Cellular senescence in ionizing radiation (Review)

  • Authors:
    • Zhengting Chen
    • Ke Cao
    • Yaoxiong Xia
    • Yunfen Li
    • Yu Hou
    • Li Wang
    • Lan Li
    • Li Chang
    • Wenhui Li
  • View Affiliations

  • Published online on: June 24, 2019     https://doi.org/10.3892/or.2019.7209
  • Pages: 883-894
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Radiotherapy (RT) is one of most common treatments for cancer. However, overcoming the failure and side effects of RT as well as radioresistance, recurrence and metastasis remains challenging in cancer treatment. Cellular senescence (CS) is permanent arrested state of cell division induced by various factors, including exposure to ionizing radiation (IR). CS induced by IR contributes to tumour cell control and often even causes side effects in normal cells. Improvement of the therapeutic RT ratio is dependent on more cancer cell death and less normal cell damage. In addition, the biological behaviour of tumour cells after IR has also been linked to CS. This review summarizes our understanding of CS in IR, which may be beneficial for providing new insight for improving the therapeutic outcomes of RT.


Senescence has been identified for decades (1), and cellular senescence (CS) represents a relatively stable state of proliferative arrest accompanied by failure to re-enter the cell division cycle. Generally, CS is divided into replicative CS resulting from telomere shortening and premature CS that is induced by various types of stress. Due to the increasing evidence of linkages between senescent cells (SNCs) and many age-related diseases, including cancer, atherosclerosis, osteoarthritis, and neurodegenerative diseases (25), methods for eradicating SNCs are a hot topic in research on these diseases (6). However, CS appears to play dual roles in cancer radiotherapy (RT). On the one hand, CS induced by ionizing radiation (IR), a major type of RT, can inhibit the proliferation of tumour cells and activate cancer immune surveillance. Many radiosensitizers are aimed at increasing CS when combined with IR (7,8). On the other hand, IR can induce senescence in surrounding and normal cells as well as in cancer cells, which leads to normal tissue fibrosis and organ dysfunction (9). Moreover, IR-induced CS (IRIS) may emerge as a method for helping cancer cells overcome RT and worsen the biological behaviour of tumour cells following IR treatment (10,11).

The aim of this review was to focus on CS in IR by evaluating radiosensitivity, IR-induced side effects, tumour cell biological behavioural changes after IRIS and underlying mechanisms. It was hypothesized that a comprehensive understanding may provide new insights into novel therapeutic modalities in RT to improve the outcomes of cancer patients.

IR-induced CS

IR kills tumour cells by causing lethal DNA damage, which can ignite the DNA damage response (DDR), and non-homologous end joining (NHEJ) and homologous recombination (HR) are the two main pathways for repairing double-strand breaks (DSBs) induced by DNA damage. The accuracy of DNA damage repair by related downstream signalling pathways determines cell fate, including senescence and apoptosis (12). Generally, DNA DSBs are an especially potent stimulus for inducing CS (13). IRIS, is also a form of stress-induced premature senescence (SIPS) (14) and can occur in many types of cells, including cancer cells, fibroblasts, epithelial cells, endothelial cells (ECs), immune cells, and stem cells. Senescent cells (SCNs) always exhibit apoptosis resistance, metabolic activity, proinflammatory and profibrotic molecule secretion and neighbouring microenvironment alteration despite that they have no cell division capacity and permanently arrested proliferation (15) (Fig. 1).

Figure 1.

Cellular senescence is induced by IR. The exposure of both tumour cells and normal cells to IR can lead to DNA damage. NHEJ and HR are two main pathways for repairing DSBs, which are especially potent stimuli for inducing CS. Inevitable DNA damage triggers cell cycle arrest accompanied by mitotic bypass. ATM, p53, p21, p16-Rb, p38-MAPK, factors in the NF-κB signalling pathway, ROS and cyclin-CDK complexes are involved in this process. SNCs demonstrate senescence-associated heterochromatin foci, activated metabolism, the SASP and SA-β-Gal-positive staining. The SASP contributes to profibrotic and proinflammatory factors and plays a role in active immune surveillance. The SASP also alters tissues and the surrounding microenvironment through paracrine, autocrine, or endocrine methods. Finally, tumour SNCs may be cleared or regrown, and normal SNCs may be obliterated, induce fibrosis or promote tumourgenisis. Furthermore, non-senescent cells may become senescent or resistant to IR. ATM, ataxia telangiectasia mutated protein; CDK, cyclin-dependent kinase; DDR, DNA damage response; DSBs, DNA double-strand breaks; HR, homologous recombination; IR, ionizing radiation; IRIS, IR-induced cellular senescence; NF-κB, nuclear factor κ-B; NHEJ, non-homologous end joining; p38MAPK, p38 mitogen-activated protein kinase; pRb, retinoblastoma protein; ROS, reactive oxygen species; SA-β-Gal, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; SASP, senescence-associated secretory phenotype; SNCs, senescent cells; tumor-SNCs, tumour senescent cells; normal-SNCs, normal senescent cells.

Cell division cycle arrest

In the senescence process induced by IR, the cell cycle is interrupted by G2 arrest after inevitable DNA damage, accompanied by mitotic bypass into the G1 phase (16). Ataxia telangiectasia-mutated protein (ATM), p53, p21, p16-Rb, p38-mitogen-activated protein kinase (p38-MAPK), NF-κB signalling pathway factors, reactive oxygen species (ROS), senescence-associated secretory phenotype (SASP) factors and cyclin-CDK complexes are involved in this process (9,16,17). Different doses of IR and DNA damage can lead to various types of cells with mitotic cell cycle delays, including arrests in the G1, G2 or S phase. G2 arrest and G2 slippage has been linked to IRIS in most previous studies and reviews (1821). SNCs can be identified by prominent β-galactosidase activity, increased p53, p21 and p16 expression, and decreased levels of Cdc2 and survivin. Notably, some features of IRIS in normal cells and cancer cells are summarized in Table I.

Table I.

Features of IRIS in normal cells and cancer cells.

Table I.

Features of IRIS in normal cells and cancer cells.

FeaturesNormal senescent cellsNeoplastic senescent cells(Refs.)
Morphological transformationLarger, flattened, increased granularity, and increased cytoplasmic vacuolar content(22,23)
Cell cycle arresta. S and G2/M-phase arrest, mitotic skipping, overexpression of cyclin D1, tetraploid cells(2426)
b. Related to the DDR-network
Special description Senoptosisa; Senescence-like growth arrest (SLGA)(27,28)
IR dose dependentLow dose resistant to CS, even promote proliferationFrom low to high dose can lead to CS(29,30)
Fraction sizeSlow-growing fibroblasts and most late-responding cells exhibit high sensitivitya. Rapidly proliferating tumour cells are not very sensitive(31,32)
b. Similar: single dose or fractioned irradiation
Cell typeAlmost all normal cells can develop IRISa. non-tumorigenic cells more prone than CSCs(3335)
b. degree of differentiation
SASPA range of pro- inflammatory and pro-fibrotic chemokines, cytokines, growth factors and proteases, such as IL-1, IL-6/8, CXCL1, CCL2, MMPs, TGF-β, HGF, GM-CSFDiffer among different cells, high heterogeneity(34,36)
Bystander effectEspecially in senescent fibroblasts and senescent ECsBreast cancer cells, CRC cells, NSCLC cells(3739)

a Phenomenon of γ-IR-induced deep senescence in HDFs with features of both senescence and apoptosis. CCL2, CC chemokine monocyte chemoattractant protein (MCP)-1; CRC, colorectal cancer; CS, cellular senescence; CSCs, cancer stem cells; CXCL1, chemokine (C-X-C motif) ligand 1; DDR, DNA damage response; SLGA, senescence-like growth arrest; ECs, endothelial cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; MMPs, matrix metalloproteinase; NSCLC, non-small cell lung cancer; IL-1α, interleukin 1α; IL-6/8, interleukin-6/8; IR, ionizing radiation; IRIS, IR-induced cellular senescence; Ref., reference; SASP, senescence-associated secretory phenotype; TGF-β, transforming growth factor-β; HDFs, human diploid fibroblasts.


The function of the tumour suppressor protein p53 is related to cell cycle control, DNA repair and apoptosis (40). p53 and phosphorylated retinoblastoma protein (pRB) are the main proteins involved in establishing and maintaining the state of irreversible growth arrest in replicative senescence in normal human cells, and p53 inactivation could reverse CS in BJ cells with a low level of p16 (41). Many studies (4245) have been carried out to explore the influence of p53 on IR-induced effects. For example, HCT116 p53+/+ cells were found to be much more susceptible to IRIS than p53–/– cells (43). IR-induced mitotic skipping during senescence-like growth arrest is associated with p53 function (24). Therefore, the mechanisms of p53, the guardian of the genome, and its related signalling pathways are well characterized in IRIS.

