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Autophagy leukemia

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https://www.readbyqxmd.com/read/28435223/efficacy-of-the-dual-pi3k-and-mtor-inhibitor-nvp-bez235-in-combination-with-imatinib-mesylate-against-chronic-myelogenous-leukemia-cell-lines
#1
Pengliang Xin, Chuntuan Li, Yan Zheng, Qunyi Peng, Huifang Xiao, Yuanling Huang, Xiongpeng Zhu
BACKGROUND: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation, apoptosis, and autophagy of chronic myelogenous leukemia (CML) cells and sensitivity of tyrosine kinase inhibitor in vitro. METHODS: Two human CML cell lines, K562 and KBM7R (T315I mutant strain), were used. The proliferation of CML cells was detected by MTS (Owen's reagent) assay...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28424408/synthetic-lethality-of-glutaminolysis-inhibition-autophagy-inactivation-and-asparagine-depletion-in-colon-cancer
#2
Jiaqiu Li, Ping Song, Liyuan Zhu, Neelum Aziz, Qiyin Zhou, Yulong Zhang, Wenxia Xu, Lifeng Feng, Dingwei Chen, Xian Wang, Hongchuan Jin
Cancer cells reprogram metabolism to coordinate their rapid growth. They addict on glutamine metabolism for adenosine triphosphate generation and macromolecule biosynthesis. In this study, we report that glutamine deprivation retarded cell growth and induced prosurvival autophagy. Autophagy inhibition by chloroquine significantly enhanced glutamine starvation induced growth inhibition and apoptosis activation. Asparagine deprivation by L-asparaginase exacerbated growth inhibition induced by glutamine starvation and autophagy blockage...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415750/xanthohumol-induces-paraptosis-of-leukemia-cells-through-p38-mitogen-activated-protein-kinase-signaling-pathway
#3
Xiangquan Mi, Chunming Wang, Chao Sun, Xu Chen, Xiang Huo, Yiming Zhang, Gang Li, Bo Xu, Jun Zhang, Jianxin Xie, Zhenhua Wang, Ji Li
Xanthohumol as a natural polyphenol demonstrates an anticancer activity, but its underlying mechanism remains unclear. In this study, we showed that xanthohumol (XN) induces paraptosis of leukemia cells. The paraptosis is one cell death which is characterized by dilation of the endoplasmic reticulum and/or mitochondria. The results demonstrated that XN treatment significantly inhibited cell proliferation and triggered extensive cytoplasmic vacuolation of HL-60 leukemia cells, but it did not cause the cleavage of caspase-3 protein or apoptosis...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407594/trifluoromethyl-arylamides-with-antileukemia-effect-and-intracellular-inhibitory-activity-over-serine-arginine-rich-protein-kinases-srpks
#4
Raoni Pais Siqueira, Marcus Vinícius de Andrade Barros, Éverton de Almeida Alves Barbosa, Thiago Souza Onofre, Victor Hugo Sousa Gonçalves, Higor Sette Pereira, Abelardo Silva Júnior, Leandro Licursi de Oliveira, Márcia Rogéria Almeida, Juliana Lopes Rangel Fietto, Róbson Ricardo Teixeira, Gustavo Costa Bressan
The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28404874/identification-of-jl1037-as-a-novel-specific-reversible-lysine-specific-demethylase-1-inhibitor-that-induce-apoptosis-and-autophagy-of-aml-cells
#5
Shuang Liu, Wenting Lu, Shouyun Li, Saisai Li, Jia Liu, Yuanyuan Xing, Shuzu Zhang, Joe Zhongxiang Zhou, Haiyan Xing, Yingxi Xu, Qing Rao, Chengjun Deng, Min Wang, Jianxiang Wang
