Radiation Induced Non-targeted Response: Mechanism and Potential Clinical Implications

Hei, Tom K.; Zhou, Hongning; Chai, Yunfei; Ponnaiya, Brian; Ivanov, Vladimir N.

doi:10.2174/1874467211104020096

Cited by 191 publications

(111 citation statements)

References 61 publications

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“…If the COX-2 gene is causally linked to the bystander signaling pathways, it should be possible to modulate the bystander response using the specific inhibitor of COX-2 enzyme activity, NS-398. Although NS-398 treatment was able to reduce the hypoxanthine guanine phosphoryl transferase negative (HRPT-) mutant fraction in the directly irradiated cell population, the reduction of suppression was only 36% [217]. …”

Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

“…Activation of extracellular signal-related kinase (ERK) by phosphorylation is a key upstream event that precedes COX-2 expression [217]. Cell culture studies with and without PD98059, a specific MAPK-ERK inhibitor, showed suppression of the phosphorylated form of ERK in both, α-particle irradiated and bystander cells.…”

Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

“…Cell culture studies with and without PD98059, a specific MAPK-ERK inhibitor, showed suppression of the phosphorylated form of ERK in both, α-particle irradiated and bystander cells. In fact, treatment of cells with a non-cytotoxic dose of PD98059 completely suppressed the bystander toxicity observed in NHLF cultures [217]. …”

Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

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Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

Brücher

Jamall

2014

Cell Physiol Biochem

180

161

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The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.

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Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

Section: (4) Cell-cell Communication and Anticancer Treatmentmentioning

confidence: 99%

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Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

Brücher

Jamall

2014

Cell Physiol Biochem

180

161

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“…1 In view of RIBE, existing radiotherapy models should be reconsidered and the carcinogenesis risk of low-dose radiation should be re-assessed. Therefore, a better understanding of the mechanisms underlying RIBE is essential.…”

Section: Introductionmentioning

confidence: 99%

MiR-663 inhibits radiation-induced bystander effects by targetingTGFB1in a feedback mode

Hu¹,

Xu²,

Yao

et al. 2014

RNA Biology

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The mechanisms of radiation-induced bystander effects (RIBE) have been investigated intensively over the past two decades. Although quite a few reports demonstrated that cytokines such as TGF-b1 are induced within the directly irradiated cells and play critical roles in mediating the bystander effects, little is known about the signaling pathways that occur in bystander cells. The crucial question as to why RIBE signals cannot be infinitely transmitted, therefore, remains unclear. In the present study, we showed that miR-663, a radiosensitive microRNA, participates in the regulation of biological effects in both directly irradiated and bystander cells via its targeting of TGF-b1. MiR-663 was downregulated, while TGFB1 was upregulated in directly irradiated cells. The regulation profile of miR-663 and TGFB1, on the other hand, was reversed in bystander cells, in which an elevated miR-663 expression was exhibited and led to downregulation of TGF-b1. Further studies revealed that miR-663 interacts with TGFB1 directly and that through its binding to the core regulation sequence, miR-663 suppresses the expression of TGFB1. Based on the results, we propose that miR-663 inhibits the propagation of RIBE in a feedback mode, in which the induction of TGF-b1 by reduced miR-663 in directly irradiated cells leads to increased level of miR-663 in bystander cells. The upregulation of miR-663 in turn suppresses the expression of TGF-b1 and limits further transmission of the bystander signals.

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“…These results are reminiscent of the GJIC-mediated propagation and amplification of cell death in glial cells during cerebral ischemia [20]. Similarly, GJIC contributes to the radiation "bystander effect" in which signaling molecules and/or reactive oxygen species induce damage in neighboring, non-irradiated cells [21] [22]. In contrast, GJIC may also reduce drug, ischemic, and radiation-induced cytotoxicity possibly by cell-cell sharing of protective molecules like glutathione [5] [23].…”

Section: Discussionmentioning

confidence: 98%

Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

Ruch¹,

Boucher²,

Gentry³

et al. 2014

JCT

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Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three-to five-fold more sensitive (IC50 0.1 mM) to HU than GJIC-deficient derivatives (IC 50 0.3 -0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% -80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding Gjb1 increased HU toxicity (IC 50 0.1 mM). The effects were not due to connexin expression per se or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% -20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.

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Radiation Induced Non-targeted Response: Mechanism and Potential Clinical Implications

Cited by 191 publications

References 61 publications

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

MiR-663 inhibits radiation-induced bystander effects by targetingTGFB1in a feedback mode

Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

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