Other proteins/factors related to p53

Increasing evidence supports that insulin-like growth factor-binding protein 5 (IGFBP-5) plays a crucial role in CS via a p53-dependent pathway and especially functions in the coagulation factor Xa- or interleukin-6 (IL-6)-induced premature senescence of ECs, smooth muscle cells (SMCs), and fibroblasts (4648). Exogenous IGFBP-5 or IGFBP-5 overexpression induces premature senescence in human umbilical vein endothelial cells (HUVECs) in vitro, and knocking down IGFBP-5 can partially alter the senescence process in vitro (48). Notably, IGFBP-5 is upregulated in the IRIS of HUVECs after chronic low-dose IR (49) and may therefore be a significant target to reduce IRIS in normal cells. In addition, the BRE gene (BRCC45) is also associated with the DNA damage-induced premature senescence of fibroblasts resulting from γ-IR (50). Downregulation of the lamin-B receptor (LBR) and LB1 is a primary response of cells to various stresses leading to senescence, and the loss of LB1 can even serve as a biomarker of senescence (51,52). Naturally, other factors involved in IRIS are independent of p53. For instance, oestrogen E2 suppressed IRIS by inhibiting the binding of cyclin E with p21 and the functional inactivation of p21, followed by permanent Rb hyperphosphorylation, but it did not affect p53 activation in MCF-7 breast cancer cells (53).

lncRNAs and miRNAs

Long non-coding RNAs and microRNAs also contribute to CS induced by IR (23,54). IRIS is modulated by miR-155 via the p53 and p38-MAPK pathways and partially regulates tumour protein 53-induced nuclear protein 1 (TP53INP1) expression in human WI-38 lung fibroblasts (23). The overexpression of miR-30e in HCT116 cells was revealed to markedly accelerate and augment the γ-IR-induced caspase-3-like DEVDase senescent phenotype because miR-30e upregulates p21 expression (55). However, miR-30e could not induce senescence in the poorly differentiated RKO colon carcinoma cells (55). This finding demonstrated that miR-30e controls IRIS and may be affected by the differentiation degree of the cell lines.

IR dose and fraction regimen

Other factors also affect the process of IRIS. For example, the IR dose plays a crucial role in inducing senescence or apoptosis upon cell exposure; a low dose (0.5–10 Gy) of IR induces senescence, while a very high dose (>10 Gy) induces apoptosis (30), and this phenomenon is related to the level of DNA damage and function of the DDR network. Recently, Velegzhaninov et al (56) reported that a single low dose (30–50 mGy) of gamma irradiation could suppress CS in normal human fibroblasts. Similarly, a single low-dose X-ray could promote the proliferation of normal cells but not of cancer cells (29). However, low-dose fractionated IR (5×1 Gy) induced temporal patterns of p53/p21 expression in MRC5 fibroblasts, resulting in more significant CS than that generated by a single 5 Gy pulse of IR, as indicated by an integrated stochastic model of DNA damage repair (57). Therefore, the fraction regimen also appears to affect IRIS and may respond differently in different cells. For example, lymphocytic leukaemia cells with exponential growth similar to that of rapidly proliferating tumour cells are not very sensitive to fraction size, while slow-growing fibroblasts and most late-responding cells show high sensitivity (31). Therefore, haematological toxicity occurs early during the RT process, and monitoring and preventing the development of leukopenia is of great importance. Other side effects of IRIS are discussed more specifically in section four.


Surviving non-tumourigenic cells were revealed to be more prone to CS, while breast cancer initiating cells (CICs) could be mobilized from the quiescent/G0 phase of the cell cycle to actively cycling cells after sublethal doses of radiation (33). CICs, also called cancer stem cells (CSCs), derived from many types of human cancers and cancer cell lines demonstrate increased therapeutic resistance, partly because they can evade differentiation and senescence induced by the immune-suppression cytokine interferon (IFN) signalling pathway (5860).

Studenckan et al (27) coined the term ‘senoptosis’, which refers to the phenomenon of γ-IR inducing deep senescence in human diploid fibroblasts (HDFs) with features of both senescence and apoptosis. Senescence-associated CD4+ T (SA-T) cells, PD-1+ and CD153+ CD44high cells could serve as suitable biomarkers of immune ageing, as well as potential targets for controlling cancer (61). These observations could lead to new theories for predicting the prognosis of patients after treatment with a combination of immune therapy and RT.

The mechanisms underlying IRIS are becoming increasingly abundant and clear, ranging from the classical cell cycle regulation, DDR and DNA damage repair processes to related miRNAs, lncRNAs, IR factors and cell heterogeneity. Moreover, numerous unelucidated and unsolved problems related to the induction of CS by IR remain, and IRIS appear to be more complex in cancer cells than in normal cells partly because of the intricate biological features of tumour cells.

CS and radiosensitivity

IRIS is the result of the inaccurate repair of damaged DNA after IR. Targeting accelerated and increased IRIS has been an important method for increasing the effectiveness of RT.

Poly (ADP-ribose) polymerase (PARP) is known to function in various DNA repair mechanisms, such as base excision repair, HR and NHEJ. PARP inhibitor (PARPi) has been used to treat tumours with BRCA1 or BRCA2 mutations (62) and can be used in combination with other treatment measures. Many studies have indicated that PARPis can sensitize most cancer cells to IR by prolonging growth arrest and CS (6365). Concurrent therapy with blockade of DNA-dependent protein kinase (DNA-PK) and PARP-1 can accelerate the senescence of irradiated non-small cell lung cancer (NSCLC) cells and irradiated H460 ×enografts further than that achieved with IR alone (66) (Table II).

Table II.

CS and radiosensitivity in typical types of cancer cells.

Table II.

CS and radiosensitivity in typical types of cancer cells.

Type of cancer (cells)Gene/medicine Mechanisms/TargetsRole of CS (Se- or Re-)(Refs.)
NSCLC (H460 and A549)PAPRi+ inhibitors of DNA-PKPromoting G2-M cell cycle arrestSe(66)
Liver cancer (Walker 256)PS62ASODNAgainst hTERTSe-(67)
hMSCTRF2Protecting and stabilizing chromosomal endsSe-(68)
GBM (U251MG, U87MG)HDAC4 silencingSustain Double strand break repairSe-(70)
GBM (U87MG) Verapamil+carmustineReducing intra-cellular ROS and calcium ion levelsSe-(72)
GBM cellsEPOR silencingInducing G2/M cell cycle arrestSe-(71)
Breast cancer cells (MCF-7 cells) Telomere-mitochondrion linkTelomere dysfunction hTERT suppressionSe-(76)
Sarcoma cellsHSP90Inducing CSSe-(77)

[i] CS, cellular senescence; DNA-PK, DNA-dependent protein kinase; EPOR, erythropoietin receptor; GBM, glioblastoma; HDAC4, histone deacetylase 4; hMSC, human mesenchymal stem cells; HNSCC, human neck squamous cell carcinoma; HSP90, heat shock protein 90; FancA, Fanconi anaemia complementation group A, hTERT, human telomerase reverse transcriptase; TRF2, telomeric repeat-binding factor 2; NSCLC, non-small cell lung cancer; PAPRi, poly(ADP-ribose) polymerase inhibitor; PS62ASODN, phosphorothioate-modified antisense oligonucleotide; SASP, senescence-associated secretory phenotype; Se, radiosensitive; Re, radioresistant; Ref., reference.

Other evidence has also demonstrated that CS and irradiation have a synergistic effect when applied in combination with irradiation. Phosphorothioate-modified antisense oligonucleotide (PS62ASODN), which inhibits human telomerase reverse transcriptase (hTERT) to stimulate senescence, enhanced the inhibition of tumour characteristics in liver cancer cells (67). Telomeric repeat-binding factor 2 (TRF2), a member of the shelterin complex that plays a key role in protecting and stabilizing chromosomal ends, markedly increased the radiosensitivity of human mesenchymal stem cells (hMSCs) compared to that of controls in both proliferation and senescence assays (68). Similarly, inhibition of the mammalian target of rapamycin (MTOR) pathway can augment the radiosensitivity of cancer cells by promoting CS (69). In glioblastoma (GBM) cells, silencing both histone deacetylase 4 (HDAC4) and erythropoietin receptor (EPOR) promoted IR-induced senescence and reversed radioresistance (7071). Moreover, GBM cells treated with verapamil in combination with carmustine and irradiation were more vulnerable to IRIS than those subjected to individual or dual-combination treatment (72).

