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BCL2 inhibitor

Tao Wang, Hui Zhao, Hua Gao, Changming Zhu, Yao Xu, Liping Bai, Junbo Liu, Feng Yan
The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are activated during pathogenesis of gastrointestinal stromal tumors (GISTs). Forkhead box protein O1 (FOXO1) is a transcription factor regulated by the MAPK and PI3K pathways and is associated with multiple metabolic reactions. The present study aims to investigate the association of FOXO1 with cell proliferation and apoptosis in the cell line, GIST-T1. Cell counting kit-8 assay revealed that cell growth was inhibited by the PI3K inhibitor, LY294002, and/or MAPK inhibitor, UO126...
April 2018: Experimental and Therapeutic Medicine
Yuzhuo Chen, Weiliang Song
The present study assessed the association between the Wnt/catenin β1 (CTNNB1)/microRNA (miR)183 signaling pathway and the recurrence and prognosis of colorectal cancer. The expression of Wnt, CTNNB1 and miR183 in primary colorectal cancer tissue was increased compared with that in the paracarcinoma tissue. Disease-free survival and overall survival were decreased in patients with colorectal cancer and increased miR183 expression compared with those in patients with colorectal cancer and decreased miR183 expression...
April 2018: Oncology Letters
Yang Yuan, Shan-Shan Pan
BACKGROUND: Late exercise preconditioning (LEP) is confirmed to have a protective effect on acute cardiovascular stress. However, the mechanisms by which mitophagy participates in EP-induced cardioprotection remain unclear. LEP may involve mitophagy mediated by the receptors PARK2 gene-encoded E3 ubiquitin ligase (Parkin) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) to scavenge damaged mitochondria. METHODS: Our exercise preconditioning (EP) protocol involved four 10-minute periods of running, separated by 10-minute recovery intervals, plus a period of exhaustive running at 24 hours after EP...
March 9, 2018: Journal of Cardiovascular Pharmacology
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
Wan Wang, Di Wen, Weisong Duan, Juntao Yin, Can Cui, Ying Wang, Zhongyao Li, Yakun Liu, Chunyan Li
Amyotrophic lateral sclerosis (ALS) is closely associated with a reduction of neurotrophic factors in the central nervous system (CNS). Insulin-like growth factor 1 (IGF1)-encoding vectors delivered via intramuscular and intraparenchymal spinal cord injections have conferred therapeutic benefits in ALS model mice, although the development of a noninvasive delivery route is still needed. Intravenous administration of adeno-associated virus (AAV) vectors has been used to induce expression of neurotrophic genes in the lumbar spinal cords of adult mice...
February 27, 2018: Brain Research Bulletin
Selma Tuzlak, Manuel D Haschka, Anna-Maria Mokina, Thomas Rülicke, Suzanne Cory, Verena Labi, Andreas Villunger
Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug-resistance, identifying these pro-survival BCL2 family members as putative drug-targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the hematopoietic system under the control of the Vav-gene promoter. Hematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous hematopoietic malignancies is not increased...
March 2, 2018: FEBS Journal
Suresh Banjara, Jiahao Mao, Timothy M Ryan, Sofia Caria, Marc Kvansakul
Programmed cell death or apoptosis is a critical mechanism for the controlled removal of damaged or infected cells, and proteins of the BCL-2 family are important arbiters of this process. Viruses have been shown to encode functional and structural homologs of BCL-2 to counter premature host-cell apoptosis and ensure viral proliferation or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the Iridoviridae family and harbors GIV66, a putative BCL-2 like protein and mitochondrially localized apoptosis inhibitor...
February 26, 2018: Journal of Biological Chemistry
Jana Mihalyova, Tomas Jelinek, Katerina Growkova, Matous Hrdinka, Michal Simicek, Roman Hajek
Inhibitors of anti-apoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. While non-selective agents have been limited by their affinity to different BCL2 members, and thus inducing excessive toxicity, the highly selective BCL2 inhibitor, venetoclax (ABT-199, Venclexta™), has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukaemia (CLL) with 17p deletion...
February 22, 2018: Experimental Hematology
J Malcikova, E Tausch, D Rossi, L A Sutton, T Soussi, T Zenz, A P Kater, C U Niemann, D Gonzalez, F Davi, M Gonzalez Diaz, C Moreno, G Gaidano, K Stamatopoulos, R Rosenquist, S Stilgenbauer, P Ghia, S Pospisilova
In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zhiren Zhang, Yanhui Zhai, Xiaoling Ma, Sheng Zhang, Xinglan An, Hao Yu, Ziyi Li
BACKGROUND/AIMS: Aberrantly high levels of H3K4me3, caused by incomplete epigenetic reprogramming, likely cause a low efficiency of somatic cell nuclear transfer (SCNT). Smal molecule inhibitors aimed at epigenetic modification can be used to improve porcine SCNT embryo development. In this study, we examined the effects of MM-102, an H3K4 histone methyltransferase inhibitor, on porcine SCNT preimplantation embryos to investigate the mechanism by which H3K4 methylation regulated global epigenetic reprograming during SCNT...
