Oncotarget
·
2020
·
IF 0
Rahaba Marima,Rodney Hull,Zodwa Dlamini,Clement Penny
The cell-cycle related genes are potential gene targets in understanding the effects of efavirenz (EFV) in lung cancer. The present study aimed at investigating the expression changes of cell-cycle related genes in response to EFV drug treatment in human non-small cell lung carcinoma (A549) and normal lung fibroblast (MRC-5) cells. The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino-2-phenylindole (DAPI) staining. Gene expression profiling was performed using human cell cycle PathwayFinder RT 2 Profiler™ PCR Array. The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined. The R 2 PCR Array analysis revealed a change in expression of selected gene targets (including MAD2L2, CASP3, AURKB). This change in gene expression was at least a two-fold between test (EFV treated) and the control. RT-qPCR confirmed the PCR array data. In addition to this, the ATM signaling pathway was shown to be upregulated following EFV treatment in MRC-5 cells. In particular, ATM’s upstream activation resulted in p53 upregulation in normal lung fibroblasts. Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis (IPA). These EFV effects are similar to those of ionizing radiation and this suggests that EFV has anti-tumour properties.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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DOI
PubMed
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 14
·7981
·
IF 6.208
Xiaolan Feng,Chen Wu,Wenhao Yang,Jiayi Wu,Pan Wang
Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform ([email protected]&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into[email protected]could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.Keywords:sonodynamic therapy;porphyrin liposomes;DOX;SRA737;DNA damage response;breast cancer
研究领域:
肿瘤学
·
化疗
·
超声治疗
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHYSICS D-APPLIED PHYSICS
·
2025
·Vol. 58
·期 13
·135207
·
IF 3.2
Liu Jinren,Wang Xiangni,Cui Yixin,Xu Guimin,Lu Jiajia,He Zhirou,Xu Yulin,Li Rongrong,Gao Lingge,Wang Hong,Gao Junhong,Wu Xili,Shi Xingmin,Zhang Guanjun
Cisplatin resistance coupled with adverse effects presents substantial hurdles in the treatment of ovarian cancer. Both cold atmospheric plasma and plasma-activated liquid (PAL) hold the ability to induce DNA damage, which is a primary target of cisplatin. In this study, we investigate the potential of PAL in augmenting cisplatin sensitivity or diminishing the necessary drug dosage by impairing the DNA of cisplatin-resistant cancer cells. We found that plasma irradiated medium exceeding 40 s could decrease the viability, induce DNA damage, trigger cell cycle arrest, and augment apoptosis and autophagy in two types of cisplatin-resistant ovarian cancer cells (A2780/DDP and SKOV3/DDP) after a 24 h incubation period. Notably, pre-treatment with 40 s plasma-activated medium (PAM) for 2 h significantly enhanced the anti-cancer effect of cisplatin administered at lower doses on these cell types. RNA-seq, quantitative real-time PCR and Western blotting analysis revealed that PAM treatment could downregulate the expression of several pivotal proteins involved in nucleotide excision repair (NER) and homologous recombination repair (HRR). The mouse xenograft tumor model demonstrated that plasma-activated saline and cisplatin synergistically inhibited tumor growth and significantly suppressed the expression of proteins related to HRR and NER pathways. We identified plasma-derived peroxide generation in PAM as crucial in these processes. These results pave the way for considering PAM as an adjuvant treatment for cisplatin-resistant ovarian cancer and other abdominal cancers. Additionally, the findings indicate the feasibility of reducing cisplatin dosage to alleviate side effects through sensitization.
