The present study made in 92 mice showed that hydrogen peroxide com-pound injected directly into the tumor could to some extent sensitize the hypoxiccells of S180 solid tumor to radiate,for example,both the tumor regr...The present study made in 92 mice showed that hydrogen peroxide com-pound injected directly into the tumor could to some extent sensitize the hypoxiccells of S180 solid tumor to radiate,for example,both the tumor regression rateand the mouse survival rate 40d after radiation in the hydrogen peroxide com-pound group were significantly greater than those in the radiation alone group.The increasing rate of tumor diameter in 10d was 77.10%,47.09%,and 47.47%-10.4% in groups of control,radiation alone,radiosensitizer alone,radiationand hydrogen peroxide compound,respectively.Some of the problems aboutthe intratumoral injection of radiosensitizer were discussed.展开更多
Radiotherapy is widely used clinically, but the toxic and side effects of nonselective killing of high-energy radiation limit its application. Finding biocompatible materials to assemble radiotherapy sensitizers and s...Radiotherapy is widely used clinically, but the toxic and side effects of nonselective killing of high-energy radiation limit its application. Finding biocompatible materials to assemble radiotherapy sensitizers and studying their sensitization patterns are of great significance for the clinical application. Here, biocompatible zinc porphyrin was chosen as sub-unit to construct various dimensional coordination frameworks. By employing top-down approach, suitable nanoframeworks with various dimensional zinc porphyrin were synthesized as radiosensitizers. The experimental data showed that high-dimensional zinc porphyrin nanoframeworks exhibit higher X-ray response performance.展开更多
Radiotherapy is one of the main therapeutic methods for cancers;however,nonselective killing of normal cells and tumor cells by X-ray inevitably results in toxicity and side effects.Developing low-toxicity and high-ef...Radiotherapy is one of the main therapeutic methods for cancers;however,nonselective killing of normal cells and tumor cells by X-ray inevitably results in toxicity and side effects.Developing low-toxicity and high-efficiency radiosensitizers to reduce the practical dose of X-ray is a promising approach to overcoming these side effects.Here,we report the use of carboxylatecontaining organic ligands to construct one-dimensional high-Z lanthanide chains for efficient response to X-ray.The onedimensional lanthanide chains are stacked through weak interactions to form coordination nanoframeworks in the presence of polyethylenimine(PEI).The morphology and activity of the synthesized nanoframeworks can be regulated through selenium atom engineering.This study presents a promising approach for effective radiotherapy through selenium-engineering stable lanthanide nanoframeworks with precise coordination structures as radiosensitizers to mitigate X-ray side effects.展开更多
Objective:To investigate the effects and underlying mechanism of 2-hexyl-4-pentynoic acid(HPTA),a derivative of valproic acid(VPA),on radiotherapy in breast cancer.Methods:MCF7 cells and 7,12-dimethylbenz-[α]-anthrac...Objective:To investigate the effects and underlying mechanism of 2-hexyl-4-pentynoic acid(HPTA),a derivative of valproic acid(VPA),on radiotherapy in breast cancer.Methods:MCF7 cells and 7,12-dimethylbenz-[α]-anthracene(DMBA)-induced transformed human normal breast cells(MCF10A–DMBA cells)were irradiated with 8 Gy X-rays.For both cells there were four groups:control,valproic acid(VPA)/HPTA,IR,and VPA/HPTA+IR groups.MTT and clonogenic survival assays were performed to assess cell proliferation,and comet assay was performed to evaluate DNA damage.Protein expression ofγH2AX,53BP1,Rad51,and BRCA1 was examined via immunofluorescence and immunoblotting.Cycloheximide chase and ubiquitination experiments were conducted to determine Rad51 ubiquitination.In vivo experiments involved a rat model of DMBA-induced breast cancer,with four fractionated doses of 2 Gy.Tumor tissue pathological changes andγH2AX,Rad51,and UCHL3 expression levels were measured by hematoxylin-eosin staining,immunohistochemistry,and immunoblotting.Results:Compared with the IR group,15μmol/L HPTA reduced the cell proliferation ability of irradiated MCF7 cells(t=2.16,P<0.05).The VPA/HPTA+IR group exhibited significantly increased DNA double-strand breaks relative to those in the IR group(VPA+IR vs.IR,t=13.37,P<0.05;HPTA+IR vs.IR,t=8.48,P<0.05).Immunofluorescence and immunoblotting experiments demonstrated that the VPA/HPTA+IR group displayed signifi-cantly increased cell foci formation,γH2AX and 53BP1 protein expression levels compared to the IR group[(γH2AX:VPA+IR vs.IR,t=8.88,P<0.05;HPTA+IR vs.IR,t=8.90,P<0.05),(53BP1,VPA+IR vs.IR,t=5.73,P<0.05;HPTA+IR vs.IR,t=6.40,P<0.05)].Further,Rad51 expression was downregulated(VPA+IR vs.IR,t=3.12,P<0.05;HPTA+IR vs.IR,t=2.70,P<0.05),and Rad51 inhibition effectively counteracted HPTA-induced radiosensitization.Ubiquitination detection further verified that HPTA inhibits Rad51 expression via UCHL3-dependent Rad51 deubiquitination.In vivo study results showed that 20 mg/kg HPTA significantly enhanced the radiosensitivity of breast tumors in rats by inhibiting Rad51 expression.Conclusions:HPTA is a highly effective radiosensitizer that enhances the radiotherapeutic efficacy of breast cancer treatment through UCHL3-dependent deubiquitination of Rad51.展开更多
The local hypoxic tumor environment substantially hampers the therapeutic efficiency of radiotherapy, which typically requires the large X-ray doses for tumor treatment but induces the serious side effects. Herein, a ...The local hypoxic tumor environment substantially hampers the therapeutic efficiency of radiotherapy, which typically requires the large X-ray doses for tumor treatment but induces the serious side effects. Herein, a bio-mimetic radiosensitized platform based on a natural in-situ oxygen-evolving photosynthetic cyanobacteria combined with two-dimensional (2D) bismuthene with high atomic-number (Z) components, is designed and engineered to effectively modulate the radiotherapy-resistant hypoxic tumor environment and achieve sufficient radiation energy deposition into tumor. Upon the exogenous sequential irradiation of 660 nm laser and X-ray beam, continuous photosynthetic oxygen evolution by the cyanobacteria and considerable generation of reactive oxygen species by the 2D bismuthene radiosensitizer substantially augmented the therapeutic efficacy of radiotherapy and suppressed the in vivo tumor growth, as demonstrated on both LLC-lung tumor xenograft-bearing C57/B6 mice model and 4T1-breast tumor xenograft-bearing Balb/c mice model, further demon-strating the photosynthetic hypoxia-alleviation capability and radiosensitization performance of the engineered biomimetic radiosensitized platform. This work exemplifies a distinct paradigm on the construction of microorganism-enabled tumor-microenvironment modulation and nanoradiosensitizer-augmented radiotherapy for efficient tumor treatment.展开更多
Primary liver cancer is a significant health problem worldwide.Hepatocellular carcinoma(HCC)is the main pathological type of primary liver cancer,accounting for 75%-85%of cases.In recent years,radiotherapy has become ...Primary liver cancer is a significant health problem worldwide.Hepatocellular carcinoma(HCC)is the main pathological type of primary liver cancer,accounting for 75%-85%of cases.In recent years,radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC.However,radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors.How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration.This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy,including epigenetics,transportation and metabolism,regulated cell death pathways,the microenvironment,and redox status,as well as the effect of nanoparticles on the radiosensitivity of liver cancer.It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.展开更多
