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Michelle J Wilkinson, Henry G Smith, Gráinne McEntee, Joan Kyula-Currie, Tim D Pencavel, David C Mansfield, Aadil A Khan, Victoria Roulstone, Andrew J Hayes, Kevin J Harrington
Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity...
October 22, 2016: Oncotarget
Douglas Matsunaga, Parameswaran G Sreekumar, Keijiro Ishikawa, Hiroto Terasaki, Ernesto Barron, Pinchas Cohen, Ram Kannan, David R Hinton
Humanin (HN) is a small mitochondrial-encoded peptide with neuroprotective properties. We have recently shown protection of retinal pigmented epithelium (RPE) cells by HN in oxidative stress; however, the effect of HN on endoplasmic reticulum (ER) stress has not been evaluated in any cell type. Our aim here was to study the effect of HN on ER stress-induced apoptosis in RPE cells with a specific focus on ER-mitochondrial cross-talk. Dose dependent effects of ER stressors (tunicamycin (TM), brefeldin A, and thapsigargin) were studied after 12 hr of treatment in confluent primary human RPE cells with or without 12 hr of HN pretreatment (1-20 μg/mL)...
2016: PloS One
Cenk Daglioglu, Burcu Okutucu
PURPOSE: Resistance to chemotherapy is one of the major problems facing current cancer research. Enhancing tumor cell response to anticancer agents increases chemotherapeutic effectiveness. We have recently addressed this issue and reported on producing multifunctional nanoparticles (Fe3O4@SiO2(FITC)-FA/AICAR/DOX) aiming to overcome chemoresistance with synergetic effect of AICAR and DOX. In the present study, we demonstrated that these nanoparticles not only show enhanced cellular uptake and cytotoxic effect but can also show enhanced pro-apoptotic and anti-proliferative effects in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat and MIA PaCa-2)...
October 25, 2016: Pharmaceutical Research
Yan Sun, Ping-An Peng, Yue Ma, Xiaoli Liu, Yi Yu, Shuo Jia, Xiaohan Xu, Sijing Wu, Yujie Zhou
Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the administration of iodinated contrast media (CM) for diagnostic and interventional cardiovascular procedures and is associated with substantial morbidity and mortality. While the preventative measures can mitigate the risk of CI-AKI, there remains a need for novel and effective therapeutic approaches. The pathogenesis of CI-AKI is complex and not completely understood. CM-induced renal tubular cell apoptosis caused by the activation of endoplasmic reticulum (ER) stress is involved in CI-AKI...
October 25, 2016: Current Vascular Pharmacology
S T Eisenman, S J Gibbons, P-J Verhulst, G Cipriani, D Saur, G Farrugia
BACKGROUND: Delayed gastric emptying in diabetic mice and humans is associated with changes in macrophage phenotype and loss of interstitial cells of Cajal (ICC) in the gastric muscle layers. In diabetic mice, classically activated M1 macrophages are associated with delayed gastric emptying, whereas alternatively activated M2 macrophages are associated with normal gastric emptying. This study aimed to determine if secreted factors from M1 macrophages could injure mouse ICC in primary culture...
October 25, 2016: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Jian-Ping Li, Zhi-Jun Huang, Xing-Sheng Lu, Yi-Chan Zhou, Yun Shao, Xiao-Pu He, Su-Rong Chen, Dong-Dong Wang, Li-Sen Qin, Wei-Hao Sun
The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells...
October 21, 2016: Oncotarget
Thomas Vercruysse, Jolien De Bie, Jasper Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan Leo Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
PURPOSE: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports many cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibition of XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in Phase-II/IIb clinical trials when dosed 1 - 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
María Virtudes Céspedes, María José Guillén, Pedro Pablo López-Casas, Francesca Sarno, Alberto Gallardo, Patricia Álamo, Carmen Cuevas, Manuel Hidalgo, Carlos María Galmarini, Paola Allavena, Pablo Avilés, Ramón Mangues
We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine may result in synergistic antitumor effect in pancreatic adenocarcinoma (PDA) models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor groove inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs).We evaluated the in vivo antitumor activity of lurbinectedin, gemcitabine (as single agents) and its combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR)...
October 20, 2016: Disease Models & Mechanisms
R J Buckley, G S Whitley, I E Dumitriu, J E Cartwright
INTRODUCTION: During the first trimester of human pregnancy, fetally-derived extravillous trophoblast (EVT) invade into the uterine decidua and remodel the uterine spiral arteries to ensure that sufficient blood reaches the maternal-fetal interface. Decidual macrophages have been implicated in the regulation of decidual remodelling, and aberrant activation of these immune cells is associated with pre-eclampsia. METHODS: The monocytic cell line THP-1 was activated to induce a classically- or alternatively-activated macrophage phenotype and the conditioned media was used to treat the EVT cell line SGHPL-4 in order to determine the effect of macrophage polarisation on trophoblast behaviour in-vitro...
November 2016: Placenta
Thanyarat Wongwananuruk, Tomomi Sato, Takeshi Kajihara, Sachiko Matsumoto, Masumi Akita, Kazuhiro Tamura, Jan J Brosens, Osamu Ishihara
INTRODUCTION: To elucidate whether trophoblast expansion and invasion are modulated by androgen signaling in an in vitro co-culture model system with decidualizing endometrial stromal cells (ESCs). METHODS: We employed an in vitro co-culture model of early embryo implantation, consisting of human ESCs (EtsT499 cells) and spheroids generated by extravillous trophoblast (EVT) derived HTR8/Svneo. The ESCs were decidualized with 8-bromo-cAMP (8-br-cAMP) in the presence or absence of dihydrotestosterone (DHT) at various concentrations for 5 days before co-culture with EVT spheroids...
