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Dna damage and cancer

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https://www.readbyqxmd.com/read/29352261/insight-into-the-role-of-pikk-family-members-and-nf-%C3%B0%C2%BAb-in-dnadamage-induced-senescence-and-senescence-associated-secretory-phenotype-of-colon-cancer-cells
#1
Anna Strzeszewska, Olga Alster, Grażyna Mosieniak, Agata Ciolko, Ewa Sikora
Senescence of cancer cells is an important outcome of treatment of many cancer types. Cell senescence is a permanent cell cycle arrest induced by stress conditions, including DNA damage. DNA damage activates DNA damage response (DDR), which involves members of the phosphatidylinositol 3-kinase-related kinase (PIKK) superfamily: protein kinases ATM, ATR, and DNA-PKcs. The so-far collected data indicate that ATM, with its downstream targets CHK2, p53, and p21, is the key protein involved in DDR-dependent senescence...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29352223/zeb1-confers-chemotherapeutic-resistance-to-breast-cancer-by-activating-atm
#2
Xiang Zhang, Zhen Zhang, Qing Zhang, Quansheng Zhang, Peiqing Sun, Rong Xiang, Guosheng Ren, Shuang Yang
Although zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor chemoresistance has not been fully understood. Here, through the study of specimens from a large cohort of human breast cancer subjects, we showed that patients with tumors that expressed high levels of ZEB1 responded poorly to chemotherapy. Moreover, ZEB1 expression was positively correlated with expression of B-cell lymphoma-extra large (Bcl-xL) and cyclin D1, which are key components of tumor chemoresistant mechanisms...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29351238/telomeres-implications-for-cancer-development
#3
REVIEW
Aina Bernal, Laura Tusell
Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints...
January 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29348875/radiosensitization-of-the-pi3k-inhibitor-hs-173-through-reduction-of-dna-damage-repair-in-pancreatic-cancer
#4
Jung Hee Park, Kyung Hee Jung, Soo Jung Kim, Zhenghuan Fang, Hong Hua Yan, Mi Kwon Son, Juyoung Kim, Yeo Wool Kang, Ji Eun Lee, Boreum Han, Joo Han Lim, Soon-Sun Hong
Activation of PI3K/AKT pathway occurs frequently in tumors and is correlated with radioresistance. The PI3K/AKT pathway can be an important target for improvement of radiotherapy. Although adding of chemotherapy to radiation therapy regimen enhances survival in patients with locally advanced pancreatic cancer, more effective therapies for increasing radiosensitivity are urgently needed. In this study, we investigated whether the novel PI3K inhibitor HS-173 could attenuate radiation-induced up-regulation of DNA damage repair processes and assessed its efficacy as a radio- and chemo-sensitizer...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348835/simultaneous-quantification-of-dna-damage-and-mitochondrial-copy-number-by-long-run-dna-damage-quantification-lord-q
#5
Benjamin Dannenmann, Simon Lehle, Sebastian Lorscheid, Stephan M Huber, Frank Essmann, Klaus Schulze-Osthoff
DNA damage and changes in the mitochondrial DNA content have been implicated in ageing and cancer development. To prevent genomic instability and tumorigenesis, cells must maintain the integrity of their nuclear and mitochondrial DNA. Advances in the research of DNA damage protection and genomic stability, however, also depend on the availability of techniques that can reliably quantify alterations of mitochondrial DNA copy numbers and DNA lesions in an accurate high-throughput manner. Unfortunately, no such method has been established yet...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348812/design-and-synthesis-of-isoquinolidinobenzodiazepine-dimers-a-novel-class-of-antibody-drug-conjugate-payload
#6
Sean W Smith, Vasu Jammalamadaka, Dmitry Borkin, Jianyu Zhu, Sylvia J Degrado, Jennifer Lu, Jianqing Huang, Ying-Ping Jiang, Nareshkumar Jain, Jagath R Junutula
Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (S,S)-D211 isomer is functionally more active than (R,R)-D221 and (S,R)-D231 isomers by >50,000-fold and ∼200-fold, respectively...