BACKGROUND Esophageal cancer is one of the most common cancers around the world, and it has high incidence and mortality rates. The conventional therapy for esophageal cancer is radiotherapy, although its effect is hi...BACKGROUND Esophageal cancer is one of the most common cancers around the world, and it has high incidence and mortality rates. The conventional therapy for esophageal cancer is radiotherapy, although its effect is highly limited by the resistance of esophageal cancer cells. Thus, strong radiosensitizers can be very crucial during radiotherapy against esophageal cancer. Brucea javanica oil emulsion (BJOE) is a widely used drug against various cancers, such as liver, colon, and ovarian cancer. However, its anti-cancer effect and mechanism and the use of BJOE as a radiosensitizer have not been explored in esophageal cancer. AIM To evaluate the anti-cancer effect and mechanism of BJOE and explore the potential use of BJOE as a radiosensitizer during radiotherapy. METHODS The inhibitory effect of BJOE and its enhancement function with radiation on cell viability were examined with the calculated half-maximal effective concentration and half-maximal lethal concentration. The influence of BJOE on cell migration and invasion were measured with EC109 and JAR cells by wound-healing and transwell assay. Clonogenesis and apoptotic rate, which was measured by Hoechst staining, were investigated to confirm its enhancement function with radiation. To investigate the molecular pathway underlying the effect of BJOE, the expressions of several apoptosis- and cycle-related proteins was detected by western blotting.cell lines more than normal cell lines, and it markedly reduced migration and invasion in esophageal cancer cells (EC109 and JAR). Moreover, it promoted cell apoptosis and enhanced the effect of radiotherapy against esophageal cancerous cells. In the viability test, the values of half-maximal effective concentration and half-maximal lethal concentration were reduced. Compared to the control, only around 1/5 colonies formed when using BJOE and radiation together in the clonogenic assay. The apoptotic rate in EC109 was obviously promoted when BJOE was added during radiotherapy. Our study suggests that the expression of the apoptosis-proteins Bax and p21 were increased, while the expression of Bcl-2 was stable. Further detection of downstream proteins revealed that the expression of cyclin D1 and cyclin-dependent kinase 4/6 were significantly decreased. CONCLUSION BJOE has a strong anti-cancer effect on esophageal cancer and can be used as a radiosensitizer to promote apoptosis in cancerous esophageal cells via the cyclin D1-cyclin-dependent kinase 4/6 axis.展开更多
AIM:To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy(intensity modulated radiotherapy,IMRT) and maintenance therapy with S-1 for ...AIM:To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy(intensity modulated radiotherapy,IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer.METHODS:Subjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases,adequate organ and marrow functions,an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy,oral administration of S-1 40 mg/m2 twice daily from day 1 to day 14 of a 21-d cycle,with 30-min intravenous infusions of gemcitabine 1000 mg/m2 on day 1 and day 8. Two weeks after the completion of chemotherapy,S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m2 per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy(1.8 Gy/d,5 times per week,28 fractions). One month after the completion of chemotherapy and radiotherapy,S-1 was administered orally at a dose of 80 mg/m2 per day twice daily for 14 d,followed by a 14-d rest period. This cycle was repeated as maintenance therapy,until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median followup was 15.6 mo(range:8.6-32.3 mo).RESULTS:Thirty-two patients completed the scheduled course of chemotherapy,while 30 patients(93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria,the objective tumor response was partial response in 17(53.1%) patients,stable disease in 9(28.1%),and progressive disease in 6(18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo,respectively. The survival rates at 1 year and 2 years were 75% and 34.4%,respectively.CONCLUSION:The combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well-tolerated,promising treatment regimen.展开更多
Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs tha...Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.展开更多
Objective:The aim of the present study was to investigate the mechanisms responsible for the radiation-sensitizing effect of antennapedia proteins,ANTP-SMACN7,on lung cancer cells treated with accelerated carbon and F...Objective:The aim of the present study was to investigate the mechanisms responsible for the radiation-sensitizing effect of antennapedia proteins,ANTP-SMACN7,on lung cancer cells treated with accelerated carbon and Fe particle irradiation.Methods:The ANTP-SMACN7 fusion peptide was synthesized and linked to fluorescein isothiocyanate to determine its ability to penetrate cells.A549 and NCI-H460 cells,human non-small cell lung cancer(NSCLC)cell lines,were irradiated with X-ray or high linear energy transfer(LET)irradiation with or without ANTP-SMACN7 treatment.Cellular survival,apoptosis,and protein expression were studied by colony formation assays,flow cytometry,and western blot analyses,respectively.Results:ANTP-SMACN7 fusion proteins entered the cells and promoted A549 and NCI-H460 cell high LET irradiation radiosensitization.High LET irradiation was more efficient for clonogenic cell killing and the induction of apoptosis(P<0.05).Treatment with ANTP-SMACN7 significantly reduced the A549 and NCI-H460 cell clone-forming percentages and increased apoptosis through inhibition of the X-linked inhibitor of apoptosis protein and the activation of caspase-3 and caspase-9.Conclusions:Regarding pharmaceutical radiosensitization,these findings provided a way to improve high-LET clinical radiotherapy for NSCLC patients.展开更多
Gold nanoparticles(AuNPs)could serve as pot ential radiother apy sensitizers because of their exceptional biocompatibility and high.Z material nature;however,since in vitro and in vivo behaviors of AuNPs are determine...Gold nanoparticles(AuNPs)could serve as pot ential radiother apy sensitizers because of their exceptional biocompatibility and high.Z material nature;however,since in vitro and in vivo behaviors of AuNPs are determined not only by their particle size but also by their surface chemistries,whether surface ligands can affect their radiosensitization has seldom been investi-gated in the radiosensitization of AuNPs.By conducting head-to-head comparison on radio-sensitization of two kinds of ultrasmall(~2 nm)near-infrared(NIR)emitting AuNPs that are coated with zwitterionic glutathione and neutr al polyethylene glyol(PEG)ligands,respectively,we found that zwitterionic glut athione coated AuNPs(GS-AuNPs)can reduce survival rates of MCF-7 cells under irr adiation of clinically used megavoltage photon beam at low dosage of~2.25 Gy.On the other hand,PEG-AuNPs can serve as a radiation-protecting agent and enabled MCF-7 cells more resistant to the irradiation,clearly indicating the key role of surface cheistry in radiosensitization of AuNPs.More detailed studies suggested that such difference was inde-pendent of cellular uptake and its eficiency,but might be related to the ligand-induced difference in photoelectron generation and/or inter actions between AuNPs and X-ray triggered reactive oxygen species(ROS).展开更多
