Human Cell
·
2025
·Vol. 38
·期 3
·1-14
·
IF 3.1
Zhu Xiao-Yu,Li Pi-Song,Qu Hui,Ai Xing,Zhao Zi-Ting,He Jia-Bei
Radiotherapy resistance, is usually caused by enhanced tumor stemness and poses a significant challenge in treating breast cancer (BRCA). In this study, we investigated the molecular regulatory mechanism of radiotherapy sensitivity in BRCA associated with replication factor C4 (RFC4) and insulin-like growth factor 2 mRNA binding protein 2 mRNA Binding Protein 2 (IGF2BP2). RFC4 expression was increased in BRCA cell lines and tissues, and high RFC4 expression in BRCA patients predicted the occurrence of lymphatic metastasis. RFC4-specific short hairpin RNA sequences or RFC4 coding sequences were subsequently cloned and inserted into plasmid vectors to downregulate or upregulate RFC4 expression. Knockdown of RFC4 attenuated stemness, as evidenced by a reduction in sphere formation and the downregulation of CD44 and SOX2. RFC4 silencing inhibited migration and invasion, promoted apoptosis, and improved sensitivity to radiotherapy (4-Gy X-ray). The results were detected by a wound healing assay, a transwell assay, and flow cytometry. The overexpression of RFC4 had the opposite effect on BRCA cells. Like RFC4 expression, IGF2BP2 expression was also increased in the cancer tissues of breast cancer patients. The results of the dual luciferase assay and RIP assay confirmed the binding of IGF2BP2 to the RFC4 mRNA coding sequence. Knockdown of RFC4 eliminated the effects of IGF2BP2 overexpression on increasing cell viability, invasion, the expression of stemness markers and radioresistance, suggesting that the effect of RFC4 on the stemness of BRCA cells was regulated by IGF2BP2. In conclusion, we reported that RFC4, a key regulator of BRCA progression, promoted radioresistance in BRCA and was positively regulated by IGF2BP2.
研究领域:
肿瘤学
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分子生物学
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医学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-23
·
IF 10.435
Wang Haijun,Jia Dianlong,Yuan Dandan,Yin Xiaolei,Yuan Fengjiao,Wang Feifei,Shi Wenna,Li Hui,Zhu Li-Min,Fan Qing
Background Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O 2 production, which in turn serves as a “radiosensitizer” to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. Results Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (Z Her2 ) mediated cisplatin-loaded mesoporous polydopamine/MnO 2 /polydopamine nanoparticles (Pt@mPDA/MnO 2 /PDA-Z Her2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O 2 . Z Her2 , produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T 1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of Z Her2 . These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. Conclusions The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics. Graphic abstract
研究领域:
纳米医学
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癌症治疗
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分子生物学
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生物医学工程
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放射生物学
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产品关联
DOI
PubMed
高影响因子
Translational Andrology and Urology
·
2022
·
IF 2.479
Shujun Sun,Kehua Jiang,Jin Zeng
Background To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer. Methods We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related genes and the relationship between their expression and bladder cancer survival and prognostic indicators. Results The 5637 cell line showed the most significant sensitivity to chemoradiotherapy. The expression levels of DNA damage repair genes in 5637 cells did not significantly change after chemoradiotherapy. In contrast, the expression levels of BRCA1 and RBBP8 genes significantly increased in J82 and TCCSUP cells after chemoradiotherapy. After combination with olaparib, which is a poly (ADP-ribose) polymerase inhibitor that initiates DNA repair, 5637 cells were significantly inhibited by chemoradiotherapy. However, chemoradiotherapy inhibition on J82 cells was weakened when combined with olaparib. A high reactive expression of BRCA1 and RBBP8 after combination with olaparib suggested that olaparib was ineffective because it did not induce synthetic lethality in which inhibiting PARP by olaparib coincided with suppression of BRCA1/2 expression result in cancer cell death. Conclusions The expression levels of RBBP8 and BRCA1 genes were associated with sensitivity to radiotherapy and chemotherapy in bladder cancer, and an increase in reactive expression after treatment led to worse sensitivity. Therefore, the reactive expression levels of BRCA1 and RBBP8 after chemoradiotherapy may be useful in evaluating the efficacy of olaparib combination therapy.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
Polymers
·
2021
·Vol. 13
·期 17
·2929
·
IF 4.329
Jing Miao,Liwen Zhang,Peng Gao,Huawei Zhao,Xianji Xie,Junyan Wang
