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Isabella Faraoni, Francesca Aloisio, Antonio De Gabrieli, Maria Irno Consalvo, Serena Lavorgna, Maria Teresa Voso, Francesco Lo-Coco, Grazia Graziani
Olaparib is a potent orally bioavailable poly(ADP-ribose) polymerase inhibitor (PARPi), approved for BRCA-mutated ovarian and breast cancers. We recently showed that olaparib at clinically achievable concentrations exerts anti-proliferative and pro-apoptotic effects in vitro as monotherapy against primary acute myeloid leukemia (AML) blasts, while sparing normal bone marrow (BM) hematopoietic cells. Since AML expresses low levels of death receptors that may contribute to apoptosis resistance, in this study we investigated whether the anti-leukemia activity of olaparib involves modulation of FAS and TRAIL receptors DR5 and DR4...
March 8, 2018: Cancer Letters
Christoph Oing, Pierre Tennstedt, Ronald Simon, Jennifer Volquardsen, Kerstin Borgmann, Carsten Bokemeyer, Cordula Petersen, Ekkehard Dikomey, Kai Rothkamm, Wael Y Mansour
Here we report that BCL2 blocks DNA double strand break (DSB) repair via nonhomologous end-joining (NHEJ), through sequestration of KU80 protein outside the nucleus. We find that this effect is associated with a repair switch to the error-prone PARP1-dependent end-joining (PARP1-EJ). We present in-vitro proof-of-concept for therapeutic targeting of this switch using PARP inhibitor to specifically enhance the radiosensitivity of BCL2-overexpressing cells. Given its erroneous behavior, PARP1-EJ might allow for the accumulation of genetic alterations and tumor progression...
March 8, 2018: Cancer Letters
Dehong Huang, Lei Jin, Zhengkang Li, Ji Wu, Ni Zhang, Dianrong Zhou, Xiaorong Ni, Tieying Hou
Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Pedro Miguel Lacal, Maria Grazia Atzori, Federica Ruffini, Lucio Tentori, Grazia Graziani
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor activated by the angiogenic factors VEGF‑A and placental growth factor (PlGF). While VEGF‑A binds to both VEGFR‑1 and VEGFR‑2, PlGF interacts exclusively with VEGFR‑1 triggering a signaling pathway involved in: i) tumor‑associated angiogenesis; ii) chemotaxis and invasion of the extracellular matrix (ECM) by cancer cells; and iii) mobilization of bone marrow‑derived myeloid cells that generate tumor‑associated macrophages...
March 5, 2018: Oncology Reports
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Sofia Genta, Massimo Aglietta, Anna Sapino, Giorgio Valabrega
BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis...
March 5, 2018: Recent Patents on Anti-cancer Drug Discovery
Qi Liu, Liliana Gheorghiu, Michael Drumm, Rebecca Clayman, Alec Eidelman, Matthew F Wszolek, Aria Olumi, Adam Feldman, Meng Wang, Lynnette Marcar, Deborah E Citrin, Chin-Lee Wu, Cyril H Benes, Jason A Efstathiou, Henning Willers
Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1...
March 7, 2018: Oncogene
W Y Mansour, P Tennstedt, J Volquardsen, C Oing, M Kluth, C Hube-Magg, K Borgmann, R Simon, C Petersen, E Dikomey, K Rothkamm
Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation...
March 2, 2018: Scientific Reports
Yize Mao, Xin Huang, Zeyu Shuang, Guohe Lin, Jun Wang, Fangting Duan, Jianlin Chen, Shengping Li
Cholangiocarcinoma (CCA) is a highly malignant tumor with resistance to radiotherapy alone. Olaparib, a highly potent poly(ADP-ribose) polymerase (PARP) inhibitor, has been shown to sensitize many types of tumor to radiotherapy. However, the effect of olaparib, either as monotherapy or as combination therapy with radiotherapy, on CCA is not known, and our study aimed to explore this. To assess radiosensitization in three CCA cell lines (QBC939, HuH28 and TFK-1), viability and clonogenic assays were conducted...