<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Concurrent chemoradiation value of the resected salivary tumor adjuvant conte...<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Concurrent chemoradiation value of the resected salivary tumor adjuvant context against regular radiation therapy alone. </span><b><span style="font-family:Verdana;">Design:</span></b><span style="font-family:Verdana;"> Prospective randomized clinical trial. </span><b><span style="font-family:Verdana;">Patients:</span></b><span style="font-family:Verdana;"> 48 patients were randomized to either adjuvant postoperative radiology alone versus concurrent chemoradiotherapy (weekly cisplatin 40 mg/m</span><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> for 6 cycles) “with resected high-risk salivary tumors of the large and minor salivary gland”. </span><b><span style="font-family:Verdana;">Main</span></b> <b><span style="font-family:Verdana;">Outcome</span></b> <b><span style="font-family:Verdana;">Measures:</span></b><span style="font-family:Verdana;"> Recurrent locoregional Free survival, distant free survival, and overall survival. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> Out of the 48 participants in the study 31 patients had parotid gland tumors. 23 patients received solely adjuvant radiation while 25 patients received concurrent chemoradiotherapy. In the chemoradiation group, platinum-based regimens were employed in all. The mean age in both groups was 48 years. Adenoid cystic carcinoma was the primary pathogenic form of both arms 56% (28 cases). Stage II patients were 35% and 32%, stage III was 39% and 48% and stage VIa were 26% and 20% in the radiation arm and chemoradiotherapy arm respectively. 40 of 48 patients (83%) had close or positive surgical margins and 30 of 48 patients (62%) have a perineural invasion. Both risk variables are more or less well balanced in both arms with no statistical difference. The 2- and 4-year estimates of the locoregional recurrence-free survival rate in the chemoradiation group were 95% and 73%, compared to 77.4% and 43.6% in the radiation arm respectively (p = 007). In the two-and four-year-old chemoradiation arm distant free metastases were 100% and 59% compared to 68% and 39% respectively in the radiation arm (p = 0.08). The overall survival estimates for 2 and 4 years were 93% and 78% respectively in the Chemoradiation Group but in the radiation-alone group were 95% and 48% respectively. The statistically significant differences were p = 0.009 by log-rank testing. Treatment was generally tolerated, although, in the chemoradiation group adverse symptoms, mainly mucositis increased. </span><b><span style="font-family:Verdana;">Conclusions:</span></b><span style="font-family:Verdana;"> Adding weekly cisplatin as a radiosensitizer for locally advanced stage or high-grade salivary gland cancer with adjuvant conventional radiation looks to be helpful and justifies further exploration in selected patients.</span></span>展开更多
AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)...AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)cell lines were treated as following:(1)PBS;(2)CQ;(3)5-fluorouracil(5-FU);(4)RT;(5)CQ and RT;(6)5-FU and RT;(7)CQ and 5-FU;and(8)5-FU and CQ and RT.Each group was then exposed to various doses of radiation(0-8 Gy)depending on the experiment.Cell viability and proliferative capacity were measured by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and clonogenic assays.Clonogenic survivalcurves were constructed and compared across treatment groups.Autophagy status was determined by assessing the LC3-Ⅱto LC3-Ⅰratio on western blot analysis,autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFPlabeled LC3 on fluorescence microscopy.Cell cycle arrest and cell death were evaluated by FACS and AnnexinⅤanalysis.All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups.RESULTS:RT(2-8 Gy)induced autophagy in HCT-116and HT-29 CRC cell lines at 4 and 6 h post-radiation,respectively,as measured by increasing LC3-Ⅱto LC3-Ⅰratio on western blot.Additionally,electron microscopy demonstrated autophagy induction in HT-29 cells24 h following irradiation at a dose of 8 Gy.Drug treatment with 5-FU(25μmol/L)induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction.CQ(10μmol/L)alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation(8 Gy;P<0.001 and 0.00001,respectively).Significant decrease in clonogenic survival was seen only in the HT-29 cell line,when CQ was combined with RT at doses of 2 and 8 Gy(P<0.5 and P=0.05,respectively).There were no differences in cell cycle progression or Annexin V staining upon CQ addition to RT.CONCLUSION:Autophagy inhibition by CQ increases CRC cell sensitivity to concurrent treatment with 5-FU and RT in vitro,suggesting that addition of CQ to chemoRT improves CRC treatment response.展开更多
AIM:To explore the potential of β-elemene as a radiosensitizer for gastric cancer cells and the underlying mechanisms.METHODS:SGC7901,MKN45,MKN28,N87,and AGS human gastric cancer cell lines were used to screen for ra...AIM:To explore the potential of β-elemene as a radiosensitizer for gastric cancer cells and the underlying mechanisms.METHODS:SGC7901,MKN45,MKN28,N87,and AGS human gastric cancer cell lines were used to screen for radioresistant gastric cancer cell lines. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium(MTT) assay was used to determine the effects of β-elemene and IPA-3 on cell viability in MKN45 and SGC7901 gastric cancer cell lines. A clonogenic survival assay and annexin V-FITC/PI apoptosis detection assay were used to evaluate cellular radiosensitivity and radiation-induced cell death,respectively. A proteomic method,isobaric tags for relative and absolute quantitation(i TRAQ),was employed to screen the proteins regulated by β-elemene pretreatment prior to ionizing radiation(IR) in SGC7901 gastric cancer cell line. IPA-3 was used as a specific small molecule inhibitor of p21-activated protein kinase 1(Pak1) to target Pak1 signaling. Protein levels of PAK1IP1(p21-activated protein kinase-interacting protein 1),total Pak1(t-Pak1),phospho-Pak1(T423),phospho-ERK1/2( Thr202/Tyr204),and cleaved caspase-3(17 k Da) were assessed by western blotting.RESULTS:MKN45 and SGC7901 gastric cancer cell lines were relatively more resistant to IR. β-elemene pretreatment decreased clonogenic survival following IR in MKN45 and SGC7901 gastric cancer cell lines. Additionally,β-elemene pretreatment prior to IR increased radiation-induced cell death compared with IR alone in MKN45(10.4% ± 0.9% vs 34.8% ± 2.8%,P < 0.05) and SGC7901(11.6% ± 0.9% vs 46.7% ± 5.2%,P < 0.05) human gastric cancer cell lines,respectively,consistent with the level of cleaved caspase-3(17 k Da). Through i TRAQ analysis and western blot validation,we found that β-elemene upregulated PAK1IP1 and downregulated phospho-Pak1(T423) and phosphoERK1/2 in SGC7901 gastric cancer cells. IR increased the level of phospho-Pak1(T423). Pretreatment with β-elemene decreased radiation-induced Pak1 and ERK1/2 phosphorylation. Inhibition of Pak1 using IPA-3 decreased clonogenic survival following IR. In addition,IPA-3 increased radiation-induced cell death in MKN45(13.4% ± 0.3% vs 26.6% ± 1.0%,P < 0.05) and SGC7901(16.0% ± 0.6% vs 37.3% ± 1.7%,P < 0.05) gastric cancer cell lines,respectively,consistent with the level of cleaved caspase-3(17 k Da). Western blotting showed that IPA-3 decreased radiation-induced Pak1 and ERK1/2 phosphorylation.CONCLUSION:This is the first demonstration that β-elemene enhances radiosensitivity of gastric cancer cells,and that the mechanism involves inhibition of Pak1 signaling.展开更多
Objective:To explore the influence of silencing Bcl-2 expression by small interfering RNA(siRNA) on Bcl-2 protein expression,cell apoptosis rale and radiosensilivity of gastric cancer BCC823 cells.Methods:siRNA segm...Objective:To explore the influence of silencing Bcl-2 expression by small interfering RNA(siRNA) on Bcl-2 protein expression,cell apoptosis rale and radiosensilivity of gastric cancer BCC823 cells.Methods:siRNA segment for Bcl-2 gene was designed and synthesized,then was induced into gastric cancer BGC 823 cells by liposome transfection.Bcl-2 protein expression was detected by Western Blotting.After X radiation,flow cytometry and clone forming assay were used to determine the effects of RNA interference on BGC823 cell apoptosis rate and radiosensitivity. Result:After the transfection of Bcl-2 siRNA,the positive expression rate of Bcl-2 protein in BGC823 cells was(35.45±2.35)%.Compared with the control group and negative siRNA transfection group,the rate was significantly decreased(P【0.01).The apoptosis rate of BGC823-RNAi cell was(10.81±0.91)%,which was significantly higher than the control group and negative siRNA transfection group(P【0.01).After 48h X radiation,the apoptosis rate of BGC823-RNAi was(28.91±1.40)%,which was significantly higher than the control group and the group without radiation (P【0.01).During clone forming assay D<sub>0</sub>,D<sub>4</sub> and SF<sub>2</sub> values in Bcl-2 siRNA1 transfection group were all lower than those in the control group.The radiosensitivity ratio was 1.28(the ratio of D<sub>0</sub>) and 1.60(the ratio of D<sub>4</sub>).Conclusions:Specific siRNA of Bcl-2 gene can effectively inhibit the expression of Bcl-2 gene,enhance the radiosensitivity and apoptosis of gastric cancer BGC823 cells,having good clinical application perspective.展开更多
