Xiaodong Jin

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The synergistic radiosensitizing effect of tirapazamine-conjugated gold nanoparticles on human hepatoma HepG2 cells under X-ray irradiation

International journal of nanomedicine, 2016

Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage... more Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by secondary electrons. In this work, polyethylene glycol-capped AuNPs were conjugated with tirapazamine (TPZ) moiety, and then thioctyl TPZ (TPZs)-modified AuNPs (TPZs-AuNPs) were synthesized. The TPZs-AuNPs were characterized by transmission electron microscopy, ultraviolet-visible spectra, dynamic light scattering, and inductively coupled plasma mass spectrometry to have a size of 16.6±2.1 nm in diameter and a TPZs/AuNPs ratio of ~700:1. In contrast with PEGylated AuNPs, the as-synthesized TPZs-AuNPs exhibited 20% increment in hydroxyl radical production in water at 2.0 Gy, and 19% increase in sensitizer enhancement ratio at 10% survival fraction for human hepatoma HepG2 cells under X-ray irradiation. The production of reactive oxygen species in HepG2 cells exposed to X-rays in vitro demonstrated a synergistic radiosens...

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$Research paper thumbnail of {"__content__"=>"Metal-basedfor Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells.", "i"=>{"__content__"=>"NanoEnhancers"}}$

{"__content__"=>"Metal-basedfor Future Radiotherapy: Radiosensitizing and Synergistic Effects on Tumor Cells.", "i"=>{"__content__"=>"NanoEnhancers"}}

Theranostics, 2018

Radiotherapy is one of the major therapeutic strategies for cancer treatment. In the past decade,... more Radiotherapy is one of the major therapeutic strategies for cancer treatment. In the past decade, there has been growing interest in using high Z (atomic number) elements (materials) as radiosensitizers. New strategies in nanomedicine could help to improve cancer diagnosis and therapy at cellular and molecular levels. Metal-based nanoparticles usually exhibit chemical inertness in cellular and subcellular systems and may play a role in radiosensitization and synergistic cell-killing effects for radiation therapy. This review summarizes the efficacy of metal-basedagainst cancers in bothandsystems for a range of ionizing radiations including gamma-rays, X-rays, and charged particles. The potential of translating preclinical studies on metal-based nanoparticles-enhanced radiation therapy into clinical practice is also discussed using examples of several metal-based(such as CYT-6091, AGuIX, and NBTXR3). Also, a few general examples of theranostic multimetallic nanocomposites are present...

format_quoteAuNPs substantially improve cell-killing effects of X-rays and fast carbon ions, enhancing hydroxyl radical production in tumor cells.format_quote

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Dynamically-enhanced retention of gold nanoclusters in HeLa cells following X-rays exposure: A cell cycle phase-dependent targeting approach

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Jan 9, 2016

Cell cycle phase could affect the cellular uptake of nanoparticles. Based on the fact that ionizi... more Cell cycle phase could affect the cellular uptake of nanoparticles. Based on the fact that ionizing radiation exposure can delay cell cycle progression including inducing G2/M phase arrest, we propose that ionizing radiation exposure is a cell cycle phase-dependent targeting approach for intracellular delivery of nano-agents in tumor cells. We synthesized luminescent gold nanoclusters (AuNCs) using a one-pot green synthetic method. Subsequently, we used the as-prepared AuNCs as both "nano-agents" and fluorescent trafficking probes for our study using human cervical carcinoma HeLa cells. Estimating the cellular uptake of AuNCs and cell cycle analysis were performed following X-rays irradiation and cell synchronization. Our work showed that X-rays irradiation could delay the division of HeLa cells and thereby enhance the retention of AuNCs in HeLa cells, which is a reverse strategy compared with other studies on synergistic nano-radiotherapy. Our results demonstrated that th...

