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PARP inhibitors

Xiao Jiang, Ning Zhang, Li Yin, Wen-Long Zhang, Fei Han, Wen-Bin Liu, Hong-Qiang Chen, Jia Cao, Jin-Yi Liu
Roundup® is extensively used for weed control worldwide. Residues of this compound may lead to side effects of the male reproductive system. However, the toxic effects and mechanisms of Roundup® of male germ cells remain unclear. We aimed to investigate the apoptosis-inducing effects of Roundup® on mouse male germ cells and explore the role of a novel tumor suppressor XAF1 (X-linked inhibitor of apoptosis-associated factor 1) involved in this process. We demonstrated that Roundup® can impair spermatogenesis, decrease sperm motility and concentration, and increase the sperm deformity rate in mice...
June 14, 2018: Toxicology Letters
Paul DiSilvestro, Angeles Alvarez Secord
Approximately 1% of women in the United States will be diagnosed with epithelial ovarian cancer (EOC) during their lifetime. It is most likely to present at a more advanced stage, requiring aggressive therapeutic measures, and most women will succumb to this illness. Due to advancements in therapy, the oncology community has begun to shift its focus to molecular targeted agents, alternative dosing schedules, and maintenance therapy. Women who achieve a response to initial adjuvant chemotherapy may be candidates for maintenance therapy, with the goal of inducing a lasting remission or prolonging the disease-free interval before recurrence...
June 5, 2018: Cancer Treatment Reviews
Richa Shrivastava, Shruti Trivedi, Pankaj Kumar Singh, Mohammad Asif, Manish Kumar Chourasia, Amit Khanna, Smrati Bhadauria
Breast cancer is most frequently diagnosed cancer and fifth leading cause of death in women. About 20-30% of all breast cancers overexpress HER2/neu receptors. Lapatinib is a dual tyrosin kinase inhibitor of EGFR and HER2. It exhibits its anticancer effect via blocking intracellular domain of HER2 receptor in breast cancer. Lapatinib belongs to class II of BSC classification due to its poor solubility restricting its clinical application. Due to presence of HER2 receptor on cardiomyocytes, it is associated with generation of cardiotoxicity...
June 13, 2018: Biochemical and Biophysical Research Communications
M Catherine Pietanza, Saiama N Waqar, Lee M Krug, Afshin Dowlati, Christine L Hann, Alberto Chiappori, Taofeek K Owonikoko, Kaitlin M Woo, Robert J Cardnell, Junya Fujimoto, Lihong Long, Lixia Diao, Jing Wang, Yevgeniva Bensman, Brenda Hurtado, Patricia de Groot, Erik P Sulman, Ignacio I Wistuba, Alice Chen, Martin Fleisher, John V Heymach, Mark G Kris, Charles M Rudin, Lauren Averett Byers
Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2 /day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent...
June 15, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Jian Ma, Shan-Shan Gao, Hai-Jie Yang, Mian Wang, Bin-Feng Cheng, Zhi-Wei Feng, Lei Wang
Proanthocyanidins (PA) are natural flavonoids widely present in many vegetables, fruits, nuts and seeds, and especially in grape seed. In the present study, we examined the neuroprotective effects of PA and the underlying molecular mechanism in rotenone model of Parkinson's disease (PD). We found that pretreatment with PA significantly reduced rotenone-induced oxidative stress in human neuroblastoma SH-SY5Y dopaminergic cells. In addition, PA markedly enhanced cell viability against rotenone neurotoxicity and considerably blocked rotenone-induced activation of caspase-9, caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP), biochemical features of apoptosis...
2018: Frontiers in Neuroscience
Luka Horvat, Mariastefania Antica, Maja Matulić
Differentiation of blood cells is one of the most complex processes in the body. It is regulated by the action of transcription factors in time and space which creates a specific signaling network. In the hematopoietic signaling system, Notch is one of the main regulators of lymphocyte development. The aim of this study was to get insight into the regulation of Notch signalization and the influence of poly(ADP-ribose)polymerase (PARP) activity on this process in three leukemia cell lines obtained from B and T cells...
June 14, 2018: Cells
Hélène Marijon, Dhong Hyun Lee, LingWen Ding, Haibo Sun, Sigal Gery, Aimery de Gramont, H Phillip Koeffler
PURPOSE: Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. METHODS: Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated...