AIM:To investigate the regulative effect of miRNA(miR)-221 on colorectal carcinoma(CRC)cell radiosensitivity and the underlying mechanisms.METHODS:A human CRC-derived cell line was cultured conventionally and exposed ...AIM:To investigate the regulative effect of miRNA(miR)-221 on colorectal carcinoma(CRC)cell radiosensitivity and the underlying mechanisms.METHODS:A human CRC-derived cell line was cultured conventionally and exposed to different doses of X-rays(0,2,4,6 and 8 Gy).The total RNA and protein of the cells were extracted 24 h after irradiation,and the alteration of miR-221 and phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene mRNA expression was detected by real-time reverse transcriptase polymerase chain reaction(PCR).The protein alteration of PTEN in the cells was detected by Western blotting.Caco2 cells were pretreated with or without anti-PTEN-siRNA prior to the addition of premiR-221 or anti-miR-221 using Lipofectamine 2000.Colony formation assay and flow cytometry analysis were used to measure the surviving cell fraction and the sensitizing enhancement ratio after irradiation.Ad-ditionally,PTEN 3′-untranslated region fragment was PCR amplified and inserted into a luciferase reporter plasmid.The luciferase reporter plasmid construct was then transfected into CRC cells together with premiR-221 or anti-miR-221,and the luciferase activity in the transfected cells was detected.RESULTS:The X-ray radiation dose had a significant effect on the expression of miR-221 and PTEN protein in human Caco2 cells in a dose-dependent manner.The miR-221 expression level improved gradually with the increase in irradiation dose,while the PTEN protein expression level reduced gradually.miR-221 expression was significantly reduced in the anti-miR-221 group compared with the pre-miR-221 and negative control groups(P<0.01).Anti-miR-221 upregulated expression of PTEN protein and enhanced the radiosensitivity of Caco2 cells(P<0.01).Moreover,the inhibitory effect was dramatically abolished by pretreatment with anti-PTEN-siRNA,suggesting that the enhancement of radiosensitivity was indeed mediated by PTEN.A significant increase of luciferase activity was detected in CRC cells that were cotransfected with the luciferase reporter plasmid construct and anti-miR-221(P<0.01).CONCLUSION:Anti-miR-221 can enhance the radiosensitivity of CRC cells by upregulating PTEN.展开更多
Breast cancer(BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been establi...Breast cancer(BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy(RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients' treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms(SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair(BER) genes and BC risk. We focusedon X-ray repair cross complementing group 1(XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly(ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.展开更多
AIM:To investigate the role of endoplasmic reticulum(ER) stress in cancer radiotherapy and its molecular mechanism.METHODS:Tunicamycin(TM) was applied to induce ER stress in human esophageal cancer cell line EC109,and...AIM:To investigate the role of endoplasmic reticulum(ER) stress in cancer radiotherapy and its molecular mechanism.METHODS:Tunicamycin(TM) was applied to induce ER stress in human esophageal cancer cell line EC109,and the radiosensitization effects were detected by acute cell death and clonogenic survival assay.Cell cycle arrest induced by TM was determined by flow cytometric analysis after the cellular DNA content was labeled with propidium iodide.Apoptosis of EC109 cells induced by TM was detected by annexin V staining and Western blotting of caspase-3 and its substrate poly ADP-ribose polymerase.Autophagic response was determined by acridine orange(AO) staining and Western blotting of microtubule-associated protein-1 light chain-3(LC3) and autophagy related gene 5(ATG5).In order to test the biological function of autophagy,specific inhibitor or Beclin-1 knockdown was used to inhibit autophagy,and its effect on cell apoptosis was thus detected.Additionally,involvement of the phosphatidylinositol-3 kinase(PI3K)/Akt/mammalian target of the rapamycin(mTOR) pathway was also detected by Western blotting.Finally,male nude mice inoculated subcutaneously with EC109 cells were used to confirm cell model observations.RESULTS:Our results showed that TM treatment enhanced cell death and reduced the colony survival fraction induced by ionizing radiation(IR),which suggested an obvious radiosensitization effect of TM.Moreover,TM and IR combination treatment led to a significant increase of G2/M phase and apoptotic cells,compared with IR alone.We also observed an increase of AO positive cells,and the protein level of LC3-II and ATG5 was induced by TM treatment,which suggested an autophagic response in EC109 cells.However,inhibition of autophagy by using a chemical inhibitor or Beclin-1 silencing led to increased cell apoptosis and decreased cell viability,which suggested a cytoprotective role of autophagy in stressed EC109 cells.Furthermore,TM treatment also activated mTORC1,and in turn reduced Akt phosphorylation,which suggested the PI3K/Akt/mTOR signal pathway was involved in the TM-induced autophagic response in EC109 cells.Tumor xenograft results also showed synergistic retarded tumor growth by TM treatment and IR,as well as the involvement of the PI3K/Akt/mTOR pathway.CONCLUSION:Our data showed that TM treatment sensitized human esophageal cancer cells to radiation via apoptosis and autophagy both in vitro and in vivo.展开更多
Objective:To observe the chitooligosaccharides(COS) effect on the proliferation inhibition and radiosensitivity of three types of human gastric cancer cell line.Mothods:CCK-8 assay was employed to obtain the inhibitio...Objective:To observe the chitooligosaccharides(COS) effect on the proliferation inhibition and radiosensitivity of three types of human gastric cancer cell line.Mothods:CCK-8 assay was employed to obtain the inhibition ratio of COS on BGC823 cells,MKN45 cells and SGC7901 cells at 48 h after treatment and the proliferation-inhibition curve was drawn with the inhibition ratio of COS on three types of cells.The clonogenic assay was used to detect the cell viability of 0,1,2,4,6 and 8 Gy(6 dose grades) in RAY group and RAY+COS group after X-ray,and the cell survival curve was used to analyze the sensitization enhancement ratio of COS.Flow cytometry was employed to detect cell cycle and apoptosis rate in control group,RAY group and RAY+COS group after 48 h treatment.Results:COS inhibited the proliferation of three types of cells.The inhibition rate was positively correlated with the concentration of COS,and the susceptibility of MKN45 cells,SGC7901 cells and BGC823 cells to COS decreased in turn.The cell viability decreased gradually with the increasing radiation dose in RAY group and RAY+COS group(P<0.01).The cell viabilities of RAY+COS group were lower than those of RAY group at all the dose grades under X-ray exposure(P<0.01),and the sensitization enhancement ratios of COS on BGC823 cells,MKN45 cells and SGC7901 cells were 1.06,1.28 and 1.15 respectively.In controlled trials,apoptosis rate and percentage in the G_2/M phase of three types of cells in RAY+COS group were higher than those in control group and RAY group,and percentage in the S phase and the G_0/G_1 phase in RAY+COS group were lower than those in the other two groups(P<0.01).Conclusions:COS can inhibit the proliferation of three types of human gastric cancer cells and enhance the radiosensitivity by inducing apoptosis and G_2/M phase arrest.展开更多
文摘The present study made in 92 mice showed that hydrogen peroxide com-pound injected directly into the tumor could to some extent sensitize the hypoxiccells of S180 solid tumor to radiate,for example,both the tumor regression rateand the mouse survival rate 40d after radiation in the hydrogen peroxide com-pound group were significantly greater than those in the radiation alone group.The increasing rate of tumor diameter in 10d was 77.10%,47.09%,and 47.47%-10.4% in groups of control,radiation alone,radiosensitizer alone,radiationand hydrogen peroxide compound,respectively.Some of the problems aboutthe intratumoral injection of radiosensitizer were discussed.