Irradiated non-small cell lung cancer (NSCLC) cells can be rendered more radiosensitive by inhibiting epidermal growth factor receptor (EGFR) in a p53-dependent senescence pathway (73). However, other evidence has revealed that senescence is a prominent mechanism of radiosensitization in 45% of NSCLC cell lines and occurs independent of the p53 status but is linked to p16 induction. Senescence and radiosensitization have also been linked to an increase in residual radiation-induced DNA damage, especially DSBs, regardless of the p53/p16 status (73). Notably, irrespective of the cell-based assay employed, caution should be paid to avoid misinterpreting radiosensitivity data in terms of reduced viability (74). Furthermore, similar to receptor tyrosine kinase (RTK) targeting strategies in cancer, IRIS could represent a potential alternative treatment outcome, both allowing tumour growth control and enabling patients to have a better quality of life (75). However, as the SASP incidence increases, IRIS appears to be a candidate mechanism contributing to Fanconi anaemia complementation group A (FancA)-mediated radioresistance in head and neck squamous cell carcinoma (11).

Collectively, these findings indicate that many radiosensitizers function based on CS. Limited benefits suggest that more complicated mechanisms should be considered and explored because CS may facilitate radioresistance in tumour cells and increase the radiosensitivity of surrounding normal cells.

CS and IR side effects

CS induced by IR in normal cells leads to tissue fibrosis and organ dysfunction and increases the risk of secondary neoplasms in almost all bodily systems (42,64). As a result, decreasing these side effects induced by IRIS has been a direction for improving the therapeutic radiation ratio with the exception of radiosensitizers. An increasing number of researchers are exploring the deeper mechanisms underlying this process, and some interference targets have exhibited potential to suppress CS in normal cells (Table III).

Table III.

Cellular senescence and IR side effects.

Table III.

Cellular senescence and IR side effects.

Side effectIrradiationExperimental cell/animalTargetsMethod(Refs.)
Premature neurodegenerative diseasesSingle 20 GyBrain microvascular endothelial cells (bEnd.3 cells)A Disintegrin And Metalloprotease 10 (ADAM10)Downregulation of ADAM 10(4)
Hippocampus damage5 Gy of cranial IRWhole-brain irradiation mousep53, p21, and IL-6 were increasedKnockout of the TRP53 or p21 gene(42)
Neuropsychological deficitsX-raysΝeural stem and progenitor cells (NSPCs)Caspase-1 activation(65)
PF17 Gy X-rayC57BL/6J mice, type2 pneumocytesMMP-3, IL-1, TGF-βInhibitor of Bcl-2/BCL-xL; rPAI-1; Rapamycin(8183)
Adult stem cell injury50 GyDrosophila melanogaster (GSCs)FOXO and mTOR homologueFOXO RNAi(89)
IR-induced DNA damage2.5 Gy and 10 Gy γ-IRHuman breast cancer and fibroblastsDifferent responses to LLLT following exposure to IRLLLT(93)
Radiation-induced collagen contraction2 Gyfibroblasts, CRC cellsFibroblasts and CRC cells present different responses to medicineManganese porphyrins -MnTnBuOE-2-PyP(96)
PF12.5 Gy thorax irradiationC57BL/6J micePathogenesis (model)RNA sequencing of lung tissue(97)
IR-induced cardiovascular disease10 Gy X-raysHuman coronary artery endothelial cellsSASP, STAT3, BSEProteomics analysis(98)
IR-Induced damage in the prostate2 Gy X-raysMouse prostate fibroblast cellsTGF-β1signaling pathwayROS scavenger (MnTE-2-PyP)(99)
BM suppression, HSC6.5 Gy of-IRMouse modelROS-p16 pathwayMnTE(100)
BM injury4 Gy γ-TBILy5.2 miceInhibit HSC senescenceMetformin(101)

[i] Bcl-2/BCL-xL, B-cell lymphoma 2/B-cell lymphoma-extra large; BM, bow marrow; BSE, bystander effect; FOXO, Forkhead box O; CRC, colorectal cancer; GSCs, germline stem cells; mTOR, mammalian target of rapamycin; HSC, hematopoietic stem cell; MMP-3, matrix metalloproteinase-3; MnTE, Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin; IR, ionizing radiation; LLLT, low-level laser therapy; PAI-1, plasminogen activator inhibitor-1; PF, pulmonary fibrosis; Ref. reference; RNAi, RNA interference; ROS, reactive oxygen species; TBI, total body irradiation; TGF-β, transforming growth factor-β; SASP, senescence-associated secretory phenotype; STAT3, signal transducer and activator of transcription 3.


The length of telomeres in somatic cells shortens over time due to increasing age or pathogenic factors, resulting in CS. Both chemotherapy and RT significantly impair telomere maintenance and function in normal human cells, which may lead to CS and ultimately result in tissue/organ damage and secondary malignancies in long-term survivors of cancer (78). However, the telomere length and the telomere length distribution in peripheral leukocytes was revealed to remain unchanged after RT (79). Residual NP-2 cells (human glioma-derived cells) exhibited CS without changes in telomere length after 6 Gy of C-ion irradiation (80).

Pulmonary fibrosis

IR-induced pulmonary fibrosis (PF) is a severe late side effect of thoracic RT. Irradiated mice administered with an inhibitor of B-cell lymphoma-2 (Bcl-2)/B-cell lymphoma-extra large (BCL-xL) via gavage after persistent PF developed reduced type II pneumocyte senescence, and PF was reversed (81). Both recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1) and rapamycin, were revealed to prevent radiation-induced fibrosis in the lungs of mice (82,83). In terms of CS, these data indicate that PF is less challenging to treat and more preventable than ever.


Total body irradiation (TBI) induces long-term bone marrow (BM) suppression via the induction of premature senescence in haematopoietic stem cells (HSCs) in a p16-independent manner (84). The selective clearance of SCNs, including senescent BM-derived HSCs and senescent muscle stem cells, by a pharmacological agent or small-molecule inhibitor of p38 MAPK was beneficial in part through its rejuvenation of aged tissue stem cells and rescue of long-term myelosuppression (85,86).

Childhood cancer survivors

Childhood cancer survivors are at an increased risk of frailty, which is partly a result of RT (87); however, IR-reduced CS in children has more profound influences. The leukocyte telomere length (LTL) was shorter in childhood acute lymphocytic leukaemia (ALL) survivors who underwent treatment with cranial IR than in survivors in the control group, which may lead to the premature development of age-related chronic conditions in survivors (88). Notably, a regeneration defect in ageing germline stem cells after IR could be treated by the loss of FOXO in an adult model of stem cell injury induced by low-dose IR (89).

RB gene and other key genes

These researchers also justified that MSCs in which members of the RB gene family were silenced did not exhibit increased apoptosis, necrosis or senescence compared with untreated cells after exposure to X-rays at 40 and 2,000 mGy. These surviving MSCs exhibited accumulated DNA damage and may have undergone neoplastic transformation (90). Therefore, attention should be paid to cancer patients with RB gene mutations in terms of evaluating the onset of secondary neoplasms following RT. Another research group used weighted gene co-expression network analysis (WGCNA) to screen for differentially expressed genes between the senescence and non-senescence groups following RT and identified six hub genes: BANK1, Tomm70a, AFAP1, Cd84, Nuf2 and NFE2 (91). The authors provided an alternate method to search for key genes linked to IRIS and built a foundation for exploring these genes (91).

Radiation sources

Different radiation sources used in IR have different effects on normal cells. Alessio et al (92) revealed that IR with α particles created less apoptosis and senescence in BM-MSCs; that is, α particles may spare healthy stem cells more efficaciously than X-rays. Low-level laser therapy (LLLT) enhanced viability and proliferation and reduced senescence of fibroblasts following γ-IR exposure, while LLLT resulted in decreased proliferation and increased senescence in breast cancer cells (MDA-MB-231 cells) (93). It is worth mentioning that the greater biological efficacy of C ions compared to that of low linear energy transfer (LET) radiation (X-rays) may be misevaluated in 2D culture experiments (94). Relevant models and beams are necessary to promote the use of charged particles with increased patient safety.

The application of senolytic agents that selectively kill senescent cells may improve organ function, including SNCs induced by IR (81,95). Other therapeutic methods, including antioxidants, free radical scavengers, mTOR inhibitors, anti-inflammatory agents, stem cell therapy and senomorphics, also have the potential to reduce side effects induced by IRIS (9). MnTnBuOE-2-PyP could inhibit radiation-induced collagen contraction and CS in fibroblasts but could not protect colorectal cancer cells from IR damage (93,96), potentially providing new options for reducing IR-induced damage. However, further investigations need to be performed in humans to evaluate their safety and efficacy.