研究领域:
肿瘤学
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分子生物学
·
医学
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产品关联
DOI
高影响因子
Biomolecules
·
2023
·Vol. 13
·期 1
·102
·
IF 5.5
Jing Yuan,Fei Lin,Zhiyong Wu,Zhilin Jiang,Ting Wang,Sitong Huo,Weinan Lai,Li Li,Chao Zhang
Radioactive substances have been used in various aspects in daily life. However, high-energy radiation could cause environmental problems, which would damage the human body. Circular RNA (CircRNA) has great potential in the minimization of ionizing radiation damage. To find a potential diagnostic and therapeutic target for reducing the damage of ionizing radiation, we selected circRNA cleavage and polyadenylation specificity factor subunit 1 (circ-CPSF1) based on its up-regulated expression after X-ray radiation and explored its effect on response to ionizing radiation usingCaenorhabditis elegans(C. elegans). Circ-CPSF1 was screened out and its up-regulated expression was verified. The measurement of lifespan and germ cell apoptosis showed that circ-CPSF1 RNAi treatment extended lifespan and reduced apoptotic germ cells. ROS levels were significantly reduced after the interference of circ-CPSF1 inC. eleganswith radiation. Mitochondrial membrane potential assay showed that the suppression of circ-CPSF1 could alleviate mitochondrial damage after radiation. Relative genes expression showed the involvement of circ-CPSF1 in radiation mediated DNA damage response pathways and apoptosis pathways. In conclusion, circ-CPSF1 exerts deleterious effects on lifespan, eggs production and germ cell apoptosis ofC. elegansthrough oxidative stress, the DNA damage response (DDR) pathway, and the core apoptotic pathway after ionizing radiation, indicating the potential of circ-CPSF1 to be an important therapeutic target of radiation damage.Keywords:radiation;circ-CPSF1;DNA damage response (DDR);apoptosis
研究领域:
放射生物学
·
分子生物学
·
遗传学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
FEBS LETTERS
·
2015
·
IF 3.169
Chen Xie,Wei Chen,Mengdie Zhang,Qiuxian Cai,Weiyi Xu,Xiaodi Li,Songshan Jiang
Despite extensive investigation into the role of let-7 miRNAs in pathological tumor processes, their involvement in the DNA damage response remains unclear. Here we show that most let-7 family members down-regulate MDM4 expression via binding to MDM4 mRNA at a conserved DNA sequence. Expression of exogenous let-7 miRNA mimics decreased MDM4 protein but not mRNA levels. Several DNA damage reagents increased let-7 expression, thereby decreasing MDM4 protein levels in glioma cells. Inhibition of endogenous let-7 with antisense RNAs rescued MDM4 protein levels with or without MG132, a proteasome-dependent degradation inhibitor. An MDM4 mutation identified in a glioma patient was associated with loss of the putative MDM4 target site. Therefore, let-7 binding to MDM4 is implicated in the DNA damage response.
研究领域:
癌症生物学
·
分子生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2018
·Vol. 50
·期 6
·567-578
·
IF 2.224
Zhang Yingying,Cong Linhai,He Jiayan,Wang Yu,Zou Yingying,Yang Zhihong,Hu Yuexin,Zhang Shiwen,He Xiaoguang
Hypopharyngeal carcinoma (HC) is one of the most malignant tumors in the upper aerodigestive tract. Currently, there are no effective treatments for HC. Gold nanoparticles (AuNPs) are a promising tool that can be used for plasmonic photothermal therapy (PPTT), which refers to the use of electromagnetic radiation, most often in near infrared (NIR) region, for the treatment of various medical conditions including cancer. AuNPs have been proved to be a promising tool for NIR spectroscopy-mediated photothermal therapies. In this study, we chemically conjugated AuNPs with a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), a cell-surface receptor that is overexpressed in many cancers. We then assessed the effect of NIR photothermal treatment with the EGFRmAb–AuNPs in FaDu HC cells. Our data showed that nanoparticle conjugation with the EGFRmAb improved the specific targeting towards FaDu cells and reduced cytotoxicity towards normal (293 T) cells which do not overexpress the EGFR. A significant amount of our EGFRmAb-conjugated AuNPs could enter the nucleus. Moreover, the expression levels of double strand DNA break repair proteins, including p-ATR, p-CHK1, and p-CHK2 were increased following AuNPs treatment, indicating the presence of DNA damage. These findings suggest that the AuNPs can potentially disrupt genome integrity and induce apoptosis. In addition, EGFRmAb–AuNPs+NIR could induce FaDu cell apoptosis, accompanied by the inhibition of the PI3K/AKT/mTOR pathway and stimulation of DNA damage response. Based on these data, PPTT using the EGFRmAb–AuNPs could be a new promising treatment for HC.
研究领域:
肿瘤学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Hongzhen Bai,Min Wu,Hongjian Zhang,Guping Tang
Cell exposure to atmospheric polycyclic aromatic hydrocarbons (PAHs) is closely associated with DNA damage and genomic instability. We assessed the mechanisms of chronic and acute PAH exposure-induced genotoxicity in two human lung epithelial cell lines, A549 and NC-H1975. We sampled atmospheric PAHs at the Xixi Campus, Zhejiang University in Hangzhou, China during August (non-haze episode) and November (haze episode) 2015. We identified vehicle emissions as a dominant anthropogenic PAH source in our study. PAHs were extracted according to the United States Environmental Protection Agency Method TO-13A. We found that chronic PAH exposure saturated lung cell xenobiotic metabolic pathways, promoting intercellular reactive oxygen species production and accumulation. Chronic alteration of the cellular redox status resulted in DNA damage and genomic instability. Chronic PAH exposure also perturbed the cellular DNA damage response, inducing S phase arrest and inhibiting apoptosis. Dysregulation of PAH metabolism and the DNA damage response altered cellular homeostasis and increased cell susceptibility to subsequent PAH exposures, thereby enhancing the likelihood of genomic mutation and instability.