基金supported by National Natural Science Foundation of China (Nos. 21877049, 22177038, 32171296)Guangdong Natural Science Foundation (Nos. 2020B1515120043, 2022A1515012235)+2 种基金Major Program for Tackling Key Problems of Industrial Technology in Guangzhou (Nos. 201902020013)Guangdong Pearl River Talent Program (No. 2017GC010354)Innovation Team Project in Guangdong Colleges and Universities (Nos. 2019KCXTD008, 2019KTSCX012)。
文摘Radiotherapy is widely used clinically, but the toxic and side effects of nonselective killing of high-energy radiation limit its application. Finding biocompatible materials to assemble radiotherapy sensitizers and studying their sensitization patterns are of great significance for the clinical application. Here, biocompatible zinc porphyrin was chosen as sub-unit to construct various dimensional coordination frameworks. By employing top-down approach, suitable nanoframeworks with various dimensional zinc porphyrin were synthesized as radiosensitizers. The experimental data showed that high-dimensional zinc porphyrin nanoframeworks exhibit higher X-ray response performance.
基金supported by the National Natural Science Foundation of China(Nos.21877049,22177038,and 32171296)Guangdong Natural Science Foundation(Nos.2022A1515012235 and 2020B1515120043)+1 种基金Guangdong Pearl River Talent Program(No.2017GC010354)Innovation Team Project in Guangdong Colleges and Universities(Nos.2019KCXTD008 and 2019KTSCX012).
文摘Radiotherapy is one of the main therapeutic methods for cancers;however,nonselective killing of normal cells and tumor cells by X-ray inevitably results in toxicity and side effects.Developing low-toxicity and high-efficiency radiosensitizers to reduce the practical dose of X-ray is a promising approach to overcoming these side effects.Here,we report the use of carboxylatecontaining organic ligands to construct one-dimensional high-Z lanthanide chains for efficient response to X-ray.The onedimensional lanthanide chains are stacked through weak interactions to form coordination nanoframeworks in the presence of polyethylenimine(PEI).The morphology and activity of the synthesized nanoframeworks can be regulated through selenium atom engineering.This study presents a promising approach for effective radiotherapy through selenium-engineering stable lanthanide nanoframeworks with precise coordination structures as radiosensitizers to mitigate X-ray side effects.
基金supported by grants from Zhejiang Provincial Natural Science Foundation of China(LQ23H14003)National Natural Science Foundation of China(81472800,82173460)+1 种基金Department of Science and Technology of Shandong Province(2019GSF108083)Zhejiang Provincial Postdoctoral Scientific Research Project Funding(ZJ2022076),China.
文摘Objective:To investigate the effects and underlying mechanism of 2-hexyl-4-pentynoic acid(HPTA),a derivative of valproic acid(VPA),on radiotherapy in breast cancer.Methods:MCF7 cells and 7,12-dimethylbenz-[α]-anthracene(DMBA)-induced transformed human normal breast cells(MCF10A–DMBA cells)were irradiated with 8 Gy X-rays.For both cells there were four groups:control,valproic acid(VPA)/HPTA,IR,and VPA/HPTA+IR groups.MTT and clonogenic survival assays were performed to assess cell proliferation,and comet assay was performed to evaluate DNA damage.Protein expression ofγH2AX,53BP1,Rad51,and BRCA1 was examined via immunofluorescence and immunoblotting.Cycloheximide chase and ubiquitination experiments were conducted to determine Rad51 ubiquitination.In vivo experiments involved a rat model of DMBA-induced breast cancer,with four fractionated doses of 2 Gy.Tumor tissue pathological changes andγH2AX,Rad51,and UCHL3 expression levels were measured by hematoxylin-eosin staining,immunohistochemistry,and immunoblotting.Results:Compared with the IR group,15μmol/L HPTA reduced the cell proliferation ability of irradiated MCF7 cells(t=2.16,P<0.05).The VPA/HPTA+IR group exhibited significantly increased DNA double-strand breaks relative to those in the IR group(VPA+IR vs.IR,t=13.37,P<0.05;HPTA+IR vs.IR,t=8.48,P<0.05).Immunofluorescence and immunoblotting experiments demonstrated that the VPA/HPTA+IR group displayed signifi-cantly increased cell foci formation,γH2AX and 53BP1 protein expression levels compared to the IR group[(γH2AX:VPA+IR vs.IR,t=8.88,P<0.05;HPTA+IR vs.IR,t=8.90,P<0.05),(53BP1,VPA+IR vs.IR,t=5.73,P<0.05;HPTA+IR vs.IR,t=6.40,P<0.05)].Further,Rad51 expression was downregulated(VPA+IR vs.IR,t=3.12,P<0.05;HPTA+IR vs.IR,t=2.70,P<0.05),and Rad51 inhibition effectively counteracted HPTA-induced radiosensitization.Ubiquitination detection further verified that HPTA inhibits Rad51 expression via UCHL3-dependent Rad51 deubiquitination.In vivo study results showed that 20 mg/kg HPTA significantly enhanced the radiosensitivity of breast tumors in rats by inhibiting Rad51 expression.Conclusions:HPTA is a highly effective radiosensitizer that enhances the radiotherapeutic efficacy of breast cancer treatment through UCHL3-dependent deubiquitination of Rad51.
基金The authors greatly acknowledge the financial support from the National Natural Science Foundation of China(Grant Nos.81703021,81772604)Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406002)+2 种基金Shanghai Science and Technology Program(Grant No.21010500100)Youth Program of National Natural Science Foundation of China(Grant No.51902334)Shanghai Pujiang Program(2020PJD56).
文摘The local hypoxic tumor environment substantially hampers the therapeutic efficiency of radiotherapy, which typically requires the large X-ray doses for tumor treatment but induces the serious side effects. Herein, a bio-mimetic radiosensitized platform based on a natural in-situ oxygen-evolving photosynthetic cyanobacteria combined with two-dimensional (2D) bismuthene with high atomic-number (Z) components, is designed and engineered to effectively modulate the radiotherapy-resistant hypoxic tumor environment and achieve sufficient radiation energy deposition into tumor. Upon the exogenous sequential irradiation of 660 nm laser and X-ray beam, continuous photosynthetic oxygen evolution by the cyanobacteria and considerable generation of reactive oxygen species by the 2D bismuthene radiosensitizer substantially augmented the therapeutic efficacy of radiotherapy and suppressed the in vivo tumor growth, as demonstrated on both LLC-lung tumor xenograft-bearing C57/B6 mice model and 4T1-breast tumor xenograft-bearing Balb/c mice model, further demon-strating the photosynthetic hypoxia-alleviation capability and radiosensitization performance of the engineered biomimetic radiosensitized platform. This work exemplifies a distinct paradigm on the construction of microorganism-enabled tumor-microenvironment modulation and nanoradiosensitizer-augmented radiotherapy for efficient tumor treatment.
基金supported by the Science and Technology Plan Project of Guangzhou(No.202102010171)National Natural Science Foundation Cultivation Project of The Third Affiliated Hospital of Sun Yat-sen University(No.2020GZRPYMS11)+1 种基金Natural Science Foundation of Guangdong Province(No.2018A030313641)CSCO-Roche Joint Cancer Research Fund(No.Y-Roche2019/20041)。
文摘Primary liver cancer is a significant health problem worldwide.Hepatocellular carcinoma(HCC)is the main pathological type of primary liver cancer,accounting for 75%-85%of cases.In recent years,radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC.However,radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors.How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration.This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy,including epigenetics,transportation and metabolism,regulated cell death pathways,the microenvironment,and redox status,as well as the effect of nanoparticles on the radiosensitivity of liver cancer.It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.