Different Roles of CHOP and JNK in Mediating Radiation-Induced Autophagy and Apoptosis in Breast Cancer Cells

Radiation research, Jan 2, 2016

Unfolded protein response (UPR) is comprised of complex and conserved stress pathways that functi... more Unfolded protein response (UPR) is comprised of complex and conserved stress pathways that function as a short-term adaptive mechanism to reduce levels of unfolded or misfolded proteins and maintain homeostasis in the endoplasmic reticulum (ER). UPR can be triggered by prolonged or persistent ER stress under many physiological or pathological conditions, including radiation exposure. Radiation-induced ER stress elicits autophagy and apoptosis in cancer cells, where C/EBP homologous protein (CHOP) and c-Jun NH2-terminal kinase (JNK) may play crucial roles. However, the specific mechanisms that regulate autophagy and apoptosis through CHOP and JNK after radiation exposure and how the balance of these activities determines the cellular radiosensitivity remain largely unclear. In this study, we found that exposure to X-ray radiation induced ER stress, UPR and high expression of CHOP and JNK. Furthermore, autophagy and apoptosis occurred in sequential order when breast cancer MDA-MB-231 ...

Genistein mediates the selective radiosensitizing effect in NSCLC A549 cells via inhibiting methylation of the keap1 gene promoter region

Oncotarget, Jan 26, 2016

Non-small cell lung cancer (NSCLC) cells often possess a hypermethylated Keap1 promoter, which de... more Non-small cell lung cancer (NSCLC) cells often possess a hypermethylated Keap1 promoter, which decreases Keap1 mRNA and protein expression levels, thus impairing the Nrf2-Keap1 pathway and thereby leading to chemo- or radio-resistance. In this study, we showed that genistein selectively exhibited a radiosensitizing effect on NSCLC A549 cells but not on normal lung fibroblast MRC-5 cells. Genistein caused oxidative stress in A549 cells rather than MRC-5 cells, as determined by the oxidation of the ROS-sensitive probe DCFH-DA and oxidative damage marked by MDA, PCO or 8-OHdG content. In A549 instead of MRC-5 cells, genistein reduced the level of methylation in the Keap1 promoter region, leading to an increased mRNA expression, thus effectively inhibited the transcription of Nrf2 to the nucleus, which suppressed the Nrf2-dependent antioxidant and resulted in the upregulation of ROS. Importantly, when combined with radiation, genistein further increased the ROS levels in A549 cells wher...

Long-term Autophagy and Nrf2 Signaling in the Hippocampi of Developing Mice after Carbon Ion Exposure

Scientific reports, 2015

To explore charged particle radiation-induced long-term hippocampus damage, we investigated the e... more To explore charged particle radiation-induced long-term hippocampus damage, we investigated the expression of autophagy and antioxidant Nrf2 signaling-related proteins in the mouse hippocampus after carbon ion radiation. Heads of immature female Balb/c mice were irradiated with carbon ions of different LETs at various doses. Behavioral tests were performed on the mice after maturation. Acute and chronic expression of LC3-II, p62/SQSTM1, nuclear Nrf2, activated caspase-3 and the Bax/Bcl-2 ratio were measured in the hippocampi. Secondary X-ray insult was adopted to amplify potential damages. Long-term behavioral changes were observed in high-LET carbon ion-irradiated mice. There were no differences in the rates of LC3-II induction and p62/SQSTM1 degradation compared to the control group regardless of whether the mice received the secondary X-ray insult. A high nuclear Nrf2 content and low apoptosis level in hippocampal cells subjected to secondary X-rays were observed for the mice exp...

