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https://www.readbyqxmd.com/read/29453076/development-of-novel-synthesized-phthalazinone-based-parp-1-inhibitors-with-apoptosis-inducing-mechanism-in-lung-cancer
#1
Hadia Almahli, Elie Hadchity, Maiy Y Jaballah, Racha Daher, Hazem A Ghabbour, Maha M Kabil, Nasser S Al-Shakliah, Wagdy M Eldehna
Herein we report the synthesis of two series of 4-phenylphthalazin-1-ones 11a-i and 4- benzylphthalazin-1-ones 16a-h as anti-lung adenocarcinoma agents with potential inhibitory activity against PARP-1. All the newly synthesized phthalazinones were evaluated for their anti-proliferative activity against A549 lung carcinoma cell line. Phthalazinones 11c-i and 16b, c showed significant cytotoxic activity against A549 cells at different concentrations (0.1, 1 and 10 μM) for two time intervals (24 h and 48 h)...
February 7, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29435178/inhibition-of-the-mek-erk-pathway-augments-nab-paclitaxel-based-chemotherapy-effects-in-preclinical-models-of-pancreatic-cancer
#2
Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A Schwarz, Roderich E Schwarz
Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29434958/anticancer-effects-of-10-hydroxycamptothecin-induce-apoptosis-of-human-osteosarcoma-through-activating-caspase-3-p53-and-cytochrome-c-pathways
#3
Xiong Min, Han Heng, Hua-Long Yu, Mao Dan, Chen Jie, Yun Zeng, He Ning, Zhi-Gang Liu, Zhi-Yong Wang, Wang Lin
In order to evaluate the anticancer effect of 10-hydroxycamptothecin (HCPT) in terms of inducing the apoptosis of human osteosarcoma cells, its apoptosis-inducing molecular mechanisms were investigated. In the present study, the anticancer effects of HCPT were revealed to result in suppressed cell viability, increased cytotoxicity, the induction of apoptosis and an augmented apoptotic nucleolus of human osteosarcoma cells. MG-63 cells were cultured with HCPT (0, 20, 40 and 80 nM) for 24 and 48 h. An MTT assay and a lactate dehydrogenase assay were used to analyze the anticancer effect of HCPT on cell viability and cytotoxicity in MG-63 cells...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434894/down-expression-of-poly-adp-ribose-polymerase-in-p53-regulated-pancreatic-cancer-cells
#4
Zhenyu Hou, Yunfeng Cui, Huizhi Xing, Xiaoyan Mu
The present study investigated whether poly(ADP-ribose) polymerase (PARP) has an effect on p53-regulated pancreatic cancer. The results of the present study demonstrated that the expression of PARP affects proliferation and apoptosis of pancreatic cancer cells. Olaparib was used to suppress the expression level of PARP-1 in PanC-1 cells. Decreased expression of PARP-1 suppressed cell proliferation and induced apoptosis of PanC-1 cells when compared with controls. Furthermore, decreased expression of PARP-1 resulted in decreased levels of pro-caspase-3 expression, increased caspase-3 activity, suppressed B-cell lymphoma 2 (Bcl-2) protein expression and increased p53 protein expression in PanC-1 cells...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29432993/oridonin-inhibits-oral-cancer-growth-and-pi3k-akt-signaling-pathway
#5
Jing Yang, Xianyue Ren, Liping Zhang, Yuanyuan Li, Bin Cheng, Juan Xia
Oridonin, a bioactive diterpenoid purified from Rabdosia rubescens, has been shown to possess anticancer capacity in several cancer types. However, its effects on oral squamous cell carcinoma (OSCC) cells remain unclear. This study aimed to investigate the anticancer ability of oridonin in OSCC cells, including proliferation, apoptosis and underlying mechanisms using the OSCC cell lines, UM1 and SCC25. The results showed that oridonin not only inhibited proliferation and clonal formation but also induced G2/M cell cycle arrest and apoptosis in UM1 and SCC25 cells in a dose-dependent manner...
February 9, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29432837/vitamin-k2-a-menaquinone-present-in-dairy-products-targets-castration-resistant-prostate-cancer-cell-line-by-activating-apoptosis-signaling
#6
Subramanyam Dasari, Angela Lincy Prem Antony Samy, Andre Kajdacsy-Balla, Maarten C Bosland, Gnanasekar Munirathinam
The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC ® CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dosedependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells...