文摘BACKGROUND Esophageal cancer is one of the most common cancers around the world, and it has high incidence and mortality rates. The conventional therapy for esophageal cancer is radiotherapy, although its effect is highly limited by the resistance of esophageal cancer cells. Thus, strong radiosensitizers can be very crucial during radiotherapy against esophageal cancer. Brucea javanica oil emulsion (BJOE) is a widely used drug against various cancers, such as liver, colon, and ovarian cancer. However, its anti-cancer effect and mechanism and the use of BJOE as a radiosensitizer have not been explored in esophageal cancer. AIM To evaluate the anti-cancer effect and mechanism of BJOE and explore the potential use of BJOE as a radiosensitizer during radiotherapy. METHODS The inhibitory effect of BJOE and its enhancement function with radiation on cell viability were examined with the calculated half-maximal effective concentration and half-maximal lethal concentration. The influence of BJOE on cell migration and invasion were measured with EC109 and JAR cells by wound-healing and transwell assay. Clonogenesis and apoptotic rate, which was measured by Hoechst staining, were investigated to confirm its enhancement function with radiation. To investigate the molecular pathway underlying the effect of BJOE, the expressions of several apoptosis- and cycle-related proteins was detected by western blotting.cell lines more than normal cell lines, and it markedly reduced migration and invasion in esophageal cancer cells (EC109 and JAR). Moreover, it promoted cell apoptosis and enhanced the effect of radiotherapy against esophageal cancerous cells. In the viability test, the values of half-maximal effective concentration and half-maximal lethal concentration were reduced. Compared to the control, only around 1/5 colonies formed when using BJOE and radiation together in the clonogenic assay. The apoptotic rate in EC109 was obviously promoted when BJOE was added during radiotherapy. Our study suggests that the expression of the apoptosis-proteins Bax and p21 were increased, while the expression of Bcl-2 was stable. Further detection of downstream proteins revealed that the expression of cyclin D1 and cyclin-dependent kinase 4/6 were significantly decreased. CONCLUSION BJOE has a strong anti-cancer effect on esophageal cancer and can be used as a radiosensitizer to promote apoptosis in cancerous esophageal cells via the cyclin D1-cyclin-dependent kinase 4/6 axis.
文摘AIM:To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy(intensity modulated radiotherapy,IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer.METHODS:Subjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases,adequate organ and marrow functions,an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy,oral administration of S-1 40 mg/m2 twice daily from day 1 to day 14 of a 21-d cycle,with 30-min intravenous infusions of gemcitabine 1000 mg/m2 on day 1 and day 8. Two weeks after the completion of chemotherapy,S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m2 per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy(1.8 Gy/d,5 times per week,28 fractions). One month after the completion of chemotherapy and radiotherapy,S-1 was administered orally at a dose of 80 mg/m2 per day twice daily for 14 d,followed by a 14-d rest period. This cycle was repeated as maintenance therapy,until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median followup was 15.6 mo(range:8.6-32.3 mo).RESULTS:Thirty-two patients completed the scheduled course of chemotherapy,while 30 patients(93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria,the objective tumor response was partial response in 17(53.1%) patients,stable disease in 9(28.1%),and progressive disease in 6(18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo,respectively. The survival rates at 1 year and 2 years were 75% and 34.4%,respectively.CONCLUSION:The combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well-tolerated,promising treatment regimen.
基金supported by Bowel Disease Research FoundationOxford Cancer Research Centre+4 种基金the National Institute for Health Research University College London Hospitals Biomedical Research Centrethe Cancer Research UK University College London Experimental Cancer Medicine CentreCRUK-UCL Centre Award (Grant No. C416/ A25145)the Cancer Research UK Centers Network Accelerator Award Grant (Grant No.A21993) to the ART-NET Consortiumthe NIHR Oxford Biomedical Research Centre
文摘Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.
基金supported by grants from the National Key R&D Program of China(Grant Nos.2018YFE0205100 and 2018YFE0205101)the National Natural Science Foundation of China(Grant Nos.11605260 and 31670859)+4 种基金the Key Research and Development Projects of Shanxi Province(Grant No.201903D321115)the Science and Technology Talent Project in Lanzhou(Grant No.2018-RC-66)the Science and Technology Project of Chengguan District of Lanzhou(Grant No.2020RCCX0038)the CAMS Innovation Fund for Medical Science(Grant No.2017-I2M-1-016)the Ministry of Education,Culture,Sports,and Science Technology Grantin-Aid for Scientific Research on Innovative Areas with Heavy Ions at NIRS-HIMAC,Japan[Grant Nos.JP15K21745,15H05944,and 15H05935(Living in Space),and Research Project Grant(14J313)].
文摘Objective:The aim of the present study was to investigate the mechanisms responsible for the radiation-sensitizing effect of antennapedia proteins,ANTP-SMACN7,on lung cancer cells treated with accelerated carbon and Fe particle irradiation.Methods:The ANTP-SMACN7 fusion peptide was synthesized and linked to fluorescein isothiocyanate to determine its ability to penetrate cells.A549 and NCI-H460 cells,human non-small cell lung cancer(NSCLC)cell lines,were irradiated with X-ray or high linear energy transfer(LET)irradiation with or without ANTP-SMACN7 treatment.Cellular survival,apoptosis,and protein expression were studied by colony formation assays,flow cytometry,and western blot analyses,respectively.Results:ANTP-SMACN7 fusion proteins entered the cells and promoted A549 and NCI-H460 cell high LET irradiation radiosensitization.High LET irradiation was more efficient for clonogenic cell killing and the induction of apoptosis(P<0.05).Treatment with ANTP-SMACN7 significantly reduced the A549 and NCI-H460 cell clone-forming percentages and increased apoptosis through inhibition of the X-linked inhibitor of apoptosis protein and the activation of caspase-3 and caspase-9.Conclusions:Regarding pharmaceutical radiosensitization,these findings provided a way to improve high-LET clinical radiotherapy for NSCLC patients.
基金supported by the NIH(1R01DK103363)CPRIT(RP120588 and RP140544)the start-up fund from the University of Texas at Dallas.
文摘Gold nanoparticles(AuNPs)could serve as pot ential radiother apy sensitizers because of their exceptional biocompatibility and high.Z material nature;however,since in vitro and in vivo behaviors of AuNPs are determined not only by their particle size but also by their surface chemistries,whether surface ligands can affect their radiosensitization has seldom been investi-gated in the radiosensitization of AuNPs.By conducting head-to-head comparison on radio-sensitization of two kinds of ultrasmall(~2 nm)near-infrared(NIR)emitting AuNPs that are coated with zwitterionic glutathione and neutr al polyethylene glyol(PEG)ligands,respectively,we found that zwitterionic glut athione coated AuNPs(GS-AuNPs)can reduce survival rates of MCF-7 cells under irr adiation of clinically used megavoltage photon beam at low dosage of~2.25 Gy.On the other hand,PEG-AuNPs can serve as a radiation-protecting agent and enabled MCF-7 cells more resistant to the irradiation,clearly indicating the key role of surface cheistry in radiosensitization of AuNPs.More detailed studies suggested that such difference was inde-pendent of cellular uptake and its eficiency,but might be related to the ligand-induced difference in photoelectron generation and/or inter actions between AuNPs and X-ray triggered reactive oxygen species(ROS).
