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https://www.readbyqxmd.com/read/29928488/mechanisms-for-mtorc1-activation-and-synergistic-induction-of-apoptosis-by-ruxolitinib-and-bh3-mimetics-or-autophagy-inhibitors-in-jak2-v617f-expressing-leukemic-cells-including-newly-established-pvtl-2
#1
Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Keigo Okada, Ayako Nogami, Gaku Oshikawa, Toshikage Nagao, Osamu Miura
The activated JAK2-V617F mutant is very frequently found in myeloproliferative neoplasms (MPNs), and its inhibitor ruxolitinib has been in clinical use, albeit with limited efficacies. Here, we examine the signaling mechanisms from JAK2-V617F and responses to ruxolitinib in JAK2-V617F-positive leukemic cell lines, including PVTL-2, newly established from a patient with post-MPN secondary acute myeloid leukemia, and the widely used model cell line HEL. We have found that ruxolitinib downregulated the mTORC1/S6K/4EBP1 pathway at least partly through inhibition of the STAT5/Pim-2 pathway with concomitant downregulation of c-Myc, MCL-1, and BCL-xL as well as induction of autophagy in these cells...
June 1, 2018: Oncotarget
https://www.readbyqxmd.com/read/29928066/ppar%C3%AE-is-critical-for-mycobacterium-tuberculosis-induction-of-mcl-1-and-limitation-of-human-macrophage-apoptosis
#2
Eusondia Arnett, Ashlee M Weaver, Kiersten C Woodyard, Maria J Montoya, Michael Li, Ky V Hoang, Andrew Hayhurst, Abul K Azad, Larry S Schlesinger
Peroxisome proliferator-activated receptor (PPAR)γ is a global transcriptional regulator associated with anti-inflammatory actions. It is highly expressed in alveolar macrophages (AMs), which are unable to clear the intracellular pathogen Mycobacterium tuberculosis (M.tb). Although M.tb infection induces PPARγ in human macrophages, which contributes to M.tb growth, the mechanisms underlying this are largely unknown. We undertook NanoString gene expression analysis to identify novel PPARγ effectors that condition macrophages to be more susceptible to M...
June 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29924888/nitidine-chloride-represses-mcl-1-protein-via-lysosomal-degradation-in-oral-squamous-cell-carcinoma
#3
In-Hyoung Yang, Won Jung, Lee-Han Kim, Ji-Ae Shin, Nam-Pyo Cho, Seong Doo Hong, Kyoung-Ok Hong, Sung-Dae Cho
BACKGROUND: We have shown previously that nitidine chloride (NC) induces apoptosis via inhibition of signal transducer and activator of transcription 3 (STAT3). However, its downstream molecules are not fully understood yet. Here we report that NC as STAT3 inhibitor down-regulates myeloid cell leukemia-1 (Mcl-1) protein in HSC-3 and HSC-4 human oral squamous cell carcinoma (OSCC) cells and a nude mouse tumor xenograft model. METHODS: This study investigated the effects of NC on Mcl-1 expression in HSC-3 and HSC-4 cells using Western blotting, RT-PCR, and Dual-luciferase assay...
June 20, 2018: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/29924730/selective-bh3-mimetics-targeting-bcl-2-bcl-xl-or-mcl-1-induce-severe-mitochondrial-perturbations
#4
Kristina Henz, Aoula Al-Zebeeby, Marion Basoglu, Simone Fulda, Gerald M Cohen, Shankar Varadarajan, Meike Vogler
Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure...
June 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29921883/annonaceous-acetogenin-mimic-aa005-suppresses-human-colon-cancer-cell-growth-in-vivo-through-downregulation-of-mcl-1
#5
Bing Han, Yu-Xia Cao, Zhan-Ming Li, Zhao-Xia Wu, Yu-Qin Mao, Hui-Ling Chen, Zhu-Jun Yao, Li-Shun Wang
Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i...