研究领域:
毒理学
·
分子生物学
·
环境科学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Haowei Fu,Xiaofang Zhu,Qiannan Di,Jiahui Sun,Qianqian Jiang,Qian Xu
Di(2-ethyl-hexyl) phthalate (DEHP), an environmental endocrine disruptor, can destroy the sperm genomic integrity and impairs spermatogenesis. N6-methyladenosine (m6A) is involved in the cellular effects of DEHP. However, the genotoxic effect of DEHP on spermatocytes and the possible role of m6A in this process remain unclear. This study demonstrated that m6A alleviates DEHP genotoxicity in GC-2 cells. In DEHP-treated mice, DNA double-strand breaks (DSBs) were induced in the testis and spermatocytes. To further explore the molecular mechanism of DEHP genotoxicity on spermatocytes, GC-2 cells were exposed to DEHP. DEHP produced distinct genotoxicity and caused DSBs, which led to the inhibition of DNA synthesis and cell cycle arrest. The DNA damage response (DDR) was initiated to repair the DSBs induced by environmentally relevant levels of DEHP (100 μM and 200 μM). During this process, METTL3 upregulated m6A, which facilitated the DDR via stabilizing the DNA damage repair factors ( Rad51 and Xrcc5 ) mRNA to maintain the pro-survival state. Moreover, Mettl3 knockdown partially inhibited DDR. Interestingly, high-dose DEHP (400 μM and 600 μM) directly induced apoptosis rather than the pro-survival state. Altogether: METTL3-mediated m6A participates in maintaining the pro-survival state by upregulating DDR, providing guidance for mitigating the genotoxicity of environment-related level DEHP exposure.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Bulletin
·
2024
·
IF 18.8
Shijie Li,Sarun Juengpanich,Win Topatana,Tianao Xie,Lidan Hou,Yiyuan Zhu,Jiadong Chen,Yukai Shan,Yina Han,Ziyi Lu,Tianen Chen,Charlie Topatana,Bin Zhang,Jiasheng Cao,Jiahao Hu,Jiafei Yan,Yingxin Chen,Zhen Gu,Jicheng Yu,Xiujun Cai,Mingyu Chen
Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal–organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-16
·
IF 39.3
Cui Bopei,Song Lifang,Wang Qian,Li Kelei,He Qian,Wu Xing,Gao Fan,Liu Mingchen,An Chaoqiang,Gao Qiushuang,Hu Chaoying,Hao Xiaotian,Dong Fangyu,Zhou Jiuyue,Liu Dong,Song Ziyang,Yan Xujia,Zhang Jialu,Bai Yu,Mao Qunying,Yang Xiaoming,Liang Zhenglun
With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.
研究领域:
肿瘤学
·
病毒学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Dan Liu,Ye Cheng,Zhipeng Tang,Xueying Mei,Xiangyu Cao,Jianli Liu
Acrolein is a hazardous air pollutant for humans and is responsible for many pulmonary diseases, but the underlying mechanisms have not been completely elucidated. This work is focused on the genotoxicity effects of human bronchial epithelial (BEAS-2B) cells induced by acrolein (20, 40, 80 μM). The molecular mechanism was investigated base on DNA damage and mitochondrial apoptosis pathways. The results showed that after exposure to acrolein, the cell viability, glutathione (GSH) of BEAS-2B cells were reduced. Reactive oxygen species (ROS) level significantly increased, accompanied by increased levels of DNA damage-related indicators 8-hydroxy-2 deoxyguanosine (8−OHdG), DNA content of comet tail (Tail DNA%), olive tail moment (OTM), and nucleus morphology. Cell arrested at the G2/M phase. Then, the DNA damage response (DDR) signaling pathway (Ataxia-telangiectasia-mutated (ATM) and Rad-3-related (ATR)/Chk1 and ATM/Chk2) and the consequent cell cycle checkpoints were activated. The expression of γ-H2AX was significantly increased, indicating that acrolein induced DNA double-strand breaks. Molecular docking assay showed that acrolein bound to DNA in a spontaneous process. Moreover, mitochondrial apoptosis pathway involved in apoptosis, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) content of BEAS-2B cells were significantly reduced, and the apoptosis rate was significantly increased. The protein expression of Bax/Bcl-2 and Cleaved Caspase-3 were increased, and JNK signaling pathway was activated. All the results indicated that acrolein induced DNA damage, activated DDR and mitochondrial apoptosis pathways, which might be the pivotal factors to mediate cytotoxicity in BEAS-2B cells.
研究领域:
细胞生物学
·
分子生物学
·
毒理学
·
环境健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
·
2021
·
IF 3.467
Lei Tao,Danxue He,Chunyan Liao,Binxiang Cai,Chao Chen,Yan Wang,Jingmeng Chen,Zuguo Liu,Yalin Wu
Retinal pigment epithelium (RPE) cell apoptosis arising from all- trans -retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N -terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response . Abca4 −/− Rdh8 −/− mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina , and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK–IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4 −/− Rdh8 −/− mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage .
研究领域:
眼科学
·
分子生物学
·
细胞生物学
·
神经退行性疾病
✓ 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）