文摘<strong>Objective:</strong><span style="font-family:""><span style="font-family:Verdana;"> Concurrent chemoradiation value of the resected salivary tumor adjuvant context against regular radiation therapy alone. </span><b><span style="font-family:Verdana;">Design:</span></b><span style="font-family:Verdana;"> Prospective randomized clinical trial. </span><b><span style="font-family:Verdana;">Patients:</span></b><span style="font-family:Verdana;"> 48 patients were randomized to either adjuvant postoperative radiology alone versus concurrent chemoradiotherapy (weekly cisplatin 40 mg/m</span><sup><span style="font-family:Verdana;">2</span></sup><span style="font-family:Verdana;"> for 6 cycles) “with resected high-risk salivary tumors of the large and minor salivary gland”. </span><b><span style="font-family:Verdana;">Main</span></b> <b><span style="font-family:Verdana;">Outcome</span></b> <b><span style="font-family:Verdana;">Measures:</span></b><span style="font-family:Verdana;"> Recurrent locoregional Free survival, distant free survival, and overall survival. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> Out of the 48 participants in the study 31 patients had parotid gland tumors. 23 patients received solely adjuvant radiation while 25 patients received concurrent chemoradiotherapy. In the chemoradiation group, platinum-based regimens were employed in all. The mean age in both groups was 48 years. Adenoid cystic carcinoma was the primary pathogenic form of both arms 56% (28 cases). Stage II patients were 35% and 32%, stage III was 39% and 48% and stage VIa were 26% and 20% in the radiation arm and chemoradiotherapy arm respectively. 40 of 48 patients (83%) had close or positive surgical margins and 30 of 48 patients (62%) have a perineural invasion. Both risk variables are more or less well balanced in both arms with no statistical difference. The 2- and 4-year estimates of the locoregional recurrence-free survival rate in the chemoradiation group were 95% and 73%, compared to 77.4% and 43.6% in the radiation arm respectively (p = 007). In the two-and four-year-old chemoradiation arm distant free metastases were 100% and 59% compared to 68% and 39% respectively in the radiation arm (p = 0.08). The overall survival estimates for 2 and 4 years were 93% and 78% respectively in the Chemoradiation Group but in the radiation-alone group were 95% and 48% respectively. The statistically significant differences were p = 0.009 by log-rank testing. Treatment was generally tolerated, although, in the chemoradiation group adverse symptoms, mainly mucositis increased. </span><b><span style="font-family:Verdana;">Conclusions:</span></b><span style="font-family:Verdana;"> Adding weekly cisplatin as a radiosensitizer for locally advanced stage or high-grade salivary gland cancer with adjuvant conventional radiation looks to be helpful and justifies further exploration in selected patients.</span></span>
文摘AIM:To investigate whether the inhibition of autophagy by chloroquine(CQ)sensitizes rectal tumors to radiation therapy(RT)or concurrent chemoradiation(chemoRT).METHODS:In vitro,HCT-116 and HT-29 colorectal cancer(CRC)cell lines were treated as following:(1)PBS;(2)CQ;(3)5-fluorouracil(5-FU);(4)RT;(5)CQ and RT;(6)5-FU and RT;(7)CQ and 5-FU;and(8)5-FU and CQ and RT.Each group was then exposed to various doses of radiation(0-8 Gy)depending on the experiment.Cell viability and proliferative capacity were measured by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and clonogenic assays.Clonogenic survivalcurves were constructed and compared across treatment groups.Autophagy status was determined by assessing the LC3-Ⅱto LC3-Ⅰratio on western blot analysis,autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFPlabeled LC3 on fluorescence microscopy.Cell cycle arrest and cell death were evaluated by FACS and AnnexinⅤanalysis.All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups.RESULTS:RT(2-8 Gy)induced autophagy in HCT-116and HT-29 CRC cell lines at 4 and 6 h post-radiation,respectively,as measured by increasing LC3-Ⅱto LC3-Ⅰratio on western blot.Additionally,electron microscopy demonstrated autophagy induction in HT-29 cells24 h following irradiation at a dose of 8 Gy.Drug treatment with 5-FU(25μmol/L)induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction.CQ(10μmol/L)alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation(8 Gy;P<0.001 and 0.00001,respectively).Significant decrease in clonogenic survival was seen only in the HT-29 cell line,when CQ was combined with RT at doses of 2 and 8 Gy(P<0.5 and P=0.05,respectively).There were no differences in cell cycle progression or Annexin V staining upon CQ addition to RT.CONCLUSION:Autophagy inhibition by CQ increases CRC cell sensitivity to concurrent treatment with 5-FU and RT in vitro,suggesting that addition of CQ to chemoRT improves CRC treatment response.
基金Supported by National Nature Science Foundation of China,No.81172357
文摘AIM:To explore the potential of β-elemene as a radiosensitizer for gastric cancer cells and the underlying mechanisms.METHODS:SGC7901,MKN45,MKN28,N87,and AGS human gastric cancer cell lines were used to screen for radioresistant gastric cancer cell lines. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium(MTT) assay was used to determine the effects of β-elemene and IPA-3 on cell viability in MKN45 and SGC7901 gastric cancer cell lines. A clonogenic survival assay and annexin V-FITC/PI apoptosis detection assay were used to evaluate cellular radiosensitivity and radiation-induced cell death,respectively. A proteomic method,isobaric tags for relative and absolute quantitation(i TRAQ),was employed to screen the proteins regulated by β-elemene pretreatment prior to ionizing radiation(IR) in SGC7901 gastric cancer cell line. IPA-3 was used as a specific small molecule inhibitor of p21-activated protein kinase 1(Pak1) to target Pak1 signaling. Protein levels of PAK1IP1(p21-activated protein kinase-interacting protein 1),total Pak1(t-Pak1),phospho-Pak1(T423),phospho-ERK1/2( Thr202/Tyr204),and cleaved caspase-3(17 k Da) were assessed by western blotting.RESULTS:MKN45 and SGC7901 gastric cancer cell lines were relatively more resistant to IR. β-elemene pretreatment decreased clonogenic survival following IR in MKN45 and SGC7901 gastric cancer cell lines. Additionally,β-elemene pretreatment prior to IR increased radiation-induced cell death compared with IR alone in MKN45(10.4% ± 0.9% vs 34.8% ± 2.8%,P < 0.05) and SGC7901(11.6% ± 0.9% vs 46.7% ± 5.2%,P < 0.05) human gastric cancer cell lines,respectively,consistent with the level of cleaved caspase-3(17 k Da). Through i TRAQ analysis and western blot validation,we found that β-elemene upregulated PAK1IP1 and downregulated phospho-Pak1(T423) and phosphoERK1/2 in SGC7901 gastric cancer cells. IR increased the level of phospho-Pak1(T423). Pretreatment with β-elemene decreased radiation-induced Pak1 and ERK1/2 phosphorylation. Inhibition of Pak1 using IPA-3 decreased clonogenic survival following IR. In addition,IPA-3 increased radiation-induced cell death in MKN45(13.4% ± 0.3% vs 26.6% ± 1.0%,P < 0.05) and SGC7901(16.0% ± 0.6% vs 37.3% ± 1.7%,P < 0.05) gastric cancer cell lines,respectively,consistent with the level of cleaved caspase-3(17 k Da). Western blotting showed that IPA-3 decreased radiation-induced Pak1 and ERK1/2 phosphorylation.CONCLUSION:This is the first demonstration that β-elemene enhances radiosensitivity of gastric cancer cells,and that the mechanism involves inhibition of Pak1 signaling.