Glucose Transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors, which is an important factor in radioresistance of laryngocarcinoma. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngocarcinoma. GLUT-1 siRNA was designed to inhibit the GLUT-1 expression, but the high molecular weight and difficult drug delivery limited the application. Herein, we constructed a glycolipid polymer chitosan oligosaccharide grafted stearic acid (CSSA) to conjugate siRNA via electrostatic interaction. The characteristics of CSSA and CSSA/siRNA were studied, as well as the radiosensitization effect of siRNA on human laryngocarcinoma epithelial (Hep-2) cells. Compared with the traditional commercial vector LipofectamineTM2000 (Lipo), CSSA exhibited lower cytotoxicity, more efficiently cellular uptake. Incubating with CSSA/siRNA, the survival rates of Hep-2 cells were significantly decreased comparing with either the group before transfection or Lipo/siRNA. CSSA is a promising carrier for efficient siRNA delivery and radiosensitization of laryngocarcinoma.Keywords:GLUT-1;siRNA;chitosan oligosaccharide grafted stearic acid;laryngocarcinoma;radiosensitization
研究领域:
癌症生物学
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药学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Jiahao Liu,Qingnian Li,Hanyu Tu,Jie Feng,Xiaofei Fan,Ze Mi,Hongpei Han,Xiaoqian Ma,Qi Liang,Zheng Zhang,Hongshuai Hou,Pengfei Rong,Wenhu Zhou
Radiotherapy is a cornerstone in the treatment of malignant tumors, yet its efficacy is often hindered by intrinsic and acquired resistance mechanisms, notably limited radiation availability and tumor hypoxia within inner tumor region. This study introduces a multifunctional nanosensitizer, CD Bi,Mn-FA @CaP, with high tumor accumulation and deep penetration capabilities via dynamic conformational change. CD Bi,Mn-FA was bismuth manganese-doped carbon dots, offering radiosensitizing properties and catalase-like activity for oxygen generation. Folic acid modification further enhances tumor cell targeting. These carbon dots are encapsulated in calcium phosphate nanoparticles to form CD Bi,Mn-FA @CaP, which demonstrates improved in vivo circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. Upon encountering the acidic tumor microenvironment, the encapsulation degrades, releasing smaller CD Bi,Mn-FA particles that deeply penetrate tumor tissues. In vitro and in vivo experiments establish that CD Bi,Mn-FA @CaP effectively targets tumor tissue, enhances radiotherapy-induced apoptosis, and suppresses tumor growth. Notably, the nanoparticle achieves a 40 % tumor cure rate and ensures 100 % survival within 45 days post-treatment. Biocompatibility studies confirm minimal systemic impact, with efficient renal and fecal elimination, indicating promising clinical translational potential. This study introduces a novel radiation therapy sensitization strategy and underscores the potential of such size changeable nanoparticles as an advanced targeted drug delivery system for tumors.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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产品关联
DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-20
·
IF 14.7
Bi Guoshu,Liang Jiaqi,Bian Yunyi,Shan Guangyao,Huang Yiwei,Lu Tao,Zhang Huan,Jin Xing,Chen Zhencong,Zhao Mengnan,Fan Hong,Wang Qun,Gan Boyi,Zhan Cheng
Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour’s metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine’s conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H 2 O 2 -dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal——iron overload——through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H 2 O 2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the “spread” of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 29
·4484-4498
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IF 5.047
Fatima Zohra Dahmani,Danni Zhong,Yuchen Qi,Aboubaker El G. Dahmani,Tingting Xie,Bo Zhou,Wanli Li,Ke Yao,Lei Li,Min Zhou
Nowadays, the design of multistimuli-responsive and deep penetrating nanotherapeutics remains an auspicious means for improving the efficiency of anticancer therapeutics. Herein, we develop a targeted size-tunable nanosystem that would concurrently and uniformly release its therapeutic cargo into tumor cells by exploiting both extracellular and intracellular signals. This nanosystem (HPDAu) is composed of self-assembled pH-responsive DOX–PAMAM (PD) conjugates and ultrasmall PAMAM-stabilized gold nanoparticles (AuNPs), incorporated into a hyaluronidase-responsive hyaluronic acid nanoshell. HPDAu nanoparticles with an initial particle size of ∼100 nm could disassemble into tiny cationic nanostructures (∼5 nm, PD and AuNPs) upon incubation with HAase, and showed a burst drug-release under tumor microenvironment-mimicking conditions (HAase and acidic conditions). Such characteristics resulted in significantly improved tumor penetration both in vitro and in vivo, along with a higher cellular uptake efficiency and tumor accumulation as compared to free drug solutions. Taking advantage of these features along with the chemotherapeutic effect (DOX) and AuNP/DOX-induced radiosensitization, HPDAu plus radiotherapy (RT) treatment resulted in a substantial increase of apoptotic and cytotoxic effects against 4T1 cells. More importantly, the radio-/chemotherapeutic feasibility of HPDAu was further validated in a 4T1 orthotropic model, revealing a prominent antitumor efficacy and reduced side-toxicity compared to monotherapy and free drug solutions. Therefore, this versatile nanoplatform with active targeting, size tunability and radio-/chemotherapeutic features could be a promising tool for tumor combinatorial therapy.