IRIS and tumour cell biological behaviour

In fact, the SLGA response to IR may reflect a key mechanism of residual-cell survival, ultimately resulting in radioresistance, tumour regrowth and dormant tumour recurrence (102). Recently, the phenomenon that SCNs can regrow after exposure to IR has attracted increasing attention, which reflects that CS plays ‘opposing roles’ in RT and other genotoxic therapies (23,103,104). SNCs appearing in the context of neoadjuvant chemoradiotherapy for rectal cancer can promote epithelial-mesenchymal transition (EMT) and further affect the residual tumour microenvironment (105).

Some DNA damage foci induced by IR may persist for a long time. However, the repair of DSBs in SCNs may ultimately result in recovery and regrowth after combination IR/PARPi treatment (106,107). Furthermore, the cells regrown after IRIS may exhibit more aggressive biological behaviours, such as enhanced proliferative ability and increased invasion and migration capacities, than those existing before IR. SCNs also acquired the ability to secrete many types of factors to facilitate growth and invasion in vitro and in vivo (5) (Fig. 2).

Figure 2.

IRIS and biological characteristics of tumour cells. On the one hand, SCNs, including tumor-SNCs and normal-SNCs acquire the ability to secrete many types of factors (e.g., SASP factors: IL-1α/β, IL-6/8, MMPs, VEGF, TGF-β, CXCL1/2/3 and HGF) and facilitate tumour cell growth and invasion in vitro and in vivo. On the other hand, the cells regrown after IRIS may also develop EMT and stem-like features with enhanced proliferation, invasion and migration capacities, than those existing before IR. Upregulation of survivin, Cdc2, and Cdk1 may help senescent tumour cell regrowth. In addition, the IR-induced BSE may have important implications in this progression, and MMPs, TIMP-2, PAI-1, ERP46, PARK7, may participate in this process. BSE, bystander effect; Cdc2, cell division cycle 2; Cdk1, cyclin-dependent kinases; CXCL1/2/3, the chemokine (C-X-C motif) ligand 1/2/3; EMT, epithelial-mesenchymal transition; ERP46, endoplasmic reticulum protein 46; HGF, hepatocyte growth factor; IL-1α/β/6/8, interleukin-1α/β/6/8; IR, ionizing radiation; IGFBP-3/5, insulin-like growth factor-binding protein-3/5; IRIS, IR-induced cellular senescence; MMPs, matrix metalloproteinases; PAI-1, plasminogen activator inhibitor 1; PARK7, Parkinsonism-associated deglycase; SASP, senescence-associated secretory phenotype; SNCs, senescent cells; TIMP-2, tissue inhibitor of metalloproteinase 2; VEGF, vascular endothelial growth factor; tumor-SNCs, tumour senescent cells; normal-SNCs, normal senescent cells.

Normal cells are more sensitive to the IR dose regarding the changes in proliferative ability induced by IRIS, while tumour cells seem to dull to the IR dose and segmentation mode. Fractionated radiation and single IR (e.g., 6 or 3×2, 12 or 6×2 Gy) exposures have equivalent abilities to inhibit tumour growth via IRIS in vitro and in vivo (32). Ablative doses (18 Gy) of radiation exhibit more inhibitory effects on the proliferative, migratory and invasive capacities of lung cancer-associated fibroblasts (CAFs) because CAFs play significant roles in cancer cell invasion and metastasis (108). A low dose of 30 mGy γ-IR was revealed to increase the overall proliferative potential of normal human fibroblasts (HELF-104) (56), while γ-IR could inhibit the growth of primary prostate epithelial cells by inducing senescence, not apoptosis (109).

Apart from proliferative arrest, the SASP is another prominent feature of senescent cells (110). The SASP includes cytokines, chemokines, growth factors and proteases and can trigger the activation of a complex signalling network (111). Irradiated ECs may adversely affect non-irradiated surrounding cells via the SASP, which has been linked to radiation-induced cardiovascular disease (98). The cytokine IL-6, an SASP component, is highly upregulated in many cancers and is considered one of the most important cytokines involved in pro- and anti-tumourigenic effects (112). Senescence-associated IL-6 and IL-8 cytokines can be triggered by paracrines, autocrines, and endocrines, which reinforce the senescent milieu and inflammatory microenvironment in breast cancer cells (36).

Furthermore, the IR-induced bystander effect (BSE) may have important implications in RT (113). The IR-induced BSE describes how cells not exposed to IR show biological changes under the influence of molecular signals secreted by irradiated neighbouring cells (113,114). Several pathways are involved in the paracrine circuit that induces senescence in neighbouring cells, such as the matrix metalloproteinase-2 (MMP-2)/tissue inhibitor of metalloproteinase-2 (TIMP-2), IGFBP3/PAI-1, and peroxiredoxin 6/endoplasmic reticulum protein 46 (ERP46)/Parkinsonism-associated deglycase (PARK7)/cathepsin D/major vault protein pathways (115). Moreover, lung fibroblasts with premature senescence resulting from IR may strongly enhance the growth of malignant human lung cancer cells (A549 and H1299) in vitro and in immunocompromised mice through increasing the expression of matrix MMPs (38).

In other words, it is common that various tumour cells can undergo SLGA after different types of IR. However, these tumour SNCs may recover their proliferative ability and exhibit more aggressive biological behaviour when the environment is suitable. While the SASP exhibited by tumour SCNs and normal SCNs is mostly responsible for this process, the BSE induced by IR also plays a crucial role via various pathways. However, the complexity of the SASP and various mechanisms of action still restrict our understanding of IRIS (35). The mechanism underlying IR-induced BSE and tumour cell escape from IRIS remains unknown, and further research is urgently required to solve this problem.

Other related mechanisms

Although the p16-pRB and p53-p21 tumour suppressor pathways are widely recognized as the main mechanisms underlying SLGA, it is still unclear what makes this arrest stable and what makes CS act as a double-edged sword in cancer treatment (116), especially in terms of improving the efficacy of RT. There may be other related mechanisms contributing to IR-induced senescence.

Mitochondrial dysfunction

Mitochondria play an important role in radiation-induced cellular damage, and different qualities of radiation affect the changes in mitochondrial dynamics (117). Cells exposed to low-dose X-rays and replicative senescent cells exhibit a residual capacity to use fatty acids and glutamine as alternative fuels, respectively (118). Several mitochondrial signalling pathways have been revealed to induce CS (119). DNA cleavage occurring in senescent HDFs after γ-irradiation was triggered by a modest decrease in the mitochondrial membrane potential, which was strong enough to release mitochondrial endonuclease G (EndoG). Then, EndoG translocated into the nucleus to induce the nonlethal cleavage of damaged DNA (27).

IR-induced senescence in quiescent ECs is mediated by at least 2 different pathways dependent on the mitochondrial oxidative stress response and p53 activation (120). hTERT suppression caused by either C ion irradiation or MST-312 impairs mitochondrial function, and telomere-mitochondrion links play a role in the induction of senescence in MCF-7 cells after C ion irradiation (76).


Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). Ferritinophagy is a lysosomal process that promotes ferritin degradation and ferroptosis. Iron accumulation in SNCs is driven by impaired ferritinophagy. The autophagy activator rapamycin could prevent both the iron accumulation phenotype of SNCs and the increase in TfR1, ferritin and intracellular iron, however, rapamycin failed to re-sensitize these cells to ferroptosis (121).

Acyl-CoA synthetase long-chain family member 4 (Acsl4) is preferentially expressed in a panel of basal-like breast cancer cell lines and predicts their sensitivity to ferroptosis. Acsl4 inhibition is a viable therapeutic approach for preventing ferroptosis-related diseases (122).

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)

cGAS is a DNA sensor in the DDR process. Genomic DNA damage leads to cGAS activation, stimulation of inflammatory responses, CS and cancer via the cGAMP/stimulator of interferon genes (STING) pathway (123). cGAS deletion also abrogated SASPs induced by IR. cGAS mediated CS and inhibited immortalization, and cGAS activated antitumour immunity (124). cGAS recognized cytosolic chromatin fragments in SNCs. The activation of cGAS, in turn, triggered the production of SASP factors via STING, thereby promoting paracrine senescence (125).

Future perspectives

Although our understanding of CS in IR is still initial, similar to RT in the treatment of cancer, IRIS functions as a ‘double-edged sword’ and crucially influences the comprehensive results of RT. First, because the SASPs created by different types of SCNs are highly different, SCNs play a complicated role in the response of cancer to RT via SASPs. Developing effective pharmacological methods, such as senolytic agents, to remove accumulated SNCs or weaken SASP intensity may be a promising method (126). In addition, combining prosenescence therapy with checkpoint immunotherapy may contribute to eradicating cancer cells from the viewpoint of CS (127). Finally, more well-designed preclinical and clinical trials have the potential to facilitate the development of targeted SNC therapy, which will ultimately improve the clinical outcomes of cancer patients subjected to RT.


Not applicable.