January 11, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29348578/a-matter-of-life-and-death-stem-cell-survival-in-tissue-regeneration-and-tumour-formation
#7
REVIEW
Despina Soteriou, Yaron Fuchs
In recent years, great strides have been made in our understanding of how stem cells (SCs) govern tissue homeostasis and regeneration. The inherent longevity of SCs raises the possibility that the unique protective mechanisms in these cells might also be involved in tumorigenesis. In this Opinion article, we discuss how SCs are protected throughout their lifespan, focusing on quiescent behaviour, DNA damage response and programmed cell death. We briefly examine the roles of adult SCs and progenitors in tissue repair and tumorigenesis and explore how signals released from dying or dormant cells influence the function of healthy or aberrant SCs...
January 19, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29348534/anti-cancer-activities-of-allyl-isothiocyanate-and-its-conjugated-silicon-quantum-dots
#8
Peng Liu, Mehrnaz Behray, Qi Wang, Wei Wang, Zhigang Zhou, Yimin Chao, Yongping Bao
Allyl isothiocyanate (AITC), a dietary phytochemical in some cruciferous vegetables, exhibits promising anticancer activities in many cancer models. However, previous data showed AITC to have a biphasic effect on cell viability, DNA damage and migration in human hepatoma HepG2 cells. Moreover, in a 3D co-culture of HUVEC with pericytes, it inhibited tube formation at high doses but promoted this at low doses, which confirmed its biphasic effect on angiogenesis. siRNA knockdown of Nrf2 and glutathione inhibition abolished the stimulation effect of AITC on cell migration and DNA damage...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348410/oxidative-stress-via-inhibition-of-the-mitochondrial-electron-transport-and-nrf-2-mediated-anti-oxidative-response-regulate-the-cytotoxic-activity-of-plumbagin
#9
Arvinder Kapur, Thomas Beres, Kavya Rathi, Amruta P Nayak, Austin Czarnecki, Mildred Felder, Amani Gillette, Spencer S Ericksen, Emmanuel Sampene, Melissa C Skala, Lisa Barroilhet, Manish S Patankar
Plumbagin, an anti-cancer agent, is toxic to cells of multiple species. We investigated if plumbagin targets conserved biochemical processes. Plumbagin induced DNA damage and apoptosis in cells of diverse mutational background with comparable potency. A 3-5 fold increase in intracellular oxygen radicals occurred in response to plumbagin. Neutralization of the reactive oxygen species by N-acetylcysteine blocked apoptosis, indicating a central role for oxidative stress in plumbagin-mediated cell death. Plumbagin docks in the ubiquinone binding sites (Q0 and Qi) of mitochondrial complexes I-III, the major sites for oxygen radicals...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348263/phosphoinositide-3-kinase-gamma-inhibition-protects-from-anthracycline-cardiotoxicity-and-reduces-tumor-growth
#10
Mingchuan Li, Valentina Sala, Maria Chiara De Santis, James Cimino, Paola Cappello, Nicola Pianca, Anna Di Bona, Jean Piero Margaria, Miriam Martini, Edoardo Lazzarini, Flora Pirozzi, Luca Rossi, Irene Franco, Julia Bornbaum, Jacqueline Heger, Susanne Rohrbach, Alessia Perino, Carlo G Tocchetti, Braulio H F Lima, Mauro M Teixeira, Paolo E Porporato, Rainer Schulz, Annalisa Angelini, Marco Sandri, Pietro Ameri, Sebastiano Sciarretta, Roberto César P Lima-Júnior, Marco Mongillo, Tania Zaglia, Fulvio Morello, Francesco Novelli, Emilio Hirsch, Alessandra Ghigo
Background -Anthracyclines, such as doxorubicin (DOX), are potent anti-cancer agents for the treatment of solid tumors and hematological malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of PI3Kγ in DOX-induced cardiotoxicity and the potential cardio-protective and anti-cancer effects of PI3Kγ inhibition. Methods -Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography and DOX-mediated signaling was assessed in whole hearts or in isolated cardiomyocytes...