The influence of non-DNA-targeted effects on carbon ion-induced low-dose hyper-radiosensitivity in MRC-5 cells

Journal of radiation research, Jan 10, 2015

Low-dose hyper-radiosensitivity (LDHRS) is a hot topic in normal tissue radiation protection. How... more Low-dose hyper-radiosensitivity (LDHRS) is a hot topic in normal tissue radiation protection. However, the primary causes for LDHRS still remain unclear. In this study, the impact of non-DNA-targeted effects (NTEs) on high-LET radiation-induced LDHRS was investigated. Human normal lung fibroblast MRC-5 cells were irradiated with high-LET carbon ions, and low-dose biological effects (in terms of various bio-endpoints, including colony formation, DNA damage and micronuclei formation) were detected under conditions with and without gap junctional intercellular communication (GJIC) inhibition. LDHRS was observed when the radiation dose was <0.2 Gy for all bio-endpoints under investigation, but vanished when the GJIC was suppressed. Based on the probability of cells being hit and micro-dose per cell calculation, we deduced that the LDHRS phenomenon came from the combined action of direct hits and NTEs. We concluded that GJIC definitely plays an important role in cytotoxic substance sp...

Microarray Analysis of Human Liver Cells irradiated by 80MeV/u Carbon Ions

Objective Biological effect of heavy ion beam has the important significance for cancer therapy a... more Objective Biological effect of heavy ion beam has the important significance for cancer therapy and space exploring owing its high LET and RBE, low OER, especially forming Bragg spike at the end of the tracks of charged particles. More serious damage for cells are induced by heavy ions and difficult repair than other irradiation such as X-ray and nu-ray . To explore the molecular mechanism of biological effect caused by heavy ionizing radiation (HIR) and to construct the gene expression profile database of HIR-induced human liver cells L02 by microarray analysis. Methods In this study, L02 cells were irradiated by 80MeV/u carbon ions at 5 Gy delivered by HIRFL (Heavy Ion Research Facility in Lanzhou) at room temperature. Total RNAs of cells incubated 6 hours and 24hours after irradiation were extracted with Trizol. Unirradiated cells were used as a control. RNAs were transcripted into cDNA by reverse transcription and labelled with cy5-dCTP and cy3-dCTP respectively. A human genome ...

Carbon ions induce autophagy effectively through stimulating the unfolded protein response and subsequent inhibiting Akt phosphorylation in tumor cells

Scientific reports, 2015

Heavy ion beams have advantages over conventional radiation in radiotherapy due to their superb b... more Heavy ion beams have advantages over conventional radiation in radiotherapy due to their superb biological effectiveness and dose conformity. However, little information is currently available concerning the cellular and molecular basis for heavy ion radiation-induced autophagy. In this study, human glioblastoma SHG44 and cervical cancer HeLa cells were irradiated with carbon ions of different linear energy transfers (LETs) and X-rays. Our results revealed increased LC3-II and decreased p62 levels in SHG44 and HeLa cells post-irradiation, indicating marked induction of autophagy. The autophagic level of tumor cells after irradiation increased in a LET-dependent manner and was inversely correlated with the sensitivity to radiations of various qualities. Furthermore, we demonstrated that high-LET carbon ions stimulated the unfolded protein response (UPR) and mediated autophagy via the UPR-eIF2α-CHOP-Akt signaling axis. High-LET carbon ions more severely inhibited Akt-mTOR through UPR ...

Effect of 80.55 MeV/u 12 C 6+ Ions on Radiosensitivity and Cell Cycle of Human Hepatoma Cell Lines

Plasma Science and Technology, 2008

In this paper, the relationship between radiosensitivity, cell cycle alteration and the change of... more

Heavy ion beams induce survivin expression in human hepatoma SMMC-7721 cells more effectively than X-rays

Acta biochimica et biophysica Sinica, 2007

High linear energy transfer (LET) heavy ion radiation is more effective in inducing biological da... more High linear energy transfer (LET) heavy ion radiation is more effective in inducing biological damage than low-LET X-rays or gamma-rays. Heavy ion beam provides good dose localization (Bragg peak) in critical cancer tissue and gives higher relative biological effectiveness in cell killing across the dose peak, so high-LET heavy ion beam is superior to low-LET radiation in cancer treatment. Survivin, as a member of the inhibitor of apoptosis protein family, might help cancerous cells to overcome the G2/M apoptotic checkpoint and favor the aberrant progression of transformed cells through mitosis. Survivin expression in the human hepatoma SMMC-7721 cell line after exposure to low-LET X-ray and high-LET carbon ion irradiation was investigated in this study. Compared with X-ray irradiation, the carbon ion beam clearly caused G2/M arrest and promoted the expression of the survivin gene in a dose-dependent manner. Clonogenic survival assay showed that SMMC-7721 cells were more radiosensit...