The present study was supported by the National Natural Science Foundation of China (nos. 81560488, 81660504 and 81860536), the Yunnan Provincial Training Special Funds for High-level Health Technical Personnel (no. H-201624), the Yunnan Health Science Foundation (nos. 2017NS191, 2018NS0065 and 2018NS0064), the Doctoral Scholar Newcomer Award of Yunnan Province and Graduate Student Innovation Fund of Kunming Medical University (2019D015).

Availability of data and materials

Not applicable.

Authors' contributions

ZC, LC, YX and WL conceived and designed the study. KC, YL, LW, LL and YH researched the literature. ZC, LC and WL wrote the manuscript. KC, YX and YL performed data analysis and designed the figures. ZC, KC, YX, YL, YH, LW, LL, LC and WL revised and edited the article. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





bone marrow


bystander effect


cancer initiating cells


cellular senescence


cancer stem cells


DNA damage response


DNA double-strand breaks


endothelial cells


epithelial-mesenchymal transition


human umbilical vein endothelial cells


ionizing radiation


IR-induced cellular senescence


matrix metalloproteinases




mitogen-activated protein kinase


mesenchymal stem cells


poly(ADP-ribose) polymerase (inhibitor)


senescence-associated β-galactosidase


senescence-associated secretory phenotype


stress-induced premature senescence


senescence-like growth arrest


senescent cells


total body irradiation


pulmonary fibrosis



Hayflick L and Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res. 25:585–621. 1961. View Article : Google Scholar : PubMed/NCBI


Sharpless NE and Sherr CJ: Forging a signature of in vivo senescence. Nat Rev Cancer. 15:397–408. 2015. View Article : Google Scholar : PubMed/NCBI


Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, Plikus MV, Verma IM and Panda S: Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 553:351–355. 2018. View Article : Google Scholar : PubMed/NCBI


McRobb LS, McKay MJ, Gamble JR, Grace M, Moutrie V, Santos ED, Lee VS, Zhao Z, Molloy MP and Stoodley MA: Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence. Aging (Albany NY). 9:1248–1262. 2017. View Article : Google Scholar : PubMed/NCBI


Davalos AR, Coppe JP, Campisi J and Desprez PY: Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. 29:273–283. 2010. View Article : Google Scholar : PubMed/NCBI


Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J and van Deursen JM: Senescent cells: An emerging target for diseases of ageing. Nat Rev Drug Discov. 16:718–735. 2017. View Article : Google Scholar : PubMed/NCBI


Eriksson D and Stigbrand T: Radiation-induced cell death mechanisms. Tumour Biol. 31:363–372. 2010. View Article : Google Scholar : PubMed/NCBI


Wang Y, Wang Y, Liu S, Liu Y, Xu H, Liang J, Zhu J, Zhang G, Su W, Dong W and Guo Q: Upregulation of EID3 sensitizes breast cancer cells to ionizing radiation-induced cellular senescence. Biomed Pharmacother. 107:606–614. 2018. View Article : Google Scholar : PubMed/NCBI


Nguyen HQ, To NH, Zadigue P, Kerbrat S, De La Taille A, Le Gouvello S and Belkacemi Y: Ionizing radiation-induced cellular senescence promotes tissue fibrosis after radiotherapy. A review. Crit Rev Oncol Hematol. 129:13–26. 2018. View Article : Google Scholar : PubMed/NCBI


Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L and Nelson PS: Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 18:1359–1368. 2012. View Article : Google Scholar : PubMed/NCBI


Hess J, Unger K, Orth M, Schötz U, Schüttrumpf L, Zangen V, Gimenez-Aznar I, Michna A, Schneider L, Stamp R, et al: Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. Cancer Lett. 386:87–99. 2017. View Article : Google Scholar : PubMed/NCBI


Noda A, Hirai Y, Hamasaki K, Mitani H, Nakamura N and Kodama Y: Unrepairable DNA double-strand breaks that are generated by ionising radiation determine the fate of normal human cells. J Cell Sci. 125:5280–5287. 2012. View Article : Google Scholar : PubMed/NCBI


Rossiello F, Herbig U, Longhese MP, Fumagalli M and d'Adda di Fagagna F: Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing. Curr Opin Genet Dev. 26:89–95. 2014. View Article : Google Scholar : PubMed/NCBI


Suzuki M and Boothman DA: Stress-induced premature senescence (SIPS)-influence of SIPS on radiotherapy. J Radiat Res. 49:105–112. 2008. View Article : Google Scholar : PubMed/NCBI


He S and Sharpless NE: Senescence in health and disease. Cell. 169:1000–1011. 2017. View Article : Google Scholar : PubMed/NCBI


Li M, You L, Xue J and Lu Y: Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: A mini review. Front Pharmacol. 9:5222018. View Article : Google Scholar : PubMed/NCBI


Nagane M, Kuppusamy ML, An J, Mast JM, Gogna R, Yasui H, Yamamori T, Inanami O and Kuppusamy P: Ataxia-telangiectasia mutated (ATM) kinase regulates eNOS expression and modulates radiosensitivity in endothelial cells exposed to ionizing radiation. Radiat Res. 189:519–528. 2018. View Article : Google Scholar : PubMed/NCBI


Gire V and Dulic V: Senescence from G2 arrest, revisited. Cell Cycle. 14:297–304. 2015. View Article : Google Scholar : PubMed/NCBI


Krenning L, Feringa FM, Shaltiel IA, Van Den Berg J and Medema RH: Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 55:59–72. 2014. View Article : Google Scholar : PubMed/NCBI


Müllers E, Silva Cascales H, Jaiswal H, Saurin AT and Lindqvist A: Nuclear translocation of Cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase. Cell Cycle. 13:2733–2743. 2014. View Article : Google Scholar : PubMed/NCBI


Ye C, Zhang X, Wan J, Chang L, Hu W, Bing Z, Zhang S, Li J, He J, Wang J and Zhou G: Radiation-induced cellular senescence results from a slippage of long-term G2 arrested cells into G1 phase. Cell Cycle. 12:1424–1432. 2013. View Article : Google Scholar : PubMed/NCBI


Kuilman T, Michaloglou C, Mooi WJ and Peeper DS: The essence of senescence. Genes Dev. 24:2463–2479. 2010. View Article : Google Scholar : PubMed/NCBI


Wang Y, Scheiber MN, Neumann C, Calin GA and Zhou D: MicroRNA regulation of ionizing radiation-induced premature senescence. Int J Radiat Oncol Biol Phys. 81:839–848. 2011. View Article : Google Scholar : PubMed/NCBI


Suzuki M, Yamauchi M, Oka Y, Suzuki K and Yamashita S: Live-cell imaging visualizes frequent mitotic skipping during senescence-like growth arrest in mammary carcinoma cells exposed to ionizing radiation. Int J Radiat Oncol Biol Phys. 83:e241–e250. 2012. View Article : Google Scholar : PubMed/NCBI


Hudson D, Kovalchuk I, Koturbash I, Kolb B, Martin OA and Kovalchuk O: Induction and persistence of radiation-induced DNA damage is more pronounced in young animals than in old animals. Aging (Albany NY). 3:609–620. 2011. View Article : Google Scholar : PubMed/NCBI


Kim BC, Han NK, Byun HO, Kim SS, Ahn EK, Chu IS, Leem SH, Lee CK and Lee JS: Time-dependently expressed markers and the characterization for premature senescence induced by ionizing radiation in MCF7. Oncol Rep. 24:395–403. 2010.PubMed/NCBI


Studencka M and Schaber J: Senoptosis: Non-lethal DNA cleavage as a route to deep senescence. Oncotarget. 8:30656–30671. 2017. View Article : Google Scholar : PubMed/NCBI


Suzuki K, Mori I, Nakayama Y, Miyakoda M, Kodama S and Watanabe M: Radiation-induced senescence-like growth arrest requires TP53 function but not telomere shortening. Radiat Res. 155:248–253. 2001. View Article : Google Scholar : PubMed/NCBI


Liang X, Gu J, Yu D, Wang G, Zhou L, Zhang X, Zhao Y, Chen X, Zheng S, Liu Q, et al: Low-dose radiation induces cell proliferation in human embryonic lung fibroblasts but not in lung cancer cells: Importance of ERK1/2 and AKT signaling pathways. Dose-Response. 14:15593258156221742016. View Article : Google Scholar : PubMed/NCBI


Wang Y, Boerma M and Zhou D: Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res. 186:153–161. 2016. View Article : Google Scholar : PubMed/NCBI


Rezáčová M, Rudolfová G, Tichý A, Bačíková A, Mutná D, Havelek R, Vávrová J, Odrážka K, Lukášová E and Kozubek S: Accumulation of DNA damage and cell death after fractionated irradiation. Radiat Res. 175:708–718. 2011. View Article : Google Scholar : PubMed/NCBI