November 2016: Placenta
Jihye Han, Joonbeom Bae, Chang-Yong Choi, Sang-Pil Choi, Hyung-Sik Kang, Eun-Kyeong Jo, Jongsun Park, Young Sik Lee, Hyun-Seuk Moon, Chung-Gyu Park, Myung-Shik Lee, Taehoon Chun
Severe hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation remains elusive. In this study, we explore the role of individual TAM family proteins during autophagy induction and evaluate their contribution to hepatic inflammation...
October 26, 2016: Autophagy
Kuan-Ho Lin, Chien-Liang Liu, Wei-Wen Kuo, Catherine Reena Paul, Wei-Kung Chen, Su-Ying Wen, Cecilia Hsuan Day, Hsi-Chin Wu, Vijaya Padma Viswanadha, Chih-Yang Huang
Cardiac trauma has been recognized as a complication associated with blunt chest trauma involving coronary artery injury, myocardium contusion and myocardial rupture. Secondary cardiac injuries after trauma supposed to be a critical factor in trauma patients, but the mechanism is not fully explored. Overproduction of TNF-alpha had been reported in multiple trauma animals, this induces oxidative stress resulting in cardiac apoptosis. Apoptosis gradually increases after trauma and reaches to a maximum level in 12 h time...
2016: PloS One
Wencheng Zheng, Xiaoming Shang, Chunlai Zhang, Xiang Gao, Barry Robinson, Jing Liu
OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. METHODS: Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake...
October 26, 2016: Cardiology
Juan Yang, Guiyuan Li, Keqiang Zhang
Apoptotic signaling provoked by death receptors, DR4 and DR5, are generally considered to promote cell death and chemosensitivity in multiple cancers, but this view is being thrown into doubt with recent findings that up-regulated DR4 and DR5 in advanced stages of ovarian cancer are associated with the poor prognosis. For this conflict, two reasonable explanations have been proposed: one is that DR4 and DR5 not exclusively mediate apoptotic pathway, but also favor survival signal; another is that apoptotic signals by DR4 and DR5 are disrupted by some regulators...
October 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Saranya Satitmanwiwat, Chinarat Changsangfa, Anuson Khanuengthong, Kornkanok Promthep, Sittiruk Roytrakul, Teerakul Arpornsuwan, Kulnasan Saikhun, Hathaitip Sritanaudomchai
AIM: This study aimed to investigate the mechanism of the induction of apoptosis of human oral cancer cells by the scorpion venom peptide BmKn2. METHODS: Human oral squamous carcinoma cells (HSC4), mouth epidermoid carcinoma cells (KB), human normal gingival cells (HGC) and dental pulp cells (DPC) were treated with BmKn-2 peptide for 24h. Cell viability was determined by the MTT assay. Apoptosis was assessed using phase contrast microscopy, by propidium iodide (PI) staining to assess nuclear morphology and by Annexin V staining...
October 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Xiao-Feng Tian, Guo-Min Huang, Hong-Liang Zang, Hong Cao
Previous studies have demonstrated the overexpression of paired basic amino acid cleaving enzyme 4 (PACE4) mRNA in prostate cancer tissues. This overexpression is correlated with higher circulating protein levels in certain patients, however, the role of PACE4 in apoptosis and the potential molecular mechanisms of pancreatic cancer remain to be elucidated. The aim of the present study was to investigate the effect and potential molecular mechanisms of PACE4 on apoptosis in the Panc‑1 pancreatic cancer cell line...
October 25, 2016: Molecular Medicine Reports
Wei Zhao, Xiaohui Zhang, Jia Liu, Bei Sun, Hua Tang, Hong Zhang
Metformin was demonstrated to have effects on breast cancer, and microRNA-27a (miR-27a) is a prognostic marker for breast cancer progression and patient survival. AMPKα2 was found to be a suppressor in breast cancer MCF-7 cells. Therefore, the present study aimed to explain this phenomenon in regards to the relationship between microRNAs (miRNAs) and their target genes and to predict how AMPKα2 may be a downstream target gene of miR-27a, thus exploring the new mechanism of metformin in the treatment of breast cancer regarding miRNAs...
October 24, 2016: Oncology Reports
Hua-Qiang Zhu, Jin-Ben Ma, Xie Song, Heng-Jun Gao, Chao-Qun Ma, Hong Chang, Hong-Guang Li, Fang-Feng Liu, Jun Lu, Xu Zhou
Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways...
October 20, 2016: Oncology Reports
Edgar Teddy Quispe-Soto, Gloria M Calaf
Global cancer burden increased to 14.1 million new cases in 2012; and breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012. Curcumin is the major bioactive ingredient extracted from the rhizome of the plant Curcuma longa (turmeric). Paclitaxel is a microtubule-stabilizing agent originally isolated from the bark of Taxus brevifolia. Curcumin and paclitaxel were evaluated with two human breast cancer cell lines as the luminal MCF-7 and the basal-like MDA-MB-231 that are either positive or negative for hormonal receptors estrogen receptor, progesterone receptor and HER2, respectively...
October 19, 2016: International Journal of Oncology
Changzheng Gao, Fen Wang, Zhiqiang Wang, Jing Zhang, Xiangjun Yang
The lactate signaling cascade has recently been linked to mitochondrial energy metabolism and cardiomyocyte apoptosis in several cardiovascular diseases. Asiatic acid (AA) exhibits a variety of pharmacological effects, including antioxidant and anti-apoptotic effects. In this study, we investigated the protective effects of AA against the lactate-induced apoptosis of cardiomyocytes, as well as its mechanisms of action. Neonatal rat cardiomyocytes were pre-treated with 20 µM AA for 24 h, followed by exposure to 20 mM lactate for a further 24 h...
October 20, 2016: International Journal of Molecular Medicine
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