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mtorc2 inhibitor

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https://www.readbyqxmd.com/read/29434241/streptomyces-sp-metabolite-s-promotes-bax-mediated-intrinsic-apoptosis-and-autophagy-involving-inhibition-of-mtor-pathway-in-cervical-cancer-cell-lines
#1
Vipin Mohan Dan, Balaji Muralikrishnan, Rahul Sanawar, Vinodh J S, Bhushan Bapusaheb Burkul, Kalanghad Puthankalam Srinivas, Asha Lekshmi, N S Pradeep, Syed G Dastager, B Santhakumari, Thankayyan R Santhoshkumar, R Ajay Kumar, Madhavan Radhakrishna Pillai
In cervical cancer, the association between HPV infection and dysregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) places mTOR as an attractive therapeutic target. The failure of current treatment modalities in advanced stages of this cancer and drawbacks of already available mTOR inhibitors demand for novel drug candidates. In the present study we identified the presence of a mTOR inhibitor in an active fraction of the ethyl acetate extract of Streptomyces sp OA293...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29432734/the-anti-osteosarcoma-cell-activity-by-a-mtorc1-2-dual-inhibitor-res-529
#2
Xujun Hu, Zirui Wang, Meikai Chen, Xuerong Chen, Wenqing Liang
mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation...
February 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428724/dual-inhibition-of-mtorc1-and-mtorc2-perturbs-cytoskeletal-organization-and-impairs-endothelial-cell-elongation
#3
Kiyomi Tsuji-Tamura, Minetaro Ogawa
Elongation of endothelial cells is an important process in vascular formation and is expected to be a therapeutic target for inhibiting tumor angiogenesis. We have previously demonstrated that inhibition of mTORC1 and mTORC2 impaired endothelial cell elongation, although the mechanism has not been well defined. In this study, we analyzed the effects of the mTORC1-specific inhibitor everolimus and the mTORC1/mTORC2 dual inhibitor KU0063794 on the cytoskeletal organization and morphology of endothelial cell lines...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29416044/a-small-molecule-inhibitor-of-rheb-selectively-targets-mtorc1-signaling
#4
Sarah J Mahoney, Sridhar Narayan, Lisa Molz, Lauren A Berstler, Seong A Kang, George P Vlasuk, Eddine Saiah
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29408410/the-role-of-mtor-mediated-signaling-in-the-regulation-of-cellular-migration
#5
REVIEW
Ailsa K Holroyd, Alison M Michie
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration...
February 3, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29402408/cc-223-inhibits-human-head-and-neck-squamous-cell-carcinoma-cell-growth
#6
Jun-Ying Wang, Xin Jin, Xin Zhang, Xiao-Feng Li
mTOR over-activation is associated with the progression of head and neck squamous cell carcinoma (HNSCC). CC-223 is a novel and potent mTOR kinase inhibitor. Its activity against human HNSCC cells is studied here. In established SCC-9 cells and primary human oral cavity carcinoma (OCC) cells, CC-223 treatment at only nM concentrations significantly inhibited survival, proliferation and cell cycle progression. Furthermore, CC-223 provoked apoptosis activation in human HNSCC cells. CC-223 is more efficient in killing HNSCC cells than other known Akt-mTOR inhibitors: RAD001, MK-2206 and AZD-2014...
January 31, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29384525/mtor-inhibitor-based-combination-therapies-for-pancreatic-cancer
#7
Zonera Hassan, Christian Schneeweis, Matthias Wirth, Christian Veltkamp, Zahra Dantes, Benedikt Feuerecker, Güralp O Ceyhan, Shirley K Knauer, Wilko Weichert, Roland M Schmid, Roland Stauber, Alexander Arlt, Oliver H Krämer, Roland Rad, Maximilian Reichert, Dieter Saur, Günter Schneider
BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance...
