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mTOR inhibitors

Delia De Lisi, Ugo De Giorgi, Cristian Lolli, Giuseppe Schepisi, Vincenza Conteduca, Cecilia Menna, Giuseppe Tonini, Daniele Santini, Alberto Farolfi
To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway...
March 20, 2018: Expert Opinion on Drug Metabolism & Toxicology
Yan Sun, Yong-Hao Huang, Feng-Ying Huang, Wen-Li Mei, Quan Liu, Cai-Chun Wang, Ying-Ying Lin, Canhua Huang, Yue-Nan Li, Hao-Fu Dai, Guang-Hong Tan
Rationale: Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells. Methods: Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry...
2018: Theranostics
Jun Zhang, Xiaohong Xiang, Shuangshuang Shu, Cuiling Zhang, Yuling Liang, Tingting Jiang, Wenying Zhang, Tingting Guo, Xiujie Liang, Xun Tang
It is well known that autophagy serves a crucial role in renal tubular epithelial cell (RTEC) injury in the pathogenesis of chronic kidney disease (CKD). The accumulation of advanced oxidation protein products (AOPPs) also participates in the progression of CKD. However, the effects of AOPPs on autophagy remain unknown. To clarify the underlying mechanism of RTEC injury in CKD, the effect of AOPPs on HK-2 cells, an RTEC cell line, was investigated. The results of the present study revealed that AOPP exposure downregulated the expression of B-cell lymphoma-2-interacting myosin-like coiled-coil protein 1, reduced the conversion of microtubule-associated proteins 1 light chain 3B (LC3)-I to LC3-II and the formation of autophagosomes, and lead to an accumulation of p62...
April 2018: Experimental and Therapeutic Medicine
Wasim Khan, Brian T Layden, Partha Chakrabarti
Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial energy metabolism and modulates activity of mammalian/mechanistic target of rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for certain types of cancer but with limited success. Since glutamine is essential for growth of many cancers, we reasoned that glutamine deprivation under conditions of mTOR inhibition should be more detrimental to cancer cell survival. However, our results show that when cells are deprived of glutamine concomitant with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which aids in their survival due to enhanced autophagic flux...
March 16, 2018: Biochimica et Biophysica Acta
Eun Jeong Jang, Sang Chan Kim, Ju-Hee Lee, Jong Rok Lee, Il Kon Kim, Su Youn Baek, Young Woo Kim
BACKGROUND: Laminaria japonica has frequently been used as a food supplement and drug in traditional oriental medicine. Among the major active constituents responsible for the bioactivities of L. japonica, fucoxanthin (FX) has been considered as a potential antioxidant. This study was conducted to examine the effects of L. japonica extract (LJE) or FX against oxidative stress on hepatocytes and to elucidate the overall their cellular mechanisms of the effects. METHODS: We constructed an in vitro model with the treatment of arachidonic acid (AA) + iron in HepG2 cells to stimulate the oxidative damage...
March 20, 2018: BMC Complementary and Alternative Medicine
Jie Lei, Lei Zhao, Yujing Zhang, Yanfeng Wu, Yanbo Liu
BACKGROUND/AIMS: The mechanisms by which high glucose (HG) results in podocyte damage remains unclear. We investigated the potential role of endoplasmic reticulum (ER) stress and mTOR signaling in HG injured podocyte. METHODS: In cultured mouse podocytes, cellular apoptosis was assessed using FITC-Annexin V and propidium iodide staining followed by flow cytometry analysis. Apoptosis-related proteins as well as the ER stress and the mTOR signals were evaluated using immunoblot assay...
March 15, 2018: Cellular Physiology and Biochemistry
Chie Ishikawa, Masachika Senba, Naoki Mori
Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). In ATL, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP-BKM120 (a pan-PI3K inhibitor) and NVP-BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV-1-infected T-cell lines were compared...
April 2018: Oncology Letters
Sheng Peng, Hong-Zhu Yan, Pei-Rong Liu, Xiao-Wei Shi, Chun-Liang Liu, Qi Liu, Yu Zhang
BACKGROUND/AIMS: Sevoflurane, a commonly used volatile anesthetic, recently has been found has neurotoxicity in the central nervous system of neonatal rodents. This study aimed to reveal whether phosphodiesterase 4 (PDE-4) inhibitor roflumilast has protective functions in sevoflurane-induced nerve damage. METHODS: Hippocampal neurons were isolated from juvenile rats, and were exposed to sevoflurane with or without roflumilast treatment. Cell viability and apoptosis were respectively assessed by CCK-8 and flow cytometry...
March 13, 2018: Cellular Physiology and Biochemistry
Arianna L Kim, Jung Ho Back, Sandeep C Chaudhary, Yucui Zhu, Mohammad Athar, David R Bickers
Currently available SMO targeted therapies in patients with basal cell nevus syndrome (BCNS) are associated with substantial tumor recurrence and clinical resistance. Strategies bypassing SMO and/or identifying additional downstream components of the Hedgehog (Hh) pathway could provide novel anti-tumor targets with a better therapeutic index. SOX9 is a Hh/GLI-regulated transcription factor known to be overexpressed in BCCs. A sequence motif search for SOX9-responsive elements identified three motifs in the promoter region of mTOR...