March 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Feng Jiang, Jin-Yong Zhou, Dan Zhang, Ming-Hao Liu, Yu-Gen Chen
The present study assessed the antitumor effect of artesunate (ART) in vitro and in vivo, as well as its underlying mechanism of action in HCT116 colon cancer cells. An MTT assay, DAPI staining, flow cytometry, western blotting, immunohistochemistry, transmission electron microscopy and TUNEL assay were performed to study the molecular mechanism underlying the antitumor effects of ART in HCT116 colon cancer cells. ART was observed to inhibit proliferation by inducing the apoptosis of HCT116 cells both in vitro and in vivo...
June 1, 2018: International Journal of Molecular Medicine
Mara Livezey, Rui Huang, Paul J Hergenrother, David J Shapiro
The endoplasmic reticulum stress sensor, the unfolded protein response (UPR), regulates intracellular protein homeostasis. While transient activation of the reactive UPR by unfolded protein is protective, prolonged and sustained activation of the reactive UPR triggers CHOP-mediated apoptosis. In the recently characterized, evolutionarily conserved anticipatory UPR, mitogenic hormones and other effectors pre-activate the UPR; how strong and sustained activation of the anticipatory UPR induces cell death was unknown...
June 13, 2018: Cell Death and Differentiation
Katherine Sullivan-Reed, Elisabeth Bolton-Gillespie, Yashodhara Dasgupta, Samantha Langer, Micheal Siciliano, Margaret Nieborowska-Skorska, Kritika Hanamshet, Elizaveta A Belyaeva, Andrea J Bernhardy, Jaewong Lee, Morgan Moore, Huaqing Zhao, Peter Valent, Ksenia Matlawska-Wasowska, Markus Müschen, Smita Bhatia, Ravi Bhatia, Neil Johnson, Mariusz A Wasik, Alexander V Mazin, Tomasz Skorski
PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells...
June 12, 2018: Cell Reports
Xiaotao Xu, Qingwei Zhu, Fangfang Niu, Rong Zhang, Yan Wang, Wenying Wang, Dawei Sun, Xintao Wang, Aizhong Wang
The epithelial barrier of the lung is destroyed during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) due to the apoptosis of alveolar epithelial cells (AECs). Therefore, treatments that block AEC apoptosis might be a therapeutic strategy to ameliorate ALI. Based on recent evidence, A2B adenosine receptor (A2BAR) plays an important role in ALI in several different animal models, but its exact function in AECs has not been clarified. We investigated the role of A2BAR in AEC apoptosis in a mouse model of oleic acid (OA)-induced ALI and in hydrogen peroxide (H2 O2 )-induced AEC (A549 cells and MLE-12 cells) injury...
June 13, 2018: American Journal of Physiology. Cell Physiology
Ying Chen, Hui Du
Epithelial ovarian cancer (EOC) accounts for 90% of all ovarian cancer. Initially, approaching 80% of EOC patients respond to standard therapeutic strategy, cytoreduction combining with postoperative auxiliary platinum-based chemotherapy. However, relapse is approximately inevitable because of drug-resistance for high-grade serous ovarian cancer (HGSOC). Recently, the nuclear enzyme poly (ADP-ribose) polymerase (PARP) represents a strikingly novel target in EOC treatment. PARP inhibitors, currently mainly including Olaparib, Niraparib, Velaparib, Rucaparib, and Talazoparib, have demonstrated promising activity in EOC treatment...
March 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Ewa Gogola, Alexandra A Duarte, Julian R de Ruiter, Wouter W Wiegant, Jonas A Schmid, Roebi de Bruijn, Dominic I James, Sergi Guerrero Llobet, Daniel J Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J Ogilvie, Marcel van Vugt, Lodewyk F A Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism...
June 11, 2018: Cancer Cell
Yan Yuan, Yajing Zhang, Shiwen Zhao, Jie Chen, Jinlong Yang, Tao Wang, Hui Zou, Yi Wang, Jianhong Gu, Xuezhong Liu, Jianchun Bian, Zongping Liu
Cadmium (Cd) is a toxic metal capable of damaging brain. Studies have demonstrated that Cd can induce apoptosis in neuronal cells. The CD95/APO-1 (Fas)/Fas Ligand (FasL) signaling pathway is one of the primary apoptosis pathways, but the role and regulatory mechanism of this pathway in neuronal cells remain unclear. Here, we demonstrated the underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells. Primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly activated expression of Fas, FasL, Fas-associated death domain (FADD) and cleaved caspase-8...
