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Xuanxuan Wang, Yanjun Gu, Hai Liu, Liming Shi, Xiaonan Sun
Background: Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line...
2018: OncoTargets and Therapy
Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
Barbara Pascucci, Alessandra Fragale, Veronica Marabitti, Giuseppe Leuzzi, Angelo Salvatore Calcagnile, Eleonora Parlanti, Annapaola Franchitto, Eugenia Dogliotti, Mariarosaria D'Errico
CS proteins have been involved in the repair of a wide variety of DNA lesions. Here, we analyse the role of CS proteins in DNA break repair by studying histone H2AX phosphorylation in different cell cycle phases and DNA break repair by comet assay in CS-A and CS-B primary and transformed cells. Following methyl methane sulphate treatment a significant accumulation of unrepaired single strand breaks was detected in CS cells as compared to normal cells, leading to accumulation of double strand breaks in S and G2 phases...
February 20, 2018: Oncotarget
Prachi Borude, Bharat Bhushan, Udayan Apte
Acetaminophen (APAP) overdose is the leading cause of Acute Liver Failure (ALF) with limited treatment options. It is known that liver regeneration following APAP induced ALF is a deciding factor in the final outcome. Previous studies from our laboratory using incremental dose model involving a regenerating (300 mg/kg, APAP300) and a non-regenerating (600 mg/kg, APAP600) dose of APAP in mice have revealed several pro- regenerative pathways that regulate regeneration after APAP overdose. Here we report that DNA damage and repair mechanisms regulate initiation liver regeneration following APAP overdose...
March 14, 2018: Gene Expression
Yi Zhao, Marcus J C Long, Yiran Wang, Sheng Zhang, Yimon Aye
Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed "G-REX"-a technique that allows controlled release of reactive electrophiles in vivo...
February 28, 2018: ACS Central Science
Jia Zhou, Jiaqi Li, Rodolfo B Serafim, Steven Ketchum, Catarina G Ferreira, Jessica C Liu, Kathryn A Coe, Brendan D Price, Timur Yusufzai
CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (γH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites...
February 26, 2018: Nucleic Acids Research
Sirimanas Jiaranuchart, Atsushi Kaida, Yusuke Onozato, Hiroyuki Harada, Masahiko Miura
OBJECTIVE: The objective of this study was to characterize the DNA damage response in two human oral cancer cell lines following X-irradiation. DESIGN: To visualize radiation-induced cell cycle alterations, two human oral cancer cell lines, HSC3 and HSC4, expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were established in this study. G2 arrest kinetics following irradiation were obtained from two-color flow cytometric analysis and pedigrees of Fucci fluorescence...
March 6, 2018: Archives of Oral Biology
Ke Li, Huaying Yan, Wenhao Guo, Mei Tang, Xinyu Zhao, Aiping Tong, Yong Peng, Qintong Li, Zhu Yuan
PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects...
March 6, 2018: Experimental Cell Research
Shasha Liu, Bingrong Liu
BACKGROUND Colorectal cancer (CRC) is the third most common cancer worldwide, making it is a serious threat to human health. It is imperative to develop new therapeutics to improve the CRC treatment efficiency. The aim of this study was to investigate the role of NPRL2 in improving sensitivity to CPT-11 in colon cancer cells. MATERIAL AND METHODS NPRL2 overexpression was established by transfecting the recombinant lentivirus-encoding NPRL2 gene into HCT116 colon cancer cells. Cell proliferation was identified using Cell Counting Kit-8 (CCK8) assay...
March 9, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Somrudee Reabroi, Arthit Chairoungdua, Rungnapha Saeeng, Teerapich Kasemsuk, Witchuda Saengsawang, Weiming Zhu, Pawinee Piyachaturawat
Hyperactivation of Wnt/β-catenin signaling implicated in oncogenesis of colorectal cancer (CRC) is a potential molecular target for chemotherapy. An andrographolide analogue, 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) has previously been reported to be potently cytotoxic toward cancer cells by unknown molecular mechanisms. The present study explored the anti-cancer activity of analogue 3A.1 on Wnt/β-catenin signaling in colon cancer cells (HT29 cells) which were more sensitive to the others (HCT116 and SW480 cells)...
March 1, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Debadrita Bhattacharya, Disha Hiregange, Basuthkar J Rao
In eukaryotes, in response to replication stress, DNA damage response kinase, ATR is activated, whose signalling abrogation leads to cell lethality due to aberrant fork remodelling and excessive origin firing. Here we report that inhibition of ATR kinase activity specifically during replication stress recovery results in persistent ATR signalling, evidenced by the presence of ATR-dependent phosphorylation marks (gamma H2AX, pChk1 and pRad17) and delayed cell cycle re-entry. Further, such disruption of ATR signalling attenuation leads to double-strand breaks, fork collapse and thereby 'replication catastrophe'...