February 16, 2018: Cellular Physiology and Biochemistry
Nathaniel Robichaud, Brian E Hsu, Roman Istomine, Fernando Alvarez, Julianna Blagih, Eric H Ma, Sebastian V Morales, David L Dai, Glenn Li, Margarita Souleimanova, Qianyu Guo, Sonia V Del Rincon, Wilson H Miller, Santiago Ramón Y Cajal, Morag Park, Russell G Jones, Ciriaco A Piccirillo, Peter M Siegel, Nahum Sonenberg
The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yi Lu, Dongdong Lu, Yu Hu
OBJECTIVES: Glucagon-like peptide 2 (GLP2) is involved in the regulation of energy absorption and metabolism. Despite the importance of the GLP2 signalling mechanisms on osteoclast, little has been studied on how GLP2 works during osteoclastogenesis. MATERIALS AND METHODS: RAW264.7 cells were infected with rLV-Green-GLP2. The induction of osteoclasts was performed by RANKL. TRAP were detected by RT-PCR, Western blotting and staining. Total nitric oxide and total NOS activity were measured...
February 19, 2018: Cell Proliferation
Chan Yoon Cheah, Nathan H Fowler
Follicular lymphoma is one of the most common non-Hodgkin's lymphomas. Although current frontline regimens are associated with high response rates, most patients still relapse. When progression is discovered, re-establishing the diagnosis and ruling out transformation in paramount. The outcomes following relapse have been improving due to the activity and increasing availability of novel agents with various mechanisms of action. Despite these advances, single agent activity is limited and the disease remains incurable in the majority of cases...
March 2018: Best Practice & Research. Clinical Haematology
Rui Li, Hongxia Zhang, Xiling Zheng
The present study aimed to investigate microRNA (miR/miRNA)-34c expression and the association of miR-34c with B cell lymphoma 2 (BCL2) in M4e laryngeal carcinoma cell line. M4e laryngeal carcinoma cells were cultured and transfected with lenti-miR-34c or scramble miRNA for 72 h. Cell viability and the percentage of cells undergoing apoptosis of transfected cells were detected using MTT and Annexin V/allophycocyanin and propidium iodide assays, respectively. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to determine BCL2 mRNA and protein expression in transfected M4e cells...
March 2018: Oncology Letters
Shuzheng Song, Guoqing Pei, Yaqiong Du, Jugang Wu, Xiaochun Ni, Shoulian Wang, Bojian Jiang, Meng Luo, Jiwei Yu
Chemoresistance in gastric cancer is the leading cause of tumor recurrence and poses a substantial therapeutic challenge. The stem cell biomarker CD133 has been implicated in drug resistance of tumor-initiating cells in a number of cancers including gastric cancer. Therefore, we investigated the molecular mechanism of CD133-associated multidrug resistance in gastric cancer cells. Using CD133 overexpressing and knockdown gastric cancer cell lines, we demonstrated that loss of CD133 significantly increased the growth inhibition of chemotherapeutic agents; whereas, overexpression significantly reduced growth inhibition...
2018: American Journal of Translational Research
Hio Teng Cheong, Fei Xu, Chi Tung Choy, Connie Wun Chun Hui, Tony Shu Kam Mok, Chi Hang Wong
Lung cancer has the highest incidence and mortality rate worldwide among all malignancy-associated mortalities, of which non-small cell lung cancer accounts for 80% of all cases. Resistance against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) develops following 8-12 months of disease progression, and is a critical issue. HCC827 cell lines with resistance to EGFR-TKIs were successfully screened. The half maximal inhibitory concentration values were 1,000-fold higher than the values for the parental HCC827 cell line, thereby demonstrating cross-resistance against the same family of TKIs...
January 2018: Oncology Letters
Xiaomei Wang, Pengda Zou, Yuanyuan He, Kai Meng, Fusheng Quan, Yong Zhang
Luteinizing hormone (LH) is a glycoprotein that regulates the function of ovarian follicular cells. Theca cells (TCs) also have a key role in follicular growth and atresia. The effects and intracellular signaling mechanisms were investigated of LH on apoptosis and steroidogenesis in goat gonadotropin-independent follicular (1.0-4.0 mm) TCs. The results indicated that LH increased androstenedione secretion and relative abundance of CYP17A1 and BCL2 mRNA in the TCs, whereas LH in combination with LY294002, a PI3K/AKT inhibitor, decreased LH-induced function...
March 2018: Animal Reproduction Science
Dongfeng Zeng, Aakash Desai, Fangfang Yan, Tiejun Gong, Haige Ye, Makhdum Ahmed, Krystle Nomie, Jorge Romaguera, Richard Champlin, Shaoying Li, Michael Wang
The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL)...
February 6, 2018: American Journal of Clinical Oncology
Ayako Sakakibara, Yuichiro Inagaki, Eiki Imaoka, Eri Ishikawa, Satoko Shimada, Kazuyuki Shimada, Yuka Suzuki, Shigeo Nakamura, Akira Satou, Kei Kohno
Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly...
February 8, 2018: Journal of Clinical and Experimental Hematopathology: JCEH
Ayano Kabashima, Petra Hirsova, Steven F Bronk, Matthew C Hernandez, Mark J Truty, Sumera Rizvi, Scott H Kaufmann, Gregory J Gores
BACKGROUND & AIMS: Myeloid cell leukemia1 (MCL1), a prosurvival member of the BCL2 protein family, plays a pivotal role in human cholangiocarcinoma (CCA) cell survival. We have previously reported that fibroblast growth factor receptor (FGFR) signaling mediates MCL1-dependent survival of CCA cells in vitro and in vivo. However, the mode and mechanisms of cell death in this model were not delineated. METHODS: Human CCA cell lines were treated with the pan-FGFR inhibitor LY2874455 and the mode of cell death examined by several complementary assays...
February 2, 2018: Journal of Hepatology
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