January 2, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29382726/otub1-suppresses-mtor-complex-1-mtorc1-activity-by-deubiquitinating-the-mtorc1-inhibitor-deptor
#8
Linlin Zhao, Xinbo Wang, Yue Yu, Lu Deng, Lei Chen, Xiaoping Peng, Chenchen Jiao, Guoli Gao, Xiao Tan, Weijuan Pan, Xin Ge, Ping Wang
Mechanistic target of rapamycin mTOR complex I (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of the mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which the DEPTOR stability is regulated are still elusive. Here, we report that OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR by a deubiquitination assay...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29378959/effects-of-rapamycin-on-growth-hormone-receptor-knockout-mice
#9
Yimin Fang, Cristal M Hill, Justin Darcy, Adriana Reyes-Ordoñez, Edwin Arauz, Samuel McFadden, Chi Zhang, Jared Osland, John Gao, Tian Zhang, Stuart J Frank, Martin A Javors, Rong Yuan, John J Kopchick, Liou Y Sun, Jie Chen, Andrzej Bartke
It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29371953/evaluation-of-the-combination-of-the-dual-m-torc1-2-inhibitor-vistusertib-azd2014-and-paclitaxel-in-ovarian-cancer-models
#10
Anne-Christine Wong Te Fong, Parames Thavasu, Sladjana Gagrica, Karen E Swales, Martin O Leach, Sabina C Cosulich, Yuen-Li Chung, Udai Banerji
Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel ( n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo ...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29358623/targeted-reduction-of-the-egfr-protein-but-not-inhibition-of-its-kinase-activity-induces-mitophagy-and-death-of-cancer-cells-through-activation-of-mtorc2-and-akt
#11
Rajasekhara Reddy Katreddy, Lakshmi Reddy Bollu, Fei Su, Na Xian, Shivangi Srivastava, Rintu Thomas, Yubing Dai, Bing Wu, Yunlu Xu, Michael A Rea, James M Briggs, Qingyuan Zhang, Xiongbin Lu, Gangxiong Huang, Zhang Weihua
The oncogenic epidermal growth factor receptor (EGFR) is commonly overexpressed in solid cancers. The tyrosine kinase activity of EGFR has been a major therapeutic target for cancer; however, the efficacy of EGFR tyrosine kinase inhibitors to treat cancers has been challenged by innate and acquired resistance at the clinic. Accumulating evidence suggests that EGFR possesses kinase-independent pro-survival functions, and that cancer cells are more vulnerable to reduction of EGFR protein than to inhibition of its kinase activity...
January 23, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29358172/selective-mtorc2-inhibitor-therapeutically-blocks-breast-cancer-cell-growth-and-survival
#12
Thomas A Werfel, Shan Wang, Meredith A Jackson, Taylor E Kavanaugh, Meghan Morrison Joly, Linus Lee, Donna J Hicks, Violeta Sanchez, Paula I Gonzalez-Ericsson, Kameron V Kilchrist, Somtochukwu C Dimobi, Samantha M Sarett, Dana M Brantley-Sieders, Rebecca S Cook, Craig Duvall
Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date...
January 22, 2018: Cancer Research
https://www.readbyqxmd.com/read/29357370/parallel-pi3k-akt-and-mtor-inhibition-is-required-to-control-feedback-loops-that-limit-tumor-therapy
#13
Anuja Sathe, Géraldine Chalaud, Immanuel Oppolzer, Kit Yeng Wong, Margarita von Busch, Sebastian C Schmid, Zhichao Tong, Margitta Retz, Juergen E Gschwend, Wolfgang A Schulz, Roman Nawroth
Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences...