February 26, 2018: Cancer Medicine
Claire Pressiat, Huu-Hien Huynh, Alain Plé, Hélène Sauvageon, Isabelle Madelaine, Cécile Chougnet, Christine Le Maignan, Samia Mourah, Lauriane Goldwirt
BACKGROUND: A simple, rapid, and sensitive LC-MS/MS method has been developed and validated for the quantification of ruxolitinib, olaparib, vismodegib, and pazopanib in human plasma. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an UPLC system coupled with MS/MS in a positive ionization mode. The mobile phase consisted of a gradient elution of 10 mmol/L formate ammonium buffer containing 0.1% (v/v) formic acid (phase A) and acetonitrile with 0...
February 22, 2018: Therapeutic Drug Monitoring
Dong Hoon Suh, Miseon Kim, Kyung Hun Lee, Keun Yong Eom, Maj Kamille Kjeldsen, Mansoor Raza Mirza, Jae Weon Kim
In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer...
March 2018: Journal of Gynecologic Oncology
Shao Q Yao, Bo Peng, Changmin Yu, Shubo Du, Si Si Liew, Xin Mao, Peiyan Yuan, Zhenkun Na
Standard small molecule microarray (SMM) is not well-suited for cell-based screening assays. Of the few attempts made thus far to render SMM cell-compatible, all were met with major limitations. We report herein the first mesoporous silica nanoparticle (MSN)-on-a-chip platform capable of conducting high-throughput cell-based screening on SMM. By making use of a glass surface on which hundreds of mesoporous silica nanoparticles, each encapsulated with a different native natural product, were immobilized in spatially defined manner, followed by on-chip mammalian cell growth and on-demand compound release, high-content screening was successfully carried out with readily available phenotypic detection methods...
February 21, 2018: Chembiochem: a European Journal of Chemical Biology
Gertrud E Feiersinger, Kristina Trattnig, Peter D Leitner, Fabian Guggenberger, Alexander Oberhuber, Sarah Peer, Martin Hermann, Ira Skvortsova, Jana Vrbkova, Jan Bouchal, Zoran Culig, Frédéric R Santer
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor Olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa we evaluated a potential use for Olaparib in combination with first-line endocrine treatments, androgen deprivation and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy...
February 21, 2018: Molecular Oncology
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
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
Pierre Daumar, Robin Dufour, Clémence Dubois, Frédérique Penault-Llorca, Mahchid Bamdad, Emmanuelle Mounetou
Olaparib is a potent PARP inhibitor in clinical use for cancer therapy. A bioanalytical assay was developed and validated for quantitation of intracellular level of olaparib in cells exposed to the drug. The assay involves an optimized and straightforward sample pretreatment with acetonitrile for olaparib solubilization, cell lysis and protein precipitation, and a high performance liquid chromatography (HPLC) method with ultraviolet detection. Several parameters in both the sample preparation and the detection steps were investigated...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
Ailing Zhong, Hongqin Zhang, Suhong Xie, Minjie Deng, Hui Zheng, Yanchun Wang, Miaomiao Chen, Renquan Lu, Lin Guo
Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81 (MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor; however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer (EOC) and have shown that its overexpression is associated with cisplatin sensitization. However, the exact functional role of MUS81 and its regulation in relation to chemotherapy sensitivity remains unknown...
January 22, 2018: Oncology Reports
Yongchang Lai, Zhenzhen Kong, Tao Zeng, Shaohong Xu, Xiaolu Duan, Shujue Li, Chao Cai, Zhijian Zhao, Wenqi Wu
Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion...
January 26, 2018: Oncology Reports
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
(no author information available yet)
The FDA has approved olaparib, a PARP inhibitor, for use in patients with metastatic breast cancer who also carry a germline BRCA1 or BRCA2 mutation. With the January 12 approval, olaparib becomes the first targeted therapy for patients with breast cancer with mutated BRCA.
January 30, 2018: Cancer Discovery
Vivek Dharwal, Amarjit S Naura
COPD is associated with high morbidity and mortality and no effective treatment is available till date. We have previously reported that PARP-1 plays an important role in the establishment of airway inflammation associated with asthma and ALI. In the present work, we have evaluated the beneficial effects of PARP-1 inhibition on COPD pathogenesis utilizing elastase induced mouse model of the disease. Our data show that PARP-1 inhibition by olaparib significantly reduced the elastase-induced recruitment of inflammatory cells particularly neutrophils in the lungs of mice when administered at a dose of 5 mg/kg b...
January 30, 2018: Biochemical Pharmacology
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