March 14, 2018: Journal of Investigative Dermatology
Jennifer R Brown, Mehdi Hamadani, John Hayslip, Ann Janssens, Nina Wagner-Johnston, Oliver Ottmann, Jon Arnason, Hervé Tilly, Michael Millenson, Fritz Offner, Nashat Y Gabrail, Siddhartha Ganguly, Sikander Ailawadh, Siddha Kasar, Arnon P Kater, Jeanette K Doorduijn, Lei Gao, Joanne J Lager, Bin Wu, Coumaran Egile, Marie José Kersten
BACKGROUND: Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. METHODS: We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia...
March 14, 2018: Lancet Haematology
Wataru Munakata, Kensei Tobinai
No abstract text is available yet for this article.
March 14, 2018: Lancet Haematology
Qinghong Zheng, Xiaohong Peng, Hai Yu
BACKGROUND: Apart from the known anesthetic and antiarrhythmic effects, recent studies also highlight the anticancer activities of local anesthetics. In line with the findings, our work shows that ropivacaine, an amide-linked local anesthetic drug, targets chronic myeloid leukemia (CML) via inhibiting PI3K/Akt/mTOR. MATERIALS AND METHODS: The effects of ropivacaine in CML cell lines and primary stem or progenitor cells were investigated using apoptosis, proliferation and colony formation assays...
March 2018: American Journal of the Medical Sciences
C Ranieri, S Di Tommaso, D C Loconte, V Grossi, P Sanese, R Bagnulo, F C Susca, G Forte, A Peserico, A De Luisi, A Bartuli, A Selicorni, D Melis, M Lerone, A D Praticò, G Abbadessa, Y Yu, B Schwartz, Martino Ruggieri, Cristiano Simone, Nicoletta Resta
Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present...
March 16, 2018: Neurogenetics
Dong-Keon Lee, Ji-Hee Kim, Joohwan Kim, Seunghwan Choi, MinSik Park, Wonjin Park, Suji Kim, Kyu-Sun Lee, Taesam Kim, Jiwon Jung, Yoon Kyung Choi, Kwon-Soo Ha, Moo-Ho Won, Timothy R Billiar, Young-Guen Kwon, Young-Myeong Kim
Regulated in development and DNA damage responses (REDD)-1, an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/- macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation...
March 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Babita Saigal, Laura Guerra
BACKGROUND: A common class-specific toxicity of mammalian target of rapamycin (mTOR) inhibitors is stomatitis. Some patients experience a severe form of mTOR inhibitor-associated stomatitis (mIAS) that can have a negative effect on nutritional status, compromise quality of life, and potentially lead to nonadherence, reducing the efficacy of cancer therapy. OBJECTIVES: This article aims to address an unmet need for education about mIAS among oncology nurses and patients and to share findings about everolimus-related stomatitis from the SWISH trial...
April 1, 2018: Clinical Journal of Oncology Nursing
Huan Gao, Yue Zhang, Lei Dong, Xiao-Yu Qu, Li-Na Tao, Yue-Ming Zhang, Jing-Hui Zhai, Yan-Qing Song
To investigate the effects of triptolide (TPI) on proliferation, autophagy and death in human breast cancer MCF-7 cells, and to elucidate the associated molecular mechanisms, intracellular alterations were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays. The results of the MTT assay revealed that TPI significantly reduced the MCF-7 cell survival rate when the concentration was >10 nmol/l. TPI activated a caspase cascade reaction by regulating Bcl-2-associated X protein (Bax), caspase-3 and B-cell lymphoma 2 expression, and promoted programmed cell death via the mitochondrial pathway...
April 2018: Experimental and Therapeutic Medicine
Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors...
2018: Frontiers in Pharmacology
Sofie Ellebæk Pollmann, Valerie S Calvert, Shruti Rao, Simina M Boca, Subha Madhavan, Ivan D Horak, Andreas Kjaer, Emanuel F Petricoin, Michael Kragh, Thomas Tuxen Poulsen
Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting non-overlapping epitopes of MET...
March 15, 2018: Molecular Cancer Therapeutics
Maioli E, Daveri E, Maellaro E, Ietta F, Cresti L, Valacchi G
In the past few years, we focused the interest on rottlerin, an old/new natural substance that, over the time, has revealed a number of cellular and molecular targets, all potentially implicated in the fight against cancer. Past and recent literature well demonstrated that rottlerin is an inhibitor of enzymes, transcription factors and signaling molecules that control cancer cell life and death. Although the rottlerin anticancer activity has been mainly ascribed to apoptosis and/or autophagy induction, recent findings unveiled the existence of additional mechanisms of toxicity...
March 12, 2018: Archives of Biochemistry and Biophysics
Hyun-Jung Moon, Hak-Bong Kim, Su-Hoon Lee, So-Eun Jeun, Chi-Dug Kang, Sun-Hee Kim
NSAIDs (non-steroidal anti-inflammatory drugs) have potential use as anticancer agents, either alone or in combination with other cancer therapies. We found that NSAIDs including celecoxib (CCB) and ibuprofen (IBU) significantly potentiated the cytotoxicity of Hsp90 inhibitors in human multidrug-resistant (MDR) cells expressing high levels of mutant p53 (mutp53) protein and P-glycoprotein (P-gp), and reversed Hsp90 inhibitor resistance caused by activation of heat shock factor 1 (HSF1) and by up-regulation of heat shock proteins (Hsps) and P-gp...
February 16, 2018: Oncotarget
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