January 18, 2018: Circulation
https://www.readbyqxmd.com/read/29345572/breaking-the-dna-damage-response-via-serine-threonine-kinase-inhibitors-to-improve-cancer-treatment
#11
Wioletta Rozpedek, Dariusz Pytel, Alicja Nowak-Zdunczyk, Dawid Lewko, Radoslaw Wojtczak, John Alan Diehl, Ireneusz Majsterek
Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29345569/a-complex-scenario-and-underestimated-challenge-the-tumor-microenvironment-er-stress-and-cancer-treatment
#12
Oleg I Chen, Yaroslav P Bobak, Oleh V Stasyk, Leoni A Kunz-Schughart
The paradoxical role of ER stress in malignant diseases is only just being unraveled and remains incompletely understood. A particular challenge is the complex interplay between spaciotemporal and locoregional microenvironmental constraints in solid tumors and stress responses upon treatment; thus, the potential for new combinatorial therapeutic options to foster the coincidence of ER stress-related deadly events is likely to be underestimated. Without claiming this review to be complete, we present a comprehensive overview of the signaling mechanisms associated with the unfolded protein response (UPR) and the molecular link to cell survival and death mechanisms...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29344636/analysis-of-the-prolonged-infusion-of-dfp-10917-a-deoxycytidine-analog-as-a-therapeutic-strategy-for-the-treatment-of-human-tumor-xenografts-in-vivo
#13
Kenzo Iizuka, Chun Zhang, Kokoro Eshima, Cheng Jin, Kiyoshi Eshima, Masakazu Fukushima
2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofranocyl-cytosine (DFP-10917, CNDAC) is a 2'-deoxycytidine analog with antitumor activity against various tumor cells. However, a clinically available therapeutic regimen for this compound needs to be established and its functional mechanisms in relation to the dosing schedule need to be clarified. In this study, we evaluated the antitumor activity and toxicity of DFP-10917 by varying the dose and administration schedule in human solid tumor and leukemia xenografts in vivo...
January 16, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29344296/cdk16-phosphorylates-and-degrades-p53-to-promote-radioresistance-and-predicts-prognosis-in-lung-cancer
#14
Jie Xie, Yan Li, Ke Jiang, Kaishun Hu, Sheng Zhang, Xiaorong Dong, Xiaofang Dai, Li Liu, Tao Zhang, Kunyu Yang, Kai Huang, Junjie Chen, Shaojun Shi, Yu Zhang, Gang Wu, Shuangbing Xu
Rationale: Radioresistance is considered the main cause of local relapse in lung cancer. However, the molecular mechanisms of radioresistance remain poorly understood. This study investigates the role of CDK16 in radioresistance of human lung cancer cells. Methods: The expression levels of CDK16 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues. Immunoprecipitation assay and GST pulldown were utilized to detect the protein-protein interaction. The phosphorylation of p53 was evaluated by in vitro kinase assay...