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Mitotic DNA damages induced by carbon-ion radiation incur additional chromosomal breaks in polyploidy

Toxicology letters, 2014

Compared with low linear energy transfer (LET) radiation, carbon-ion radiation has been proved to... more Compared with low linear energy transfer (LET) radiation, carbon-ion radiation has been proved to induce high frequency of more complex DNA damages, including DNA double strands (DSBs) and non-DSB clustered DNA lesions. Chemotherapeutic drug doxorubicin has been reported to elicit additional H2AX phosphorylation in polyploidy. Here, we investigated whether mitotic DNA damage induced by high-LET carbon-ion radiation could play the same role. We demonstrate that impairment of post-mitotic G1 and S arrest and abrogation of post-mitotic G2-M checkpoint failed to prevent mis-replication of damaged DNA and mis-separation of chromosomes. Meanwhile, mitotic slippage only nocodazole-related, cytokinesis failure and cell fusion collectively contributed to the formation of binucleated cells. Chk1 and Cdh1 activation was inhibited when polyploidy emerged in force, both of which are critical components for mitotic exit and cytokinesis. Carbon-ion radiation irrelevant of nocodazole incurred addit...

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The dependence of radiation enhancement effect on the concentration of gold nanoparticles exposed to low- and high-LET radiations

Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB), 2015

We examined the dependence of hydroxyl radical production on the concentration of 15 nm citrate-c... more We examined the dependence of hydroxyl radical production on the concentration of 15 nm citrate-capped AuNPs and dose using coumarin-3-carboxylic acid in phosphate buffered saline (PBS), and investigated the radiosensitisation of different concentration AuNPs on human cervix carcinoma HeLa cells through clonogenic survival assay for X-rays and carbon ions. The enhancement factor of AuNPs for hydroxyl radical production reached a maximum 3.66 for X-rays at the concentration of 0.1 μg/mL while the maximum was 5.52 for carbon ions in presence of 1.0 μg/mL AuNPs in PBS. At 50% survival level, the sensitizer enhancement ratios of X-rays and carbon ions varied from 1.14 to 2.88 and from 1.27 to 1.44, respectively, when cells were co-cultured with 1.5-15.0 μg/mL AuNPs. Our data indicate AuNPs showed radiosensitisation in terms of hydroxyl radical production and cell killing for low- and high-LET radiations. The concentration of AuNPs in PBS and cells played an important role in radiosensit...

Radiobiological response of human hepatoma and normal liver cells exposed to carbon ions generated by Heavy Ion Research Facility in Lanzhou

Science in China Series G, 2006

Human hepatoma and normal liver cells were irradiated with 12 C 6+ ion beams (LET = 96.05 keV/μm)... more Human hepatoma and normal liver cells were irradiated with 12 C 6+ ion beams (LET = 96.05 keV/μm) and γ-rays at Heavy Ion Research Facility in Lanzhou (HIRFL). The chromatid breaks and break types were detected using the premature chromosome condensation technique. Our experimental results showed that chromatid breaks seem to have a good relation with 12 C 6+ absorbed dose and 12 C 6+ are more effective to induce chromatid breaks as compared to the γ-rays. For 12 C 6+ ion irradiation the major break was isochromatid break, while chromatid breaks were dominant for γ-ray irradiation. We also observed that the Relative Biology Effectiveness (RBE) of 12 C 6+ ion is about 2.5 times higher than that of γ-rays.

format_quoteBoth cell lines exhibited linear increases in chromatid breaks with dose escalation, with SMMC-7721 showing higher rates than L02.format_quote

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Studies on advantages of heavy ions in radiotherapy compared with γ-rays

Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 2007

Hepatoma and melanoma cells were exposed to 12 C 6+ beams generated by HIRFL facility and c-rays ... more Hepatoma and melanoma cells were exposed to 12 C 6+ beams generated by HIRFL facility and c-rays and the cell response was studied by colony assays as well as the analysis of RBE of carbon ions was evolved. The survival curves of cells irradiated by heavy ions were different from those of cells irradiated by c-rays. And two kinds of cell showed the obvious discrepancy in response to the photon and ion irradiation. The results showed that heavy ions have special physical properties and mighty potency to kill cell in both single and fractional irradiation meanwhile it can kill tumor cells with high radioresistance more efficiently. When involved in clinical therapy, heavy ions will enhance the therapy efficiency and decrease the suffering of patients because it can impair the repair for sublethal damage of cells which can lead to fewer irradiation fractions.

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Bystander effect in human hepatoma HepG2 cells caused by medium transfers at different times after high-LET carbon ion irradiation

Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 2011

Although radiation-induced bystander effects have been well documented in a variety of biological... more Although radiation-induced bystander effects have been well documented in a variety of biological systems, whether irradiated cells have the ability to generate bystander signaling persistently is still unclear and the clinical relevance of bystander effects in radiotherapy remains to be elucidated. This study examines tumor cellular bystander response to autologous medium from cell culture irradiated with high-linear energy transfer (LET) heavy ions at a therapeutically relevant dose in terms of clonogenic cell survival.

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Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis

Molecules, 2013

The aim of the present study was to investigate the radiosensitizing effect of genistein, and the... more The aim of the present study was to investigate the radiosensitizing effect of genistein, and the corresponding mechanisms of action on breast cancer cells with different estrogen receptor (ER) status. Human breast cancer cell lines such as MCF-7 (ER-positive, harboring wild-type p53) and MDA-MB-231 (ER-negative, harboring mutant p53) were irradiated with X-rays in the presence or absence of genistein. Cell survival, DNA damage and repair, cell cycle distribution, cell apoptosis, expression of proteins related to G₂/M cell cycle checkpoint and apoptosis were measured with colony formation assays, immunohistochemistry, flow cytometry and western blot analysis, respectively. Genistein showed relatively weak toxicity to both cell lines at concentrations in the range of 5-20 μM. Using the dosage of 10 μM genistein, the sensitizer enhancement ratios after exposure to X-rays at a 10% cell survival (IC₁₀) were 1.43 for MCF-7 and 1.36 for MDA-MB-231 cells, respectively. Significantly increased DNA damages, arrested cells at G₂/M phase, decreased homologous recombination repair protein Rad51 foci formation and enhanced apoptotic rates were observed in both cell lines treated by genistein combined with X-rays compared with the irradiation alone. The combined treatment obviously up-regulated the phosphorylation of ATM, Chk2, Cdc25c and Cdc2, leading to permanent G₂/M phase arrest, and up-regulated Bax and p73, down-regulated Bcl-2, finally induced mitochondria-mediated apoptosis in both cell lines. These results suggest that genistein induces G₂/M arrest by the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway and ultimately enhances the radiosensitivity of both ER+ and ER- breast cancer cells through a mitochondria-mediated apoptosis pathway.

Heavy-ion conformal irradiation in the shallow-seated tumor therapy terminal at HIRFL

Medical & Biological Engineering & Computing, 2007

Basic research related to heavy-ion cancer therapy has been done at the Institute of Modern Physi... more Basic research related to heavy-ion cancer therapy has been done at the Institute of Modern Physics (IMP), Chinese Academy of Sciences since 1995. Now a plan of clinical trial with heavy ions has been launched at IMP. First, superficially placed tumor treatment with heavy ions is expected in the therapy terminal at the Heavy Ion Research Facility in Lanzhou (HIRFL), where carbon ion beams with energy up to 100 MeV/u can be supplied. The shallow-seated tumor therapy terminal at HIRFL is equipped with a passive beam delivery system including two orthogonal dipole magnets, which continuously scan pencil beams laterally and generate a broad and uniform irradiation field, a motor-driven energy degrader and a multi-leaf collimator. Two different types of range modulator, ripple filter and ridge filter with which Guassian-shaped physical dose and uniform biological effective dose Bragg peaks can be shaped for therapeutic ion beams respectively, have been designed and manufactured. Therefore, two-dimensional and three-dimensional conformal irradiations to tumors can be performed with the passive beam delivery system at the earlier therapy terminal. Both the conformal irradiation methods have been verified experimentally and carbon-ion conformal irradiations to patients with superficially placed tumors have been carried out at HIRFL since November 2006.