June 19, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29921126/increasing-enzyme-stability-and-activity-through-hydrogen-bond-enhanced-halogen-bonds
#6
Anna-Carin C Carlsson, Matthew R Scholfield, Rhianon Kay Rowe, Melissa Coates Ford, Austin T Alexander, Ryan A Mehl, Pui Shing Ho
The construction of more stable proteins is important in biomolecular engineering, particularly in the design of biologics based therapeutics. We show here that replacing the tyrosine at position 18 (Y18) of T4 lysozyme with the unnatural amino acid meta-chlorotyrosine (mCl Y) increases both the thermal stability (raising the melting temperature by ~1°C and melting enthalpy by 3 kcal/mol) and enzymatic activity at elevated temperatures (15% higher than the parent enzyme at 40°C) of this classic enzyme. The chlorine of mCl Y forms a halogen bond (XB) to the carbonyl oxygen of the peptide bond at glycine 28 (G28) in a tight loop near the active site...
June 19, 2018: Biochemistry
https://www.readbyqxmd.com/read/29916268/anti-gpc3-antibody-modified-sorafenib-loaded-nanoparticles-significantly-inhibited-hepg2-hepatocellular-carcinoma
#7
Xiaolong Tang, Longzhou Chen, Amin Li, Shiyu Cai, Yinci Zhang, Xueke Liu, Zhenyou Jiang, Xinkuang Liu, Yong Liang, Dong Ma
Sorafenib (SFB) has improved the treatment of hepatocellular carcinoma (HCC) and has fewer severe side effects than other agents used for that purpose. However, due to a lack of tumor-specific targeting, the concentration of the drug in tumor tissue cannot be permanently maintained at a level that inhibits tumor growth. To overcome this problem, we developed a novel SFB-loaded polymer nanoparticle (NP). The NP (a TPGS-b-PCL copolymer that was synthesized from ε-caprolactone and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via ring-opening polymerization) contains Pluronic P123 and SFB, and its surface is modified with anti-GPC3 antibody to produce the polymer nanoparticle (NP-SFB-Ab)...
November 2018: Drug Delivery
https://www.readbyqxmd.com/read/29915371/inhibitory-effects-of-isocryptotanshinone-on-gastric-cancer
#8
Zhang-Ming Chen, Lei Huang, Miao-Miao Li, Lei Meng, Song-Cheng Ying, A-Man Xu
Gastric cancer (GC) is one of the most common digestive malignancies globally, and the prognosis of patients with advanced tumors remains poor. Isocryptotanshinone (ICTS), isolated from Salvia miltiorrhiza, was found to inhibit the proliferation of lung and breast cancer cells. However, whether ICTS has anticancer activities against GC is unknown. In the present study, we reported that the proliferation of GC cells was inhibited by ICTS in a dose- and time-dependent manner. After treatment with ICTS, GC cells were arrested in the G1/G0 phase of cell cycle and the apoptotic cells were induced in a dose-dependent manner...
June 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29914872/metformin-and-jq1-synergistically-inhibit-obesity-activated-thyroid-cancer
#9
Sunmi Park, Mark Willingham, Jun Qi, Sheue-Yann Cheng
Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/- mice). The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. The ThrbPV/PVPten+/- mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics...
June 18, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29912596/understanding-resistance-mechanisms-to-btk-and-bcl2-inhibitors-in-mantle-cell-lymphoma-implications-for-design-of-clinical-trials
#10
Rishu Agarwal, Mark A Dawson, Martin Dreyling, Constantine S Tam
Novel targeted therapeutics has significantly improved the outlook of patients with relapsed/refractory mantle cell lymphoma (R/R MCL). Despite significant efficacy, one of the major limitations of these targeted agents is presence of primary or acquired resistance to these novel drugs. Patients who fail primary therapy especially with ibrutinib have poor outcomes and may respond poorly to subsequent therapies. Hence, it is important to understand resistance mechanisms a priori to identify patients who are unlikely to respond, and to explore alternative therapeutic strategies...