Lysine-specific demethylase 1 (LSD1) has been recognized as a potential therapeutic target for acute myeloid leukemia (AML). Herein, we identified a novel LSD1 inhibitor, JL1037, via Computer Aided Drug Design technology. JL1037 is a potent, selective and reversible LSD1 inhibitor with IC50s of 0.1 μM and >1.5 μM for LSD1 and monoamine oxidases A/B (MAO-A/B), respectively. Treatment of THP-1 and Kasumi-1 cell lines with JL1037 resulted in dose dependent accumulation of H3K4me1 and H3K4me2, the major substrates of LSD1, as well as inhibition of cell proliferation, blockade of cell cycle and induction of apoptosis...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401217/activation-of-autophagy-by-elevated-reactive-oxygen-species-rather-than-released-silver-ions-promotes-cytotoxicity-of-polyvinylpyrrolidone-coated-silver-nanoparticles-in-hematopoietic-cells
#6
Lingying Zhu, Dawei Guo, Lili Sun, Zhihai Huang, Xiuyan Zhang, Wenjuan Ma, Jie Wu, Lun Xiao, Yun Zhao, Ning Gu
Silver nanoparticles (AgNPs) are the most commonly used engineered nanomaterials in commercialized products because of their antimicrobial activity. Previously, we have shown that polyvinylpyrrolidone (PVP)-coated AgNPs have an anti-leukemia effect against human myeloid leukemia cells; however, whether AgNPs are able to trigger autophagy in normal hematopoietic cells and the role of autophagy in AgNP-induced cytotoxicity remain unclear. In the current study, we observed that AgNPs were taken up by murine pro-B cells (Ba/F3), and then promoted accumulation of autophagosomes, which resulted from the induction of autophagy rather than the blockade of autophagic flux...
April 12, 2017: Nanoscale
https://www.readbyqxmd.com/read/28392570/human-t-cell-lymphotropic-virus-type-1-and-its-oncogenesis
#7
REVIEW
Lan-Lan Zhang, Jing-Yun Wei, Long Wang, Shi-le Huang, Ji-Long Chen
Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), a rapidly progressing clonal malignancy of CD4+ T lymphocytes. Exploring the host-HTLV-1 interactions and the molecular mechanisms underlying HTLV-1-mediated tumorigenesis is critical for developing efficient therapies against the viral infection and associated leukemia/lymphoma. It has been demonstrated to date that several HTLV-1 proteins play key roles in the cellular transformation and immortalization of infected T lymphocytes...
April 10, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28390196/pi3k-isoform-inhibition-associated-with-anti-bcr-abl-drugs-shows-in-vitro-increased-anti-leukemic-activity-in-philadelphia-chromosome-positive-b-acute-lymphoblastic-leukemia-cell-lines
#8
Simona Ultimo, Carolina Simioni, Alberto M Martelli, Giorgio Zauli, Camilla Evangelisti, Claudio Celeghini, James A McCubrey, Giorgia Marisi, Paola Ulivi, Silvano Capitani, Luca M Neri
B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28381396/caspase-3-controls-aml1-eto-driven-leukemogenesis-via-autophagy-modulation-in-a-ulk1-dependent-manner
#9
Na Man, Yurong Tan, Xiao-Jian Sun, Fan Liu, Guoyan Cheng, Sarah Greenblatt, Camilo Martinez, Daniel L Karl, Koji Ando, Ming Sun, Dan Hou, Bingyi Chen, Mingjiang Xu, Feng-Chun Yang, Zhu Chen, Saijuan Chen, Stephen D Nimer, Lan Wang
AML1-ETO (AE), a fusion oncoprotein, generated by the t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML...
April 5, 2017: Blood
https://www.readbyqxmd.com/read/28371355/bosutinib-an-src-inhibitor-induces-caspase-independent-cell-death-associated-with-permeabilization-of-lysosomal-membranes-in-melanoma-cells
#10
S Noguchi, S Shibutani, K Fukushima, T Mori, M Igase, T Mizuno
BACKGROUND: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. MATERIALS AND METHODS: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining...