文摘Objective:To explore the influence of silencing Bcl-2 expression by small interfering RNA(siRNA) on Bcl-2 protein expression,cell apoptosis rale and radiosensilivity of gastric cancer BCC823 cells.Methods:siRNA segment for Bcl-2 gene was designed and synthesized,then was induced into gastric cancer BGC 823 cells by liposome transfection.Bcl-2 protein expression was detected by Western Blotting.After X radiation,flow cytometry and clone forming assay were used to determine the effects of RNA interference on BGC823 cell apoptosis rate and radiosensitivity. Result:After the transfection of Bcl-2 siRNA,the positive expression rate of Bcl-2 protein in BGC823 cells was(35.45±2.35)%.Compared with the control group and negative siRNA transfection group,the rate was significantly decreased(P【0.01).The apoptosis rate of BGC823-RNAi cell was(10.81±0.91)%,which was significantly higher than the control group and negative siRNA transfection group(P【0.01).After 48h X radiation,the apoptosis rate of BGC823-RNAi was(28.91±1.40)%,which was significantly higher than the control group and the group without radiation (P【0.01).During clone forming assay D<sub>0</sub>,D<sub>4</sub> and SF<sub>2</sub> values in Bcl-2 siRNA1 transfection group were all lower than those in the control group.The radiosensitivity ratio was 1.28(the ratio of D<sub>0</sub>) and 1.60(the ratio of D<sub>4</sub>).Conclusions:Specific siRNA of Bcl-2 gene can effectively inhibit the expression of Bcl-2 gene,enhance the radiosensitivity and apoptosis of gastric cancer BGC823 cells,having good clinical application perspective.
基金Supported by National Natural Science Foundation of China,No.81101896the National Research Foundation for Doctoral Program of Higher Education of China,No.20124433110010
文摘AIM:To investigate the regulative effect of miRNA(miR)-221 on colorectal carcinoma(CRC)cell radiosensitivity and the underlying mechanisms.METHODS:A human CRC-derived cell line was cultured conventionally and exposed to different doses of X-rays(0,2,4,6 and 8 Gy).The total RNA and protein of the cells were extracted 24 h after irradiation,and the alteration of miR-221 and phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene mRNA expression was detected by real-time reverse transcriptase polymerase chain reaction(PCR).The protein alteration of PTEN in the cells was detected by Western blotting.Caco2 cells were pretreated with or without anti-PTEN-siRNA prior to the addition of premiR-221 or anti-miR-221 using Lipofectamine 2000.Colony formation assay and flow cytometry analysis were used to measure the surviving cell fraction and the sensitizing enhancement ratio after irradiation.Ad-ditionally,PTEN 3′-untranslated region fragment was PCR amplified and inserted into a luciferase reporter plasmid.The luciferase reporter plasmid construct was then transfected into CRC cells together with premiR-221 or anti-miR-221,and the luciferase activity in the transfected cells was detected.RESULTS:The X-ray radiation dose had a significant effect on the expression of miR-221 and PTEN protein in human Caco2 cells in a dose-dependent manner.The miR-221 expression level improved gradually with the increase in irradiation dose,while the PTEN protein expression level reduced gradually.miR-221 expression was significantly reduced in the anti-miR-221 group compared with the pre-miR-221 and negative control groups(P<0.01).Anti-miR-221 upregulated expression of PTEN protein and enhanced the radiosensitivity of Caco2 cells(P<0.01).Moreover,the inhibitory effect was dramatically abolished by pretreatment with anti-PTEN-siRNA,suggesting that the enhancement of radiosensitivity was indeed mediated by PTEN.A significant increase of luciferase activity was detected in CRC cells that were cotransfected with the luciferase reporter plasmid construct and anti-miR-221(P<0.01).CONCLUSION:Anti-miR-221 can enhance the radiosensitivity of CRC cells by upregulating PTEN.
文摘Breast cancer(BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy(RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients' treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms(SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair(BER) genes and BC risk. We focusedon X-ray repair cross complementing group 1(XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly(ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.
基金Supported by A Grant from the National Natural Science Foundation of China,No. 30870746
文摘AIM:To investigate the role of endoplasmic reticulum(ER) stress in cancer radiotherapy and its molecular mechanism.METHODS:Tunicamycin(TM) was applied to induce ER stress in human esophageal cancer cell line EC109,and the radiosensitization effects were detected by acute cell death and clonogenic survival assay.Cell cycle arrest induced by TM was determined by flow cytometric analysis after the cellular DNA content was labeled with propidium iodide.Apoptosis of EC109 cells induced by TM was detected by annexin V staining and Western blotting of caspase-3 and its substrate poly ADP-ribose polymerase.Autophagic response was determined by acridine orange(AO) staining and Western blotting of microtubule-associated protein-1 light chain-3(LC3) and autophagy related gene 5(ATG5).In order to test the biological function of autophagy,specific inhibitor or Beclin-1 knockdown was used to inhibit autophagy,and its effect on cell apoptosis was thus detected.Additionally,involvement of the phosphatidylinositol-3 kinase(PI3K)/Akt/mammalian target of the rapamycin(mTOR) pathway was also detected by Western blotting.Finally,male nude mice inoculated subcutaneously with EC109 cells were used to confirm cell model observations.RESULTS:Our results showed that TM treatment enhanced cell death and reduced the colony survival fraction induced by ionizing radiation(IR),which suggested an obvious radiosensitization effect of TM.Moreover,TM and IR combination treatment led to a significant increase of G2/M phase and apoptotic cells,compared with IR alone.We also observed an increase of AO positive cells,and the protein level of LC3-II and ATG5 was induced by TM treatment,which suggested an autophagic response in EC109 cells.However,inhibition of autophagy by using a chemical inhibitor or Beclin-1 silencing led to increased cell apoptosis and decreased cell viability,which suggested a cytoprotective role of autophagy in stressed EC109 cells.Furthermore,TM treatment also activated mTORC1,and in turn reduced Akt phosphorylation,which suggested the PI3K/Akt/mTOR signal pathway was involved in the TM-induced autophagic response in EC109 cells.Tumor xenograft results also showed synergistic retarded tumor growth by TM treatment and IR,as well as the involvement of the PI3K/Akt/mTOR pathway.CONCLUSION:Our data showed that TM treatment sensitized human esophageal cancer cells to radiation via apoptosis and autophagy both in vitro and in vivo.
基金supported by Youth Science Fund Project(No.81400612)
文摘Objective:To observe the chitooligosaccharides(COS) effect on the proliferation inhibition and radiosensitivity of three types of human gastric cancer cell line.Mothods:CCK-8 assay was employed to obtain the inhibition ratio of COS on BGC823 cells,MKN45 cells and SGC7901 cells at 48 h after treatment and the proliferation-inhibition curve was drawn with the inhibition ratio of COS on three types of cells.The clonogenic assay was used to detect the cell viability of 0,1,2,4,6 and 8 Gy(6 dose grades) in RAY group and RAY+COS group after X-ray,and the cell survival curve was used to analyze the sensitization enhancement ratio of COS.Flow cytometry was employed to detect cell cycle and apoptosis rate in control group,RAY group and RAY+COS group after 48 h treatment.Results:COS inhibited the proliferation of three types of cells.The inhibition rate was positively correlated with the concentration of COS,and the susceptibility of MKN45 cells,SGC7901 cells and BGC823 cells to COS decreased in turn.The cell viability decreased gradually with the increasing radiation dose in RAY group and RAY+COS group(P<0.01).The cell viabilities of RAY+COS group were lower than those of RAY group at all the dose grades under X-ray exposure(P<0.01),and the sensitization enhancement ratios of COS on BGC823 cells,MKN45 cells and SGC7901 cells were 1.06,1.28 and 1.15 respectively.In controlled trials,apoptosis rate and percentage in the G_2/M phase of three types of cells in RAY+COS group were higher than those in control group and RAY group,and percentage in the S phase and the G_0/G_1 phase in RAY+COS group were lower than those in the other two groups(P<0.01).Conclusions:COS can inhibit the proliferation of three types of human gastric cancer cells and enhance the radiosensitivity by inducing apoptosis and G_2/M phase arrest.