Study on the apoptosis and Bcl-2/Bax expression of human hepatoma SMMC-7721 cells after exposure to heavy-ion and X-ray irradiations

Journal of Radioanalytical and Nuclear Chemistry, 2007

ABSTRACT This study is aimed at observing the apoptosis and Bcl-2/Bax gene expression of mammalia... more ABSTRACT This study is aimed at observing the apoptosis and Bcl-2/Bax gene expression of mammalian cells following heavy-ion and X-ray irradiations. Exponentially growing human hepatoma SMMC-7721 cells cultured in vitro were irradiated with a 12C ion beam of 50 MeV/u (corresponding to a LET value of 44.56 keV/μm) from Heavy Ion Research Facility in Lanzhou (HIRFL) at doses varying from 0 to 3 Gy. The X-ray irradiation (8 MV) was performed in the therapy unit of the General Hospital of the Lanzhou Military Area. Survival fractions of irradiated cells at various doses were measured by means of MTT assay. Apoptotic cells after irradiation were analyzed with fluorescence microscope and flow cytometer (FCM). Immuno-histological assay were applied to detect the expression of Bcl-2/Bax genes in the irradiated cells. The survival fraction of SMMC-7721 cells decreased gradually (vs. control p&lt;0.05) with increasing the dose of the carbon ion beam more obviously than X-ray irradiation, and the carbon ion irradiation efficiently induced cell apoptosis and significantly promoted the expression of Bax gene while Bcl-2 gene expression was restrained. High-LET heavy ion beam would induce cell apoptosis effectively than low-LET X-ray, and the apoptosis rate is correlated with the transcription of Bcl-2/Bax and the ratio of Bcl-2/Bax in human hepatoma SMMC-7721 cells after irradiation to heavy ion beam.

High LET Radiation Enhances Nocodazole Induced Cell Death in HeLa Cells through Mitotic Catastrophe and Apoptosis

Journal of Radiation Research, 2011

To understand how human tumor cells respond to the combined treatment with nocodazole and high LE... more To understand how human tumor cells respond to the combined treatment with nocodazole and high LET radiation, alterations in cell cycle, mitotic disturbances and cell death were investigated in the present study. Human cervix carcinoma HeLa cells were exposed to nocodazole for 18 h immediately followed by high LET iron ion irradiation and displayed a sequence of events leading to DNA damages, mitotic aberrations, interphase restitution and endocycle as well as cell death. A prolonged mitotic arrest more than 10 h was observed following nocodazole exposure, no matter the irradiation was present or not. The occurrence of mitotic slippage following the mitotic arrest was only drug-dependent and the irradiation did not accelerate it. The amount of polyploidy cells was increased following mitotic slippage. No detectable G2 or G1 arrest was observed in cells upon the combined treatment and the cells reentered the cell cycle still harboring unrepaired cellular damages. This premature entry caused an increase of multipolar mitotic spindles and amplification of centrosomes, which gave rise to lagging chromosomal material, failure of cytokinesis and polyploidization. These mitotic disturbances and their outcomes confirmed the incidence of mitotic catastrophe and delayed apoptotic features displayed by TUNEL method after the combined treatment. These results suggest that the addition of high-LET iron ion irradiation to nocodazole enhanced mitotic catastrophe and delayed apoptosis in HeLa cells. These might be important cell death mechanisms involved in tumor cells in response to the treatment of antimitotic drug combined with high LET radiation.

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