June 11, 2018: Scientific Reports
Kyung Oh Jung, Hunho Jo, Jung Ho Yu, Sanjiv Sam Gambhir, Guillem Pratx
Treating the hypoxic region of the tumor remains a significant challenge. The goals of this study are to develop an exosome platform that can target regions of tumor hypoxia and that can be monitored in vivo using magnetic particle imaging (MPI). Four types of exosomes (generated under hypoxic or normoxic conditions, and with or without exposure to X-ray radiation) were isolated from MDA-MB-231 human breast cancer cells. Exosomes were labeled by DiO, a fluorescent lipophilic tracer, to quantify their uptake by hypoxic cancer cells...
May 29, 2018: Biomaterials
Shenglin Fang, Xiaonan Yu, Haoxuan Ding, Jianan Han, Jie Feng
Iron overload causes many diseases, while the underlying etiologies of these diseases are unclear. Cell death processes including apoptosis, necroptosis, cyclophilin D-(CypD)-dependent necrosis and a recently described additional form of regulated cell death called ferroptosis, are dependent on iron or iron-dependent reactive oxygen species (ROS). However, whether the accumulation of intracellular iron itself induces ferroptosis or other forms of cell death is largely elusive. In present study, we study the role of intracellular iron overload itself-induced cell death mechanisms by using ferric ammonium citrate (FAC) and a membrane-permeable Ferric 8-hydroxyquinoline complex (Fe-8HQ) respectively...
June 8, 2018: Biochemical and Biophysical Research Communications
Liza Douiev, Ann Saada
Mitochondrial cytochrome c oxidase (COX, respiratory chain complex IV), contributes to ATP production via oxidative phosphorylation (OXPHOS). Clinical presentation of COX deficiency is heterogeneous ranging from mild to severe neuromuscular diseases. Anemia is among the symptoms and we have previously reported Fanconi anemia like features in COX4-1 deficiency, suggesting genomic instability and our preliminary results detected nuclear double stranded DNA breaks (DSB). We now quantified the DSB by phospho histone H2AX Ser139 staining of COX4-1 and COX6B1 deficient fibroblasts (225% and 215% of normal, respectively) and confirmed their occurrence by neutral comet assay...
June 7, 2018: Biochimica et Biophysica Acta
Narjust Duma, Kelly C Gast, Grace M Choong, Roberto A Leon-Ferre, Ciara C O'Sullivan
PURPOSE OF REVIEW: To provide an overview of the clinical development of poly(ADP-ribose) polymerase inhibitors (PARPi) in breast cancer to date and to review existing challenges and future research directions. RECENT FINDINGS: We summarize the clinical development of PARPi in breast cancer from bench to bedside, and discuss the results of recent phase 3 trials in patients with metastatic breast cancer (MBC) and germline mutations in BRCA1/2 (gBRCAm). We will also provide an update regarding mechanisms of action and resistance to PARPi, and review clinical trials of PARPi as monotherapy or in combination regimens...
June 8, 2018: Current Oncology Reports
Yessenia Valverde, Raghuvaran Narayanan, Satish B Alapati, Fanny Chmilewsky, Chun-Chieh Huang, Sriram Ravindran, Seung H Chung
INTRODUCTION: The nuclear enzyme poly(adenosine phosphate ribose) polymerase 1 (PARP-1) has been implicated in the maintenance and differentiation of several stem cells. The role of PARP-1 in dental pulp stem cell (DPSC) differentiation, especially in the context of its ability to modulate nerve regeneration factors, has not been investigated. Regeneration of neuronal components in pulp tissue is important for the assessment of tooth vitality. Brain-derived neurotrophic factor (BDNF) is known to play an integral signaling factor during nerve regeneration...
June 5, 2018: Journal of Endodontics
Domenica Lorusso, Elisa Tripodi, Giuseppa Maltese, Stefano Lepori, Ilaria Sabatucci, Giorgio Bogani, Francesco Raspagliesi
Epithelial ovarian cancer is the sixth most common cancer among women worldwide and the first cause of death among gynecological malignancies. Most of the patients present recurrent disease and unfortunately cannot be cured. The unsatisfactory results obtained with salvage chemotherapy have elicited investigators to search for novel biological agents capable of achieving a better control of the disease. In the setting of homologous recombination deficiency, the DNA errors that occur cannot be accurately repaired, and the treatment with poly(ADP-ribose) polymerase (PARP) inhibition results in definitive cell death in a process called synthetic lethality...
2018: Drug Design, Development and Therapy
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