Kim BC, Yoo HJ, Lee HC, Kang KA, Jung SH, Lee HJ, Lee M, Park S, Ji YH, Lee YS, et al: Evaluation of premature senescence and senescence biomarkers in carcinoma cells and xenograft mice exposed to single or fractionated irradiation. Oncol Rep. 31:2229–2235. 2014. View Article : Google Scholar : PubMed/NCBI


Lagadec C, Vlashi E, Della Donna L, Meng Y, Dekmezian C, Kim K and Pajonk F: Survival and self-renewing capacity of breast cancer initiating cells during fractionated radiation treatment. Breast Cancer Res. 12:R132010. View Article : Google Scholar : PubMed/NCBI


Liakou E, Mavrogonatou E, Pratsinis H, Rizou S, Evangelou K, Panagiotou PN, Karamanos NK, Gorgoulis VG and Kletsas D: Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: The role of TGF-β. Aging (Albany NY). 8:1650–1668. 2016. View Article : Google Scholar : PubMed/NCBI


Hernandez-Segura A, de Jong TV, Melov S, Guryev V, Campisi J and Demaria M: Unmasking transcriptional heterogeneity in senescent cells. Curr Biol. 27:2652–2660.e4. 2017. View Article : Google Scholar : PubMed/NCBI


Ortiz-Montero P, Londoño-Vallejo A and Vernot JP: Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun Signal. 15:172017. View Article : Google Scholar : PubMed/NCBI


Johnston CJ, Hernady E, Reed C, Thurston SW, Finkelstein JN and Williams JP: Early alterations in cytokine expression in adult compared to developing lung in mice after radiation exposure. Radiat Res. 173:522–535. 2010. View Article : Google Scholar : PubMed/NCBI


Papadopoulou A and Kletsas D: Human lung fibroblasts prematurely senescent after exposure to ionizing radiation enhance the growth of malignant lung epithelial cells in vitro and in vivo. Int J Oncol. 39:989–999. 2011.PubMed/NCBI


Liao EC, Hsu YT, Chuah QY, Lee YJ, Hu JY, Huang TC, Yang PM and Chiu SJ: Radiation induces senescence and a bystander effect through metabolic alterations. Cell Death Dis. 5:e12552014. View Article : Google Scholar : PubMed/NCBI


Sugrue MM, Shin DY, Lee SW and Aaronson SA: Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc Natl Acad Sci USA. 94:9648–9653. 1997. View Article : Google Scholar : PubMed/NCBI


Beauséjour CM, Krtolica AF, Galimi F, Narita M, Lowe SW, Yaswen P and Campisi J: Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J. 22:4212–4222. 2014. View Article : Google Scholar


Cheng Z, Zheng YZ, Li YQ and Wong CS: Cellular senescence in mouse hippocampus after irradiation and the role of p53 and p21. J Neuropathol Exp Neurol. 76:260–269. 2017. View Article : Google Scholar : PubMed/NCBI


Widel M, Lalik A, Krzywon A, Poleszczuk J, Fujarewicz K and Rzeszowska-Wolny J: The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status. Mutat Res. 778:61–70. 2015. View Article : Google Scholar : PubMed/NCBI


Lindgren T, Stigbrand T, Råberg A, Riklund K, Johansson L and Eriksson D: Genome wide expression analysis of radiation-induced DNA damage responses in isogenic HCT116 p53+/+ and HCT116 p53-/- colorectal carcinoma cell lines. Int J Radiat Biol. 91:99–111. 2015. View Article : Google Scholar : PubMed/NCBI


Gong L, Gong H, Pan X, Chang C, Ou Z, Ye S, Yin L, Yang L, Tao T, Zhang Z, et al: p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage. Cell Res. 25:351–369. 2015. View Article : Google Scholar : PubMed/NCBI


Sanada F, Taniyama Y, Muratsu J, Otsu R, Iwabayashi M, Carracedo M, Rakugi H and Morishita R: Activated factor X induces endothelial cell senescence through IGFBP-5. Sci Rep. 6:355802016. View Article : Google Scholar : PubMed/NCBI


Sanada F, Taniyama Y, Muratsu J, Otsu R, Shimizu H, Rakugi H and Morishita R: IGF binding protein-5 induces cell senescence. Front Endocrinol (Lausanne). 9:532018. View Article : Google Scholar : PubMed/NCBI


Kim K, Seu Y, Baek S, Kim MJ, Kim KJ, Kim JH and Kim JR: Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism. Mol Biol Cell. 18:4543–4552. 2007. View Article : Google Scholar : PubMed/NCBI


Rombouts C, Aerts A, Quintens R, Baselet B, El-Saghire H, Harms-Ringdahl M, Haghdoost S, Janssen A, Michaux A, Yentrapalli R, et al: Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation. Int J Radiat Biol. 90:560–574. 2014. View Article : Google Scholar : PubMed/NCBI


Shi W, Tang MK, Yao Y, Tang C, Chui YL and Lee KK: BRE plays an essential role in preventing replicative and DNA damage-induced premature senescence. Sci Rep. 6:235062016. View Article : Google Scholar : PubMed/NCBI


Lukášová E, Kovarˇík A, Bacˇíková A, Falk M and Kozubek S: Loss of lamin B receptor is necessary to induce cellular senescence. Biochem J. 474:281–300. 2017. View Article : Google Scholar : PubMed/NCBI


Freund A, Laberge RM, Demaria M and Campisi J: Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. 23:2066–2075. 2012. View Article : Google Scholar : PubMed/NCBI


Toillon RA, Magné N, Laïos I, Castadot P, Kinnaert E, Van Houtte P, Desmedt C, Leclercq G and Lacroix M: Estrogens decrease gamma-ray-induced senescence and maintain cell cycle progression in breast cancer cells independently of p53. Int J Radiat Oncol Biol Phys. 67:1187–1200. 2007. View Article : Google Scholar : PubMed/NCBI


Abdelmohsen K, Panda A, Kang MJ, Xu J, Selimyan R, Yoon JH, Martindale JL, De S, Wood WH III, Becker KG and Gorospe M: Senescence-associated lncRNAs: Senescence-associated long noncoding RNAs. Aging Cell. 12:890–900. 2013. View Article : Google Scholar : PubMed/NCBI


Sohn D, Peters D, Piekorz RP, Budach W and Jänicke RU: miR-30e controls DNA damage-induced stress responses by modulating expression of the CDK inhibitor p21WAF1/CIP1 and caspase-3. Oncotarget. 7:15915–15929. 2016. View Article : Google Scholar : PubMed/NCBI


Velegzhaninov IO, Ermakova AV and Klokov DY: Low dose ionizing irradiation suppresses cellular senescence in normal human fibroblasts. Int J Radiat Biol. 94:825–828. 2018. View Article : Google Scholar : PubMed/NCBI


Dolan DW, Zupanic A, Nelson G, Hall P, Miwa S, Kirkwood TB and Shanley DP: Integrated stochastic model of DNA damage repair by non-homologous end joining and p53/p21-mediated early senescence signalling. PLoS Comput Biol. 11:e10042462015. View Article : Google Scholar : PubMed/NCBI


Celià-Terrassa T, Liu DD, Choudhury A, Hang X, Wei Y, Zamalloa J, Alfaro-Aco R, Chakrabarti R, Jiang YZ, Koh BI, et al: Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis. Nat Cell Biol. 19:711–723. 2017. View Article : Google Scholar : PubMed/NCBI


Bai X, Fisher DE and Flaherty KT: Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways. Nat Rev Clin Oncol. Apr 9–2019.(Epub ahead of print) Doi: 10.1038/s41571-019-0204-6. View Article : Google Scholar : PubMed/NCBI


Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, et al: T-helper-1-cell cytokines drive cancer into senescence. Nature. 494:361–365. 2013. View Article : Google Scholar : PubMed/NCBI


Sato K, Kato A, Sekai M, Hamazaki Y and Minato N: Physiologic thymic involution underlies age-dependent accumulation of senescence-associated CD4(+) T cells. J Immunol. 199:138–148. 2017. View Article : Google Scholar : PubMed/NCBI


Lord CJ and Ashworth A: PARP inhibitors: Synthetic lethality in the clinic. Science. 355:1152–1158. 2017. View Article : Google Scholar : PubMed/NCBI


Efimova EV, Mauceri HJ, Golden DW, Labay E, Bindokas VP, Darga TE, Chakraborty C, Barreto-Andrade JC, Crawley C, Sutton HG, et al: Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors. Cancer Res. 70:6277–6282. 2010. View Article : Google Scholar : PubMed/NCBI


Barreto-Andrade JC, Efimova EV, Mauceri HJ, Beckett MA, Sutton HG, Darga TE, Vokes EE, Posner MC, Kron SJ and Weichselbaum RR: Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiati on. Mol Cancer Ther. 10:1185–1193. 2011. View Article : Google Scholar : PubMed/NCBI