March 2018: Journal of Biosciences
Qiang Zhao, Wang Chen, Xu He, Zili Feng, Qi Liang
BACKGROUND: The natural products containing a common 3,4-diarylpyrrole skeleton have attracted considerable attention due to their unique structures and multiplex biological activities. In our previous study, lycogarubin C was synthesized and showed cytotoxicity against MDA-MB-231, A549, PC3 and HeLa cell lines and topoisomerase II inhibitory activities. OBJECTIVE: We present the design, synthesis and antitumor studies of 3,4-diarylprrole derivatives. Their antitumor activities and inhibitory activities against Topo I and Topo IIα of these compounds were assayed...
February 26, 2018: Medicinal Chemistry
F Berardinelli, A Sgura, A Facoetti, S Leone, B Vischioni, M Ciocca, A Antoccia
The pentacyclic acridine RHPS4 is a highly potent and specific G-quadruplex (G4) ligand, which binds and stabilizes telomeric G4 leading to the block of the replication forks at telomeres and consequently to telomere dysfunctionalization. In turn, the cell recognizes unprotected telomeres as DNA double-strand breaks with consequent activation of DNA repair response at telomeres, cellular growth impairment and death. Data from the literature showed the capability of this compound to sensitize U251MG glioblastoma radioresistant cell line to X-rays sparsely ionizing radiations...
February 27, 2018: FEBS Journal
Weidong Zhang, Yong Zhao, Fuli Li, Lan Li, Yanni Feng, Lingjiang Min, Dongxue Ma, Shuai Yu, Jing Liu, Hongfu Zhang, Tianhong Shi, Fuwei Li, Wei Shen
Zinc oxide nanoparticles (ZnO NPs), known for their chemical stability and strong adsorption, are used in everyday items such as cosmetics, sunscreens, and prophylactic drugs. However, they have also been found to adversely affect organisms; previously we found that ZnO NPs disrupt pubertal ovarian development, inhibit embryonic development by upsetting γ-H2AX and NF-κB pathways, and even disturb skin stem cells. Non-targeted metabolomic analysis of biological organisms has been suggested as an unbiased tool for the investigation of perturbations in response to NPs and their underlying mechanisms...
2018: Frontiers in Pharmacology
Hideaki Nakamura, Hidemasa Bono, Keiko Hiyama, Takeshi Kawamoto, Yukio Kato, Takeshi Nakanishi, Masahiko Nishiyama, Eiso Hiyama, Nobuyuki Hirohashi, Eisaburo Sueoka, Lorenz Poellinger, Keiji Tanimoto
Tumor hypoxia contributes to a biologically aggressive phenotype and therapeutic resistance. Recent studies have revealed that hypoxia reduces expression of several DNA damage recognition and repair (DRR) genes via both hypoxia-inducible factor (HIF)-independent and -dependent pathways, and this induced genomic instability in cancer cells. We show here that one of the HIF-target genes-differentiated embryo chondrocyte (DEC)-plays a role in DNA damage response via transcriptional repression. Comprehensive gene expression and database analyses have revealed systemic repression of DNA-DRR genes in cancer and non-cancer cells under hypoxic conditions...
2018: PloS One
Jiangsong Jiang, Nishant Mohan, Yukinori Endo, Yi Shen, Wen Jin Wu
Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. In this study, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity, in human primary cardiomyocytes...
January 19, 2018: Oncotarget
Jianbin Lai, Jieming Jiang, Qian Wu, Ning Mao, Danlu Han, Huan Hu, Chengwei Yang
DNA damage occurs in all cells and can hinder chromosome stability and cell viability. Structural Maintenance of Chromosomes 5/6 (SMC5/6) is a protein complex that functions as an evolutionarily conserved chromosomal ATPase critical for repairing DNA double-strand breaks (DSBs). However, the mechanisms regulating this complex in plants are poorly understood. Here, we identified the transcriptional coactivator ALTERATION/DEFICIENCY IN ACTIVATION 2B (ADA2b) as an interactor of SMC5 in Arabidopsis thaliana. ADA2b is a conserved component of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, which functions in transcriptional regulation...
February 20, 2018: Plant Physiology
Paula M De Angelis, Aasa R Schjølberg, Juliana B Hughes, Henrik S Huitfeldt, Solveig Norheim Andersen, Anne Carine Østvold
Background: The colon and rectum are continuously exposed to oxidative stress that generates reactive oxygen species, which are a major cause of DNA double-strand breaks (DSB). Furthermore, chronic inflammatory diseases such as ulcerative colitis (UC) are characterized by an excess of reactive nitrogen species that can also lead to DNA double-strand breakage and genomic instability. We investigated the expression of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) protein in UC and sporadic colorectal cancer (CRC) due to its involvement in both DNA double-strand break repair and inflammatory signaling...
February 15, 2018: Inflammatory Bowel Diseases
Ayman B Farag, Heba A Ewida, Mahmoud Salama Ahmed
Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety...
February 10, 2018: European Journal of Medicinal Chemistry
Nikki A Evensen, P Pallavi Madhusoodhan, Julia Meyer, Jason Saliba, Ashfiyah Chowdhury, David J Araten, Jacob Nersting, Teena Bhatla, Tiffaney L Vincent, David Teachey, Stephen P Hunger, Jun Yang, Kjeld Schmiegelow, William L Carroll
Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents...
February 15, 2018: Haematologica
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