June 18, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29912594/deferred-treatment-is-a-safe-and-viable-option-for-selected-patients-with-mantle-cell-lymphoma
#11
Oscar Calzada, Jeffrey M Switchenko, Joseph J Maly, Kristie A Blum, Natalie Grover, Stephanie Mathews, Steven I Park, Max Gordon, Alexey Danilov, Narendranath Epperla, Timothy S Fenske, Mehdi Hamadani, Christopher R Flowers, Jonathon B Cohen
Prospective identification of candidates for deferred therapy is not standardized and many patients receive immediate therapy regardless of risk. We conducted a retrospective, multi-center cohort analysis of MCL patients with comprehensive clinical data to examine the use and safety of deferred therapy for newly diagnosed patients. Previously untreated patients ≥18 years-old with MCL diagnosed in 1993-2015 at five academic sites were included. Of 395 patients, 72 (18%) received deferred therapy (defined as receipt of first treatment >90 days following initial diagnosis)...
June 18, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29910833/cryptococcal-meningoencephalitis-in-patients-with-mantle-cell-lymphoma-on-ibrutinib
#12
Kai Sun, Saro Kasparian, Swaminathan Iyer, Sai Ravi Pingali
Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been increasingly widely used in relapsed and refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia [1, 2]. With its use becoming more common, there have been emerging case reports of opportunistic infections like cryptococcal infections [3-8]. These infections in patients receiving ibrutinib were mostly reported in patients with chronic lymphocytic leukaemia, who have poor immune reconstitution. Here, we report two cases of cryptococcal meningoencephalitis in patients with MCL on ibrutinib...
2018: Ecancermedicalscience
https://www.readbyqxmd.com/read/29906621/deoxynivalenol-decreased-the-growth-performance-and-impaired-intestinal-physical-barrier-in-juvenile-grass-carp-ctenopharyngodon-idella
#13
Chen Huang, Pei Wu, Wei-Dan Jiang, Yang Liu, Yun-Yun Zeng, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
Deoxynivalenol (DON) is one of the most common mycotoxin contaminants of animal feed worldwide and brings significant threats to the animal production. However, studies concerning the effect of DON on fish intestine are scarce. This study explored the effects of DON on intestinal physical barrier in juvenile grass carp (Ctenopharyngodon idella). A total of 1440 juvenile grass carp (12.17 ± 0.01 g) were fed six diets containing graded levels of DON (27, 318, 636, 922, 1243 and 1515 μg/kg diet) for 60 days...
June 12, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29901111/dihydrocelastrol-exerts-potent-antitumor-activity-in-mantle-cell-lymphoma-cells-via-dual-inhibition-of-mtorc1-and-mtorc2
#14
Yongsheng Xie, Bo Li, Wenxuan Bu, Lu Gao, Yong Zhang, Xiucai Lan, Jun Hou, Zhijian Xu, Shuaikang Chang, Dandan Yu, Bingqian Xie, Yingcong Wang, Houcai Wang, Yiwen Zhang, Xiaosong Wu, Weiliang Zhu, Jumei Shi
Mantle cell lymphoma (MCL) is a distinct and highly aggressive subtype of B-cell non-Hodgkin lymphoma. Dihydrocelastrol (DHCE) is a dihydro-analog of celastrol, which is isolated from the traditional Chinese medicinal plant Tripterygium wilfordii. The present study aimed to investigate the effects of DHCE treatment on MCL cells, and to determine the mechanism underlying its potent antitumor activity in vitro and in vivo using the Cell Counting kit-8 assay, clonogenic assay, apoptosis assay, cell cycle analysis, immunofluorescence staining, western blotting and tumor xenograft models...