Chatterjee P, Choudhary GS, Sharma A, Singh K, Heston WD, Ciezki J, Klein EA and Almasan A: PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-def icient prostate cancer cells. PLoS One. 8:e604082013. View Article : Google Scholar : PubMed/NCBI


Azad A, Bukczynska P, Jackson S, Haupt Y, Cullinane C, McArthur GA and Solomon B: Co-targeting deoxyribonucleic acid-dependent protein kinase and poly(adenosine diphosphate-ribose) polymerase-1 promotes accelerated senescence of irradiated cancer cells. Int J Radiat Oncol Biol Phys. 88:385–394. 2014. View Article : Google Scholar : PubMed/NCBI


Cao F, Ju X, Chen D, Jiang L, Zhu X, Qing S, Fang F, Shen Y, Jia Z and Zhang H: Phosphorothioatemodified antisense oligonucleotides against human telomerase reverse transcriptase sensitize cancer cells to radiotherapy. Mol Med Rep. 16:2089–2094. 2017. View Article : Google Scholar : PubMed/NCBI


Orun O, Tiber PM and Serakinci N: Partial knockdown of TRF2 increase radiosensitivity of human mesenchymal stem cells. Int J Biol Macromol. 90:53–58. 2016. View Article : Google Scholar : PubMed/NCBI


Nam HY, Han MW, Chang HW, Kim SY and Kim SW: Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence. Autophagy. 9:1631–1632. 2013. View Article : Google Scholar : PubMed/NCBI


Marampon F, Megiorni F, Camero S, Crescioli C, McDowell HP, Sferra R, Vetuschi A, Pompili S, Ventura L, De Felice F, et al: HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. Cancer Lett. 397:1–11. 2017. View Article : Google Scholar : PubMed/NCBI


Pérès EA, Gérault AN, Samuel V, Roussel S, Toutain J, Divoux D, Guillamo JS, Sanson M, Bernaudin M and Petit E: Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe. Oncotarget. 6:2101–2119. 2015. View Article : Google Scholar : PubMed/NCBI


Ham SW, Jeon HY and Kim H: Verapamil augments carmustine- and irradiation-induced senescence in glioma cells by reducing intracellular reactive oxygen species and calcium ion levels. Tumour Biol. 39:10104283176922442017. View Article : Google Scholar : PubMed/NCBI


Wang M, Morsbach F, Sander D, Gheorghiu L, Nanda A, Benes C, Kriegs M, Krause M, Dikomey E, Baumann M, et al: EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks. Cancer Res. 71:6261–6269. 2011. View Article : Google Scholar : PubMed/NCBI


Mirzayans R, Andrais B and Murray D: Impact of premature senescence on radiosensitivity measured by high throughput cell-based assays. Int J Mol Sci. 18:E14602017. View Article : Google Scholar : PubMed/NCBI


Francica P, Aebersold DM and Medova M: Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer. Biochem Pharmacol. 126:1–12. 2017. View Article : Google Scholar : PubMed/NCBI


Miao GY, Zhou X, Zhang X, Xie Y, Sun C, Liu Y, Gan L and Zhang H: Telomere-mitochondrion links contribute to induction of senescence in MCF-7 cells after carbon-ion irradiation. Asian Pac J Cancer Prev. 17:1993–1998. 2016. View Article : Google Scholar : PubMed/NCBI


Ernst A, Anders H, Kapfhammer H, Orth M, Hennel R, Seidl K, Winssinger N, Belka C, Unkel S and Lauber K: HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas. Cancer Lett. 365:211–222. 2015. View Article : Google Scholar : PubMed/NCBI


Li P, Hou M, Lou F, Björkholm M and Xu D: Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells. Int J Biochem Cell Biol. 44:1531–1540. 2012. View Article : Google Scholar : PubMed/NCBI


Maeda T, Nakamura K, Atsumi K, Hirakawa M, Ueda Y and Makino N: Radiation-associated changes in the length of telomeres in peripheral leukocytes from inpatients with cancer. Int J Radiat Biol. 89:106–109. 2013. View Article : Google Scholar : PubMed/NCBI


Jinno-Oue A, Shimizu N, Hamada N, Wada S, Tanaka A, Shinagawa M, Ohtsuki T, Mori T, Saha MN, Hoque AS, et al: Irradiation with carbon ion beams induces apoptosis, autophagy, and cellular senescence in a human glioma-derived cell line. Int J Radiat Oncol Biol Phys. 76:229–241. 2010. View Article : Google Scholar : PubMed/NCBI


Pan J, Li D, Xu Y, Zhang J, Wang Y, Chen M, Lin S, Huang L, Chung EJ, Citrin DE, et al: Inhibition of Bcl-2/xl with ABT-263 selectively kills senescent type II pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. Int J Radiat Oncol Biol Phys. 99:353–361. 2017. View Article : Google Scholar : PubMed/NCBI


Chung EJ, McKay-Corkum G, Chung S, White A, Scroggins BT, Mitchell JB, Mulligan-Kehoe MJ and Citrin D: Truncated plasminogen activator inhibitor-1 protein protects from pulmonary fibrosis mediated by irradiation in a murine model. Int J Radiat Oncol Biol Phys. 94:1163–1172. 2016. View Article : Google Scholar : PubMed/NCBI


Chung EJ, Sowers A, Thetford A, McKay-Corkum G, Chung SI, Mitchell JB and Citrin DE: Mammalian target of rapamycin inhibition with rapamycin mitigates radiation-induced pulmonary fibrosis in a murine model. Int J Radiat Oncol Biol Phys. 96:857–866. 2016. View Article : Google Scholar : PubMed/NCBI


Shao L, Feng W, Li H, Gardner D, Luo Y, Wang Y, Liu L, Meng A, Sharpless NE and Zhou D: Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner. Blood. 123:3105–3115. 2014. View Article : Google Scholar : PubMed/NCBI


Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, et al: Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 22:78–83. 2016. View Article : Google Scholar : PubMed/NCBI


Lu L, Wang YY, Zhang JL, Li DG and Meng AM: p38 MAPK inhibitor insufficiently attenuates HSC senescence administered long-term after 6 Gy total body irradiation in mice. Int J Mol Sci. 17:E9052016. View Article : Google Scholar : PubMed/NCBI


Ness KK, Armstrong GT, Kundu M, Wilson CL, Tchkonia T and Kirkland JL: Frailty in childhood cancer survivors. Cancer. 121:1540–1547. 2015. View Article : Google Scholar : PubMed/NCBI


Ariffin H, Azanan MS, Abd Ghafar SS, Oh L, Lau KH, Thirunavakarasu T, Sedan A, Ibrahim K, Chan A, Chin TF, et al: Young adult survivors of childhood acute lymphoblastic leukemia show evidence of chronic inflammation and cellular aging. Cancer. 123:4207–4214. 2017. View Article : Google Scholar : PubMed/NCBI


Artoni F, Kreipke RE, Palmeira O, Dixon C, Goldberg Z and Ruohola-Baker H: Loss of foxo rescues stem cell aging in Drosophila germ line. eLife. 6:e278422017. View Article : Google Scholar : PubMed/NCBI


Alessio N, Capasso S, Di Bernardo G, Cappabianca S, Casale F, Calarco A, Cipollaro M, Peluso G and Galderisi U: Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy. Cell Cycle. 16:251–258. 2017. View Article : Google Scholar : PubMed/NCBI


Xing Y, Zhang J, Lu L, Li D, Wang Y, Huang S, Li C, Zhang Z, Li J and Meng A: Identification of hub genes of pneumocyte senescence induced by thoracic irradiation using weighted gene coexpression network analysis. Mol Med Rep. 13:107–116. 2016. View Article : Google Scholar : PubMed/NCBI


Alessio N, Esposito G, Galano G, De Rosa R, Anello P, Peluso G, Tabocchini MA and Galderisi U: Irradiation of mesenchymal stromal cells with low and high doses of alpha particles induces senescence and/or apoptosis. J Cell Biochem. 118:2993–3002. 2017. View Article : Google Scholar : PubMed/NCBI


Ramos Silva C, Cabral FV, de Camargo CF, Núñez SC, Mateus Yoshimura T, de Lima Luna AC, Maria DA and Ribeiro MS: Exploring the effects of low-level laser therapy on fibroblasts and tumor cells following gamma radiation exposure. J Biophotonics. 9:1157–1166. 2016. View Article : Google Scholar


Hamdi DH, Chevalier F, Groetz JE, Durantel F, Thuret JY, Mann C and Saintigny Y: Comparable senescence induction in three-dimensional human cartilage model by exposure to therapeutic doses of x-rays or C-ions. Int J Radiat Oncol Biol Phys. 95:139–146. 2016. View Article : Google Scholar : PubMed/NCBI


Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL and van Deursen JM: Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 479:232–236. 2011. View Article : Google Scholar : PubMed/NCBI


Kosmacek EA, Chatterjee A, Tong Q, Lin C and Oberley-Deegan RE: MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells. Oncotarget. 7:34532–34545. 2016. View Article : Google Scholar : PubMed/NCBI


Beach TA, Johnston CJ, Groves AM, Williams JP and Finkelstein JN: Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes. Exp Lung Res. 43:134–149. 2017. View Article : Google Scholar : PubMed/NCBI


Philipp J, Azimzadeh O, Subramanian V, Merl-Pham J, Lowe D, Hladik D, Erbeldinger N, Ktitareva S, Fournier C, Atkinson MJ, et al: Radiation-induced endothelial inflammation is transferred via the secretome to recipient cells in a STAT-mediated process. J Proteome Res. 16:3903–3916. 2017. View Article : Google Scholar : PubMed/NCBI


Chatterjee A, Kosmacek EA and Oberley-Deegan RE: MnTE-2-PyP treatment, or NOX4 inhibition, protects against radiation-induced damage in mouse primary prostate fibroblasts by inhibiting the TGF-Beta 1 signaling pathway. Radiat Res. 187:367–381. 2017. View Article : Google Scholar : PubMed/NCBI


Li H, Wang Y, Pazhanisamy SK, Shao L, Batinic-Haberle I, Meng A and Zhou D: Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression. Free Radic Biol Med. 51:30–37. 2011. View Article : Google Scholar : PubMed/NCBI


Xu G, Wu H, Zhang J, Li D, Wang Y, Wang Y, Zhang H, Lu L, Li C, Huang S, et al: Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med. 87:15–25. 2015. View Article : Google Scholar : PubMed/NCBI


Kaur E, Rajendra J, Jadhav S, Shridhar E, Goda JS, Moiyadi A and Dutt S: Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence. Carcinogenesis. 36:685–695. 2015. View Article : Google Scholar : PubMed/NCBI


Roberson RS, Kussick SJ, Vallieres E, Chen SY and Wu DY: Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in huma n lung cancers. Cancer Res. 65:2795–2803. 2005. View Article : Google Scholar : PubMed/NCBI


Chakradeo S, Elmore LW and Gewirtz DA: Is senescence reversible? Curr Drug Targets. 17:460–466. 2016. View Article : Google Scholar : PubMed/NCBI


Tato-Costa J, Casimiro S, Pacheco T, Pires R, Fernandes A, Alho I, Pereira P, Costa P, Castelo HB, Ferreira J and Costa L: Therapy-induced cellular senescence induces epithelial-to-mesenchymal transition and increases invasiveness in rectal cancer. Clin Colorectal Cancer. 15:170–178.e3. 2016. View Article : Google Scholar : PubMed/NCBI


Gewirtz DA, Alotaibi M, Yakovlev VA and Povirk LF: Tumor cell recovery from senescence induced by radiation with PARP inhibition. Radiat Res. 186:327–332. 2016. View Article : Google Scholar : PubMed/NCBI


Alotaibi M, Sharma K, Saleh T, Povirk LF, Hendrickson EA and Gewirtz DA: Radiosensitization by PARP inhibition in DNA repair proficient and deficient tumor cells: Proliferative recovery in senescent cells. Radiat Res. 185:229–245. 2016. View Article : Google Scholar : PubMed/NCBI


Hellevik T, Pettersen I, Berg V, Winberg JO, Moe BT, Bartnes K, Paulssen RH, Busund LT, Bremnes R, Chalmers A and Martinez-Zubiaurre I: Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced. Radiat Oncol. 7:592012. View Article : Google Scholar : PubMed/NCBI


Frame FM, Savoie H, Bryden F, Giuntini F, Mann VM, Simms MS, Boyle RW and Maitland NJ: Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy include senescence, necrosis, and autophagy, but not apoptosis. Cancer Med. 5:61–73. 2016. View Article : Google Scholar : PubMed/NCBI


Malaquin N, Martinez A and Rodier F: Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype. Exp Gerontol. 82:39–49. 2016. View Article : Google Scholar : PubMed/NCBI


Wiley CD and Campisi J: From ancient pathways to aging cells-connecting metabolism and cellular senescence. Cell Metab. 23:1013–1021. 2016. View Article : Google Scholar : PubMed/NCBI


Rodier F and Campisi J: Four faces of cellular senescence. J Cell Biol. 192:547–556. 2011. View Article : Google Scholar : PubMed/NCBI


Rzeszowska-Wolnyab J and Widel M: Ionizing radiation-induced bystander effects, potential targets for modulation of radiotherapy. Eur J Pharmacol. 625:156–164. 2009. View Article : Google Scholar : PubMed/NCBI


Jalal N, Haq S, Anwar N, Nazeer S and Saeed U: Radiation induced bystander effect and DNA damage. J Cancer Res Ther. 10:819–833. 2014. View Article : Google Scholar : PubMed/NCBI


Özcan S, Alessio N, Acar MB, Mert E, Omerli F, Peluso G and Galderisi U: Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging (Albany NY). 8:1316–1329. 2016. View Article : Google Scholar : PubMed/NCBI


Mowla SN, Lam EW and Jat PS: Cellular senescence and aging: The role of B-MYB. Aging Cell. 13:773–779. 2014. View Article : Google Scholar : PubMed/NCBI


Jin X, Li F, Liu B, Zheng X, Li H, Ye F, Chen W and Li Q: Different mitochondrial fragmentation after irradiation with X-rays and carbon ions in HeLa cells and its influence on cellular apoptosis. Biochem Biophys Res Commun. 500:958–965. 2018. View Article : Google Scholar : PubMed/NCBI


Capasso S, Alessio N, Squillaro T, Di Bernardo G, Melone MA, Cipollaro M, Peluso G and Galderisi U: Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells. Oncotarget. 6:39457–39468. 2015. View Article : Google Scholar : PubMed/NCBI


Ziegler DV, Wiley CD and Velarde MC: Mitochondrial effectors of cellular senescence: Beyond the free radical theory of aging. Aging Cell. 14:1–7. 2015. View Article : Google Scholar : PubMed/NCBI


Lafargue A, Degorre C, Corre I, Alves-Guerra MC, Gaugler MH, Vallette F, Pecqueur C and Paris F: Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex II dysfunction and superoxide generation. Free Radic Biol Med. 108:750–759. 2017. View Article : Google Scholar : PubMed/NCBI


Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos AT, Haupt S, Haupt Y, Denoyer D, Adlard PA, Bush AI and Cater MA: Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol. 14:100–115. 2018. View Article : Google Scholar : PubMed/NCBI


Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, et al: ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 13:91–98. 2017. View Article : Google Scholar : PubMed/NCBI


Li T and Chen ZJ: The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 215:1287–1299. 2018. View Article : Google Scholar : PubMed/NCBI


Yang H, Wang H, Ren J, Chen Q and Chen ZJ: cGAS is essential for cellular senescence. Proc Natl Acad Sci USA. 114:E4612–E4620. 2017. View Article : Google Scholar : PubMed/NCBI


Glück S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, Bridgeman A, Rehwinkel J, Zender L and Ablasser A: Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 19:1061–1070. 2017. View Article : Google Scholar : PubMed/NCBI


Sun Y, Coppé JP and Lam EW: Cellular senescence: The sought or the unwanted? Trends Mol Med. 24:871–885. 2018. View Article : Google Scholar : PubMed/NCBI


Leite de Oliveira R and Bernards R: Anti-cancer therapy: Senescence is the new black. EMBO J. 37:e993862018. View Article : Google Scholar : PubMed/NCBI

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Chen Z, Cao K, Xia Y, Li Y, Hou Y, Wang L, Li L, Chang L and Li W: Cellular senescence in ionizing radiation (Review). Oncol Rep 42: 883-894, 2019
Chen, Z., Cao, K., Xia, Y., Li, Y., Hou, Y., Wang, L. ... Li, W. (2019). Cellular senescence in ionizing radiation (Review). Oncology Reports, 42, 883-894. https://doi.org/10.3892/or.2019.7209
Chen, Z., Cao, K., Xia, Y., Li, Y., Hou, Y., Wang, L., Li, L., Chang, L., Li, W."Cellular senescence in ionizing radiation (Review)". Oncology Reports 42.3 (2019): 883-894.
Chen, Z., Cao, K., Xia, Y., Li, Y., Hou, Y., Wang, L., Li, L., Chang, L., Li, W."Cellular senescence in ionizing radiation (Review)". Oncology Reports 42, no. 3 (2019): 883-894. https://doi.org/10.3892/or.2019.7209