February 9, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29432179/parp-1-dependent-recruitment-of-cold-inducible-rna-binding-protein-promotes-double-strand-break-repair-and-genome-stability
#7
Jung-Kuei Chen, Wen-Ling Lin, Zhang Chen, Hung-Wen Liu
Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29431122/poly-adp-ribose-polymerase-1-regulates-fibroblast-activation-in-systemic-sclerosis
#8
Yun Zhang, Sebastian Pötter, Chih-Wei Chen, Ruifang Liang, Kolja Gelse, Ingo Ludolph, Raymund E Horch, Oliver Distler, Georg Schett, Jörg H W Distler, Clara Dees
OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry...
February 3, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29421518/mir-7-5p-overexpression-suppresses-cell-proliferation-and-promotes-apoptosis-through-inhibiting-the-ability-of-dna-damage-repair-of-parp-1-and-brca1-in-tk6-cells-exposed-to-hydroquinone
#9
Hao Luo, Hairong Liang, Yuting Chen, Shaoyun Chen, Yongchun Xu, Longmei Xu, Jiaxian Liu, Kairu Zhou, Jucheng Peng, Guoqiang Guo, Bei Lai, Li Song, Hui Yang, Linhua Liu, Jianming Peng, Zhidong Liu, Lin Tang, Wen Chen, Huanwen Tang
Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p)...
February 5, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29416738/parp-1-inhibitors-sensitize-hnscc-cells-to-apr-246-by-inactivation-of-thioredoxin-reductase-1-trxr1-and-promotion-of-ros-accumulation
#10
Zhi-Xian Yin, Wei Hang, Gang Liu, Yi-Shu Wang, Xiang-Feng Shen, Qian-Hui Sun, Dong-Dong Li, Yong-Ping Jian, Yang-He Zhang, Cheng-Shi Quan, Qinghua Zeng, Yu-Lin Li, Rui-Xun Zhao, Qiang Ding, Zhi-Xiang Xu
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1 Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416015/multiple-molecular-mechanisms-form-a-positive-feedback-loop-driving-amyloid-%C3%AE-42-peptide-induced-neurotoxicity-via-activation-of-the-trpm2-channel-in-hippocampal-neurons
#11
Xin Li, Lin-Hua Jiang
Emerging evidence supports an important role for the ROS-sensitive TRPM2 channel in mediating age-related cognitive impairment in Alzheimer's disease (AD), particularly neurotoxicity resulting from generation of excessive neurotoxic Aβ peptides. Here we examined the elusive mechanisms by which Aβ42 activates the TRPM2 channel to induce neurotoxicity in mouse hippocampal neurons. Aβ42-induced neurotoxicity was ablated by genetic knockout (TRPM2-KO) and attenuated by inhibition of the TRPM2 channel activity or activation through PARP-1...
February 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29414646/morin-hydrate-ameliorates-cisplatin-induced-er-stress-inflammation-and-autophagy-in-hek-293-cells-and-mice-kidney-via-parp-1-regulation
#12
Mahendra Pal Singh, Anil Kumar Chauhan, Sun Chul Kang
The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 μM, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels...
February 1, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29393478/co-treatment-with-gemcitabine-and-nab-paclitaxel-exerts-additive-effects-on-pancreatic-cancer-cell-death
#13
Ilaria Passacantilli, Valentina Panzeri, Francesca Terracciano, Gianfranco Delle Fave, Claudio Sette, Gabriele Capurso
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and current treatments exert small effects on life expectancy. The most common adjuvant treatment for PDAC is gemcitabine. However, relapse almost invariably occurs and most patients develop metastatic, incurable disease. The aim of the present study was to assess the activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) alone or in combination with gemcitabine in PDAC cell lines displaying different degrees of sensitivity to gemcitabine treatment...
January 25, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29393342/cthrc1-mediates-il%C3%A2-1%C3%AE-%C3%A2-induced-apoptosis-in-chondrocytes-via-jnk1-2-signaling
#14
Qi Zhang, Zong-Sheng Yin, Fu-Wen Zhang, Kun Cao, He-Yan Sun
Osteoarthritis (OA), also known as degenerative joint disease or degenerative arthritis, is characterized by chondrocyte apoptosis. The aim of the present study was to investigate the effects of collagen triple helix repeat containing 1 (CTHRC1) and the c‑Jun N‑terminal kinase (JNK) 1/2 inhibitor SP600125 on rat chondrocytes cultured in vitro with interleukin (IL)‑1β. Chondrocytes were treated with different doses of IL‑1β and cell viability and CTHRC1 expression were assessed using Cell Counting Kit‑8 and western blot assays, respectively...