研究领域:
肿瘤学
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药剂学
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生物医学工程
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Hailiang Li,Zheng Ma,Wanfu Yang,Yifan Zhang,Jinping Sun,Haifeng Jiang,Faxuan Wang,Li Hou,Hechun Xia
Introduction Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Standard therapies are followed by poor patient’s survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Metformin has been reported to have anti-cancer effects. However, the precise mechanism underlying these effects remains elusive. A better understanding of its underlying mechanism will inform future experimental designs exploring metformin as a potential adjuvant therapy for GBM. This research aimed to elucidate the potential molecular mechanism of metformin in GBM by integrating proteomics and transcriptomics. Methods The study examined the effects of metformin on GBM cell lines using various methods. The U87, U251 and HA1800 were cultured and modified through PER2 knockdown and overexpression. Cell viability was assessed using the CCK8 assay, and G6PDH activity and intracellular NADPH + levels were measured with specific kits. ROS levels, mitochondrial membrane potential, cell cycle distribution and apoptosis were analyzed by flow cytometry. RNA was extracted for transcriptomic analysis through RNA sequencing, while proteomic analysis was performed on total protein from treated cells. WB detected specific proteins, and RT-qPCR quantified gene expression. In vivo experiments, GBM xenograft on nude mice treated with metformin combining radiotherapy was evaluated and received IHC and TUNEL staining for protein expression and apoptosis assessment. Statistical analyses were conducted using Prism software to identify significant group differences. Results We found that differential expressional genes and proteins relating to circadian rhythm were enriched in proteomic or transcriptomic. The expression of PER2, the key circadian gene, was up-regulated in GBM cell lines when treated with metformin. Furthermore, the expression of silent information regulator 2(SIRT2) was down-regulated, while the expression of the G6PD protein just slightly increased in GBM cell lines. Meanwhile, NADPH+ production and G6PDH enzyme activity significantly decreased. Further study validated that metformin inhibited the cell growth of GBM cell lines through up-regulating PER2 and inhibited SIRT2/G6PD signaling pathway, enhancing radiotherapy(RT) sensitivity. We also found that the inhibition of SIRT2 caused by metformin is mediated by PER2. Discussion We found the pivotal role of metformin as an effective circadian rhythm regulator. Targeting circadian clock gene to modify and rescue the dysfunctional circadian clock of GBM cells at molecular level might be an innovative way to administer cancer chronotherapy and maintain metabolic homeostasis in real world practice.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Li Yang,Gu Xinquan,Yu Fan
Hypoxia in the tumor microenvironment induces radioresistance in cancer cells, which reduces the treatment efficiency of radiotherapy. Therefore, it is critical to produce sufficient oxygen to alleviate hypoxia to enhance the effect of ionizing radiation. Here, we constructed nanorod-shaped PdTe nanoenzymes to overcome hypoxia and promote the effects of thermoradiotherapy. Both palladium and tellurium are high-Z elements, which interacted with X-rays to generate more DNA radicals in the tumor regions. Moreover, PdTe nanoenzyme could catalyze the conversion of intratumoral overexpressed H2O2 to oxygen, alleviating hypoxia in the tumor regions. Photothermal therapy mediated by PdTe nanoenzymes not only ablated tumors but also accelerated the blood flow, in turn, modulating hypoxia. With good biocompatibility, PdTe nanoenzyme exhibited remarkable oxygen generation ability both in vitro and in vivo, indicating potential ability for radiosensitization. Further investigation using MBT-2 cells and MBT-2 tumor-bearing mice demonstrated that PdTe nanoenzyme could effectively enhance the treatment efficiency of radiotherapy. Thus, our work presented a novel nanoenzyme to overcome hypoxia in tumors for effective thermoradiotherapy.
