular recovery following low LET irradiation.

Health Risks of Space Exploration: Targeted and Nontargeted Oxidative Injury by High-Charge and High-Energy Particles

“…In this context, our studies have shown that the magnitude of the effects due to connexin channels in enhancing or reducing the propagation of radiation-induced oxidative stress is a function of radiation quality (LET effect). The abundance of reactive species along the track of an HZE particle may be the factor that affects permeability of connexin channels (9)(10)(11). These results are consistent with earlier studies showing that the cellular redox environment together with gap junction communication are the major mediators of the propagation of stressful responses from a particle-irradiated cells to bystander cells in the vicinity (13,17,201,308).…”

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

“…For example, early and late generation of radiation-induced mitochondrial ROS/RNS mediates changes in mitochondrial DNA copy number [141], mutations [142] and gene expression [143; 144], autophagy [145; 146], apoptosis [147; 148; 149], propagation of non-targeted responses [73; 150; 151; 152; 153; 154; 155], the induction of nuclear DNA damage [156], genomic instability [157], neoplastic transformation [158], and degenerative conditions [37; 63; 159] among other outcomes [2; 37]. We investigated effects of ionizing radiation on mitochondrial protein import, assembly of large protein complexes, protein oxidation and activity of metabolic and antioxidant enzymes [10; 11; 45; 48; 160; 161]. Significantly, the persistence of radiation effects that lead to mitochondrial dysfunction in progeny cells has serious consequences to health risks [2; 162].…”

Induction of lethal bystander effects in human breast cancer cell cultures by DNA-incorporated Iodine-125 depends on phenotype

“…The patterns of radiation exposure that arise as a consequence of these properties can be highly non-uniform, and lead to conditions that are favorable for eliciting radiation-induced bystander effects. As summarized in a recent review (Blyth and Sykes 2011), many studies have provided strong evidence to support the existence of a variety of radiation-induced bystander effects (Brooks et al 1974, Nagasawa and Little 1992, Mothersill and Seymour 1997, Azzam et al 1998, Wright 1998, Zhou et al 2000, Autsavapromporn et al 2011, Buonanno et al 2011). These effects may be toxic or protective in cells that are not directly irradiated; they can result from a variety of signals from neighboring irradiated cells (Wright and Coates 2006).…”