2018: Theranostics
https://www.readbyqxmd.com/read/29344260/dr2-blocker-thioridazine-a-promising-drug-for-ovarian-cancer-therapy
#15
Min Yong, Tinghe Yu, Si Tian, Shuaibin Liu, Jiao Xu, Jianguo Hu, Lina Hu
Dopamine receptor 2 (DR2) may be a biomarker for various types of cancer. Ovarian cancer cells overexpress DR2; therefore, blocking DR2 may be a novel treatment strategy for ovarian cancer. Thioridazine, a DR2 blocker, has antineoplastic activity in a variety of cancer cells. In view of the requirement for novel therapeutic agents in ovarian cancer, the present study aimed to determine the potential effects of thioridazine in vitro and in vivo. It was revealed that the DR2 blocker thioridazine induced cell death in a dose-dependent manner in ovarian cancer cells...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29343567/parainfluenza-virus-infection-sensitizes-cancer-cells-to-dna-damaging-agents-implications-for-oncolytic-virus-therapy
#16
Candace R Fox, Griffith D Parks
We have previously shown that the Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells results in the majority of the cells dying, but unexpectedly, over time there is an emergence of a population of cells which survive as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly dependent on activity of cellular inhibitors of apoptosis (IAPs) such as Survivin and XIAP...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29342233/quantumclone-clonal-assessment-of-functional-mutations-in-cancer-based-on-a-genotype-aware-method-for-clonal-reconstruction
#17
Paul Deveau, Leo Colmet Daage, Derek Oldridge, Virginie Bernard, Angela Bellini, Mathieu Chicard, Nathalie Clement, Eve Lapouble, Valerie Combaret, Anne Boland, Vincent Meyer, Jean-Francois Deleuze, Isabelle Janoueix-Lerosey, Emmanuel Barillot, Olivier Delattre, John Maris, Gudrun Schleiermacher, Valentina Boeva
Motivation: In cancer, clonal evolution is assessed based on information coming from single nucleotide variants and copy number alterations. Nonetheless, existing methods often fail to accurately combine information from both sources to truthfully reconstruct clonal populations in a given tumor sample or in a set of tumor samples coming from the same patient. Moreover, previously published methods detect clones from a single set of variants. As a result, compromises have to be done between stringent variant filtering (reducing dispersion in variant allele frequency estimates, VAFs) and using all biologically relevant variants...
January 12, 2018: Bioinformatics
https://www.readbyqxmd.com/read/29341116/rare-missense-mutations-in-recql-and-polg-associate-with-inherited-predisposition-to-breast-cancer
#18
Anna Tervasmäki, Tuomo Mantere, Jaana M Hartikainen, Saila Kauppila, Hang-Mao Lee, Susanna Koivuluoma, Mervi Grip, Peeter Karihtala, Arja Jukkola-Vuorinen, Arto Mannermaa, Robert Winqvist, Katri Pylkäs
Several known breast cancer susceptibility genes with moderate-to-high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein-truncating variants, and the role of rare missense mutations has remained poorly addressed. In order to identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious...
January 17, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29340215/genome-stability-maintenance-in-naked-mole-rat
#19
I O Petruseva, A N Evdokimov, O I Lavrik
The naked mole-rat (Heterocephalus glaber) is one of the most promising models used to study genome maintenance systems, including the effective repair of damage to DNA. The naked mole-rat is the longest lived rodent species, which is extraordinarily resistant to cancer and has a number of other unique phenotypic traits. For at least 80% of its lifespan, this animal shows no signs of aging or any increased likelihood of death and retains the ability to reproduce. The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance...
October 2017: Acta Naturae
https://www.readbyqxmd.com/read/29340047/inhibition-of-polo-like-kinase-4-plk4-a-new-therapeutic-option-for-rhabdoid-tumors-and-pediatric-medulloblastoma
#20
Simone Treiger Sredni, Anders W Bailey, Amreena Suri, Rintaro Hashizume, Xingyao He, Nundia Louis, Tufan Gokirmak, David R Piper, Daniel M Watterson, Tadanori Tomita
Rhabdoid tumors (RT) are highly aggressive and vastly unresponsive embryonal tumors. They are the most common malignant CNS tumors in infants below 6 months of age. Medulloblastomas (MB) are embryonal tumors that arise in the cerebellum and are the most frequent pediatric malignant brain tumors. Despite the advances in recent years, especially for the most favorable molecular subtypes of MB, the prognosis of patients with embryonal tumors remains modest with treatment related toxicity dreadfully high. Therefore, new targeted therapies are needed...
December 19, 2017: Oncotarget
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