研究领域:
肿瘤学
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生物医学工程
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放射医学
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DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 41
·35124-35134
·
IF 3.289
Zhirong Bao,Mingyang He,Hong Quan,Dazhen Jiang,Yanhong Zheng,Wenjing Qin,Yunfeng Zhou,Feng Ren,Mingxiong Guo,Changzhong Jiang
Chemoradiotherapy is a well-established treatment paradigm in oncology to consistently improve local tumor control compared to the sole administration of chemotherapy or radiotherapy. Despite its importance, few agents have been identified to further improve the therapeutic ratio and reduce the incidence of complications. Advances in nanomedicine have offered innovative strategies to improve chemoradiotherapy. In the present study, we evaluated the efficacy and safety of FePt nanoparticles (NPs) in chemoradiotherapy using HeLa cells and HEK293T cells. FexPt100−x NPs at different compositions (x = 26, 53 and 77) were synthesized and characterized by means of X-ray diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. After ligand exchange, the cytotoxicity of FexPt100−x NPs was evaluated by MTT assay in HEK293T cells while the composition effects of FePt NPs on the cytotoxicity and the potential application of FePt NPs in combination with X-ray radiation at clinically relevant MV energies were investigated in HeLa cells in vitro. Besides, the cellular uptake of NPs was measured indirectly by atomic absorption spectroscopy and transmission electron microscopy. The results indicated that FexPt100−x NPs inhibited the growth of HeLa cells in a concentration- and composition-dependent manner after 24 h incubation, with low cytotoxicity to HEK293T cells at the given concentrations (0–20 μg mL−1). Furthermore, the combination of FePt NPs and radiotherapy resulted in a marked inhibition of HeLa cells, in contrast with that of the individual FePt NPs treated group or the radiation alone group. Moreover, Fe53Pt47 NPs, exhibiting significant cytotoxicity and enhanced radiosensitization effects on HeLa cells without damage to HEK293T cells, might theoretically satisfy the ultimate goal of personalized chemoradiotherapy. Our present work exhibited high therapeutic efficacy of FePt NPs in combination with radiotherapy without apparent cytotoxicity, suggesting the potential of FePt NPs as a promising nanoprobe in improving the outcome of tumor chemoradiotherapy.
研究领域:
肿瘤学
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纳米医学
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放射生物学
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产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Lihua Shao,Dun Liu,Xuexue Liu,Xueyuan Wang,Xian Yang,Runyan Niu,Shaoping Yin,Peipei Xu,Yonghuan Mao,Xiao Du,Lin Yang
In recent years, the integration of radiotherapy and nanocatalytic medicine has gained widespread attention in the treatment of breast cancer. Herein, the glucose oxidase (GOx) and MnO 2 nanoparticles co-modified multifunctional liposome of GOx-MnO 2 @Lip was constructed for enhanced radiotherapy. Introduction of GOx would not only elevate the glucose consumption to starve the cancer cells, but also increased the endogenous H 2 O 2 level. Meanwhile, high intracellular GSH concentration facilitated the release of Mn 2+ to amplify the cytotoxic ·OH through cascade catalytic reactions within the tumor microenvironment, resulting in a favorable tumor suppression rate of 74.45 %. Furthermore, the blood biochemical and blood routine demonstrated that GOx-MnO 2 @Lip had no obvious toxic side effects. Therefore, this work provided a potential vehicle for synergistic cancer starving therapy, chemodynamic therapy and radiotherapy for improving therapeutic efficacy of breast cancer.
研究领域:
肿瘤学
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纳米医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2021
·Vol. 27
·期 1
·128
·
IF 4.412
Lixia Chen,Yang Zhang,Xinming Zhang,Ruijuan Lv,Rongtian Sheng,Ruimeng Sun,Ting Du,Yuhan Li,Yanfei Qi
Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2to O2and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2self-supplement composites provide a promising radiosensitizer for the radiotherapy field.Keywords:radiosensitizer;polyoxometalates;catalase;O2self-supplement;radiotherapy
研究领域:
癌症治疗
·
放射肿瘤学
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材料科学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）