2018: PloS One
https://www.readbyqxmd.com/read/29344639/therapeutic-potential-of-a-dual-mtorc1-2-inhibitor-for-the-prevention-of-posterior-capsule-opacification-an-in-vitro-study
#14
Hao Feng, Zhibo Yang, Xue Bai, Meirong Yang, Yuan Fang, Xiaonan Zhang, Qiqiang Guo, Hong Ning
Mammalian target of rapamycin (mTOR) serves a central role in regulating cell growth and survival, and has been demonstrated to be involved in the pathological progression of posterior capsule opacification (PCO). In the present study, the potency of PP242, a novel dual inhibitor of mTOR complex 1/2 (mTORC1/2), in the suppression of the growth of human lens epithelial cells (HLECs) was investigated. Using a Cell Counting Kit‑8 and a wound healing assay, it was demonstrated that PP242 inhibited the proliferation and migration of HLECs...
January 18, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29251327/survival-pathway-of-cholangiocarcinoma-via-akt-mtor-signaling-to-escape-raf-mek-erk-pathway-inhibition-by-sorafenib
#15
Kenta Yokoi, Akira Kobayashi, Hiroaki Motoyama, Masato Kitazawa, Akira Shimizu, Tsuyoshi Notake, Takahide Yokoyama, Tomio Matsumura, Michiko Takeoka, Shin-Ichi Miyagawa
Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29245915/curcumin-interacts-with-sildenafil-to-kill-gi-tumor-cells-via-endoplasmic-reticulum-stress-and-reactive-oxygen-nitrogen-species
#16
Jane L Roberts, Andrew Poklepovic, Laurence Booth
The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by ∼50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2α-dependent fashion...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242283/phase-ii-study-of-bez235-versus-everolimus-in-patients-with-mammalian-target-of-rapamycin-inhibitor-na%C3%A3-ve-advanced-pancreatic-neuroendocrine-tumors
#17
Ramon Salazar, Rocio Garcia-Carbonero, Steven K Libutti, Andrew E Hendifar, Ana Custodio, Rosine Guimbaud, Catherine Lombard-Bohas, Sergio Ricci, Heinz-Josef Klümpen, Jaume Capdevila, Nicholas Reed, Annemiek Walenkamp, Enrique Grande, Sufiya Safina, Tim Meyer, Oliver Kong, Herve Salomon, Ranjana Tavorath, James C Yao
LESSONS LEARNED: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy...
December 14, 2017: Oncologist
https://www.readbyqxmd.com/read/29207163/preclinical-analysis-of-mtor-complex-1-2-inhibition-in-diffuse-intrinsic-pontine-glioma
#18
Patrick C Flannery, John A DeSisto, Vladimir Amani, Sujatha Venkataraman, Rakeb T Lemma, Eric W Prince, Andrew Donson, Erin E Moroze, Lindsey Hoffman, Jean M Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam L Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy...
November 29, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29204135/recombinant-uncarboxylated-osteocalcin-per-se-enhances-mouse-skeletal-muscle-glucose-uptake-in-both-extensor-digitorum-longus-and-soleus-muscles
#19
Xuzhu Lin, Lewan Parker, Emma Mclennan, Xinmei Zhang, Alan Hayes, Glenn McConell, Tara C Brennan-Speranza, Itamar Levinger
Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29195143/metabolite-identification-and-pharmacokinetic-profiling-of-pp242-an-atp-competitive-inhibitor-of-mtor-using-ultra-high-performance-liquid-chromatography-and-mass-spectrometry
#20
Md Mamunur Rashid, Hyunbeom Lee, Byung Hwa Jung
PP242 is a second generation novel selective ATP-competitive inhibitor of mTOR that displayed promising anti-cancer activity over several cancer types by inhibiting both the complexes of mTOR (mTORC1 and mTORC2). The purpose of this study is to identify the possible metabolites and to evaluate the pharmacokinetic profile of PP242 after a single oral administration to Sprague-Dawley (SD) rats. Two metabolites, including one phase I and one phase II, were identified by in vitro and in vivo studies using rat liver microsomes (RLMs) as well as rat plasma, urine and feces, respectively, through ultra high-performance liquid chromatography-linear ion trap quadrupole-orbitrap-mass spectrometry (UHPLC-LTQ-Orbitrap-MS)...
November 23, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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