June 12, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29901084/plumbagin-a-natural-naphthoquinone-inhibits-the-growth-of-esophageal-squamous-cell-carcinoma-cells-through-inactivation-of-stat3
#15
Yan Cao, Xiang Yin, Yiping Jia, Bingyan Liu, Shaoqiu Wu, Mingyi Shang
Although plumbagin, a natural naphthoquinone, has exhibited antiproliferative activity in numerous types of cancer, its anticancer potential in esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, the effect of plumbagin on the growth of ESCC cells was investigated in vitro and in vivo. ESCC cells were treated with plumbagin and tested for cell cycle distribution and apoptosis. The involvement of STAT3 signaling in the effect of plumbagin was examined. The results demonstrated that plumbagin treatment suppressed ESCC cell viability and proliferation, yet normal esophageal epithelial cell viability was not affected...
June 7, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29901068/mitotic-kinase-pbk-topk-as-a-therapeutic-target-for-adult-t%C3%A2-cell-leukemia-lymphoma
#16
Chie Ishikawa, Masachika Senba, Naoki Mori
Adult T‑cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV‑1)-infected T‑cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T‑lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT‑PCR...
June 1, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29899871/folic-acid-conjugated-mesoporous-silica-particles-as-nanocarriers-of-natural-prodrugs-for-cancer-targeting-and-antioxidant-action
#17
Khaled AbouAitah, Anna Swiderska-Sroda, Ahmed A Farghali, Jacek Wojnarowicz, Agata Stefanek, Stanislaw Gierlotka, Agnieszka Opalinska, Abdou K Allayeh, Tomasz Ciach, Witold Lojkowski
Naturally derived prodrugs have a wide range of pharmacological activities, including anticancer, antioxidant, and antiviral effects. However, significant barriers inhibit their use in medicine, e.g. their hydrophobicity. In this comprehensive study, we investigated simple and effective nanoformulations consisting of amine-functionalized and conjugated with folic acid (FA) mesoporous silica nanoparticles (MSNs). Two types of MSNs were studied: KCC- 1, with mean size 324 nm and mean pore diameter 3.4 nm, and MCM - 41, with mean size 197 and pore diameter 2 nm...
May 29, 2018: Oncotarget
https://www.readbyqxmd.com/read/29899826/synthetic-lethality-in-ccne1-amplified-high-grade-serous-ovarian-cancer-through-combined-inhibition-of-polo-like-kinase-1-and-microtubule-dynamics
#18
Sabrina Noack, Monika Raab, Yves Matthess, Mourad Sanhaji, Andrea Krämer, Balázs Győrffy, Lars Kaderali, Ahmed El-Balat, Sven Becker, Klaus Strebhardt
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1 -amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1 -amplified HGSOC cells that may influence clinical paclitaxel response...
May 25, 2018: Oncotarget
https://www.readbyqxmd.com/read/29899555/magnolin-promotes-autophagy-and-cell-cycle-arrest-via-blocking-lif-stat3-mcl-1-axis-in-human-colorectal-cancers
#19
Haiyang Yu, Shuangshuang Yin, Shiyue Zhou, Yingying Shao, Jiachen Sun, Xu Pang, Lifeng Han, Yi Zhang, Xiumei Gao, Chengyun Jin, Yuling Qiu, Tao Wang
Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1...
June 13, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29896158/prebiotics-supplementation-impact-on-the-reinforcing-and-motivational-aspect-of-feeding
#20
Anne-Sophie Delbès, Julien Castel, Raphaël G P Denis, Chloé Morel, Mar Quiñones, Amandine Everard, Patrice D Cani, Florence Massiera, Serge H Luquet
Energy homeostasis is tightly regulated by the central nervous system which responds to nervous and circulating inputs to adapt food intake and energy expenditure. However, the rewarding and motivational aspect of food is tightly dependent of dopamine (DA) release in mesocorticolimbic (MCL) system and could be operant in uncontrolled caloric intake and obesity. Accumulating evidence indicate that manipulating the microbiota-gut-brain axis through prebiotic supplementation can have beneficial impact of the host appetite and body weight...
2018: Frontiers in Endocrinology
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