January 18, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29392078/parp-1-inhibition-rescues-short-lifespan-in-hyperglycemic-c-elegans-and-improves-glp-1-secretion-in-human-cells
#15
Qianghua Xia, Sumei Lu, Julian Ostrovsky, Shana E McCormack, Marni J Falk, Struan F A Grant
TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C...
February 2018: Aging and Disease
https://www.readbyqxmd.com/read/29383691/early-treatment-with-poly-adp-ribose-polymerase-1-inhibitor-jpi-289-reduces-infarct-volume-and-improves-long-term-behavior-in-an-animal-model-of-ischemic-stroke
#16
Youngchul Kim, Young Seo Kim, Hyun Young Kim, Min-Young Noh, Ji Young Kim, Young-Jun Lee, Jeongmin Kim, Jiseon Park, Seung Hyun Kim
In patients with stroke and neurodegenerative diseases, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) causes harmful effects by inducing apoptosis, necrosis, neuroinflammation, and immune dysregulation. The current study investigated the neuroprotective effect of a novel PARP-1 inhibitor, JPI-289, in an animal model of ischemic stroke. A transient middle cerebral artery occlusion (tMCAO, 2 h) model was used to determine the therapeutic effect and the most effective dose and time window of administration of JPI-289...
January 30, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29383150/molecular-crosstalk-between-ferroptosis-and-apoptosis-emerging-role-of-er-stress-induced-p53-independent-puma-expression
#17
Se Hoon Hong, Dae-Hee Lee, Young-Sun Lee, Min Jee Jo, Yoon A Jeong, William T Kwon, Haroon A Choudry, David L Bartlett, Yong J Lee
Ferroptosis is a type of programmed cell death that depends on iron and is characterized by the accumulation of lipid peroxides. In the present study, we investigated the nature of the interplay between ferroptosis and other forms of cell death such as apoptosis. Human pancreatic cancer PANC-1 and BxPC-3 and human colorectal cancer HCT116 cells were treated with ferroptotic agents such as erastin and artesunate (ART) in combination with the apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29377384/paris-saponin-vii-induces-cell-cycle-arrest-and-apoptosis-by-regulating-akt-mapk-pathway-and-inhibition-of-p-glycoprotein-in-k562-adr-cells
#18
Ting Yan, Gaosheng Hu, Anhua Wang, Xianduo Sun, Xiangyong Yu, Jingming Jia
Paris saponinVII (PSVII) is a steroidal saponin isolated from the roots and rhizomes of Trillium tschonoskii Maxim. We found that PSVII could inhibit the growth of adriamycin-resistant human leukemia cells (K562/ADR) in a dose-dependent manner. Furthermore, the molecular mechanism underlying the cytotoxicity and downregulation of P-glycoprotein (P-gp) expression by PSVII was clarified. PSVII significantly suppressed cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious decrease in cyclin B1/D1 and CDK2/4/6 protein expression...
January 29, 2018: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/29374454/resistance-to-plum-pox-virus-ppv-in-apricot-prunus-armeniaca-l-is-associated-with-down-regulation-of-two-mathd-genes
#19
Elena Zuriaga, Carlos Romero, Jose Miguel Blanca, Maria Luisa Badenes
BACKGROUND: Plum pox virus (PPV), causing Sharka disease, is one of the main limiting factors for Prunus production worldwide. In apricot (Prunus armeniaca L.) the major PPV resistance locus (PPVres), comprising ~ 196 kb, has been mapped to the upper part of linkage group 1. Within the PPVres, 68 genomic variants linked in coupling to PPV resistance were identified within 23 predicted transcripts according to peach genome annotation. Taking into account the predicted functions inferred from sequence homology, some members of a cluster of meprin and TRAF-C homology domain (MATHd)-containing genes were pointed as PPV resistance candidate genes...
January 27, 2018: BMC Plant Biology
https://www.readbyqxmd.com/read/29371919/sensitizing-ewing-sarcoma-to-chemo-and-radiotherapy-by-inhibition-of-the-dna-repair-enzymes-dna-protein-kinase-dna-pk-and-poly-adp-ribose-polymerase-parp-1-2
#20
Britta Vormoor, Yvonne T Schlosser, Helen Blair, Abhishek Sharma, Sarah Wilkinson, David R Newell, Nicola Curtin
Background: DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality. Results: In clonogenic assays, single agent rucaparib LD50 values for continuously exposed cells were similar to those observed in HRR-defective cells (CAPAN-1 cell line, BRCA2 defective); however, both ES cell lines (TC-71, CADO-ES1) had functional HRR...
December 26, 2017: Oncotarget
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