March 28, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28366933/a-novel-ahi-1-bcr-abl-dnm2-complex-regulates-leukemic-properties-of-primitive-cml-cells-through-enhanced-cellular-endocytosis-and-ros-mediated-autophagy
#11
X Liu, K Rothe, R Yen, C Fruhstorfer, T Maetzig, M Chen, D L Forrest, K Humphries, X Jiang
Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction...
April 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28358370/the-role-of-autophagy-in-asparaginase-induced-immune-suppression-of-macrophages
#12
Ping Song, Ziyu Wang, Xuyao Zhang, Jiajun Fan, Yubin Li, Qicheng Chen, Shaofei Wang, Peipei Liu, Jingyun Luan, Li Ye, Dianwen Ju
Erwinia asparaginase, a bacteria-derived enzyme drug, has been used in the treatment of various cancers, especially acute lymphoblastic leukemia (ALL). One of the most significant side effects associated with asparaginase administration is immune suppression, which limits its application in clinic. Macrophages are phagocytic immune cells and have a central role in inflammation and host defense. We reported here that asparaginase disturbed the function of macrophages including phagocytosis, proliferation, ROS and nitric oxide secretion, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) secretion, and major histocompatibility complex II (MHC-II) molecule expression, thus induced immune suppression in interferon-γ and lipopolysaccharide-stimulated macrophages...
March 30, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28346428/autophagy-is-required-for-cell-survival-under-l-asparaginase-induced-metabolic-stress-in-acute-lymphoblastic-leukemia-cells
#13
H Takahashi, J Inoue, K Sakaguchi, M Takagi, S Mizutani, J Inazawa
L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy...
March 27, 2017: Oncogene
https://www.readbyqxmd.com/read/28342808/role-of-mtorc1-s6k1-signaling-pathway-in-regulation-of-hematopoietic-stem-cell-and-acute-myeloid-leukemia
#14
REVIEW
Joydeep Ghosh, Reuben Kapur
Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions...
March 22, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28339029/hydroxychloroquine-sensitizes-chronic-myeloid-leukemia-cells-to-v%C3%AE-9v%C3%AE-2-t-cell-mediated-lysis-independent-of-autophagy
#15
Biqing Han, Yanmin Zhao, Yu Lin, Shan Fu, Limengmeng Wang, Mingming Zhang, Ruxiu Tie, Binsheng Wang, Yi Luo, Lizhen Liu, Jian Yu, He Huang
Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7...
March 24, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28325262/the-roles-of-reactive-oxygen-species-ros-and-autophagy-in-the-survival-and-death-of-leukemia-cells
#16
REVIEW
Yong-Feng Chen, Hao Liu, Xin-Jing Luo, Zhiqiang Zhao, Zhen-You Zou, Jing Li, Xiao-Jing Lin, Yong Liang
As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regulating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and tissues...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28283035/inhibition-of-autophagy-enhances-the-selective-anti-cancer-activity-of-tigecycline-to-overcome-drug-resistance-in-the-treatment-of-chronic-myeloid-leukemia
#17
Ziyuan Lu, Na Xu, Bolin He, Chengyun Pan, Yangqing Lan, Hongsheng Zhou, Xiaoli Liu
BACKGROUND: Drug resistance and disease progression are still the major obstacles in the treatment of chronic myeloid leukemia (CML). Increasing researches have demonstrated that autophagy becomes activated when cancer cells are subjected to chemotherapy, which is involved in the development of drug resistance. Therefore, combining chemotherapy with inhibition of autophagy serves as a new strategy in cancer treatment. Tigecycline is an antibiotic that has received attention as an anti-cancer agent due to its inhibitory effect on mitochondrial translation...
March 10, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28282266/autophagy-is-dispensable-for-kmt2a-mll-mllt3-af9-aml-maintenance-and-anti-leukemic-effect-of-chloroquine
#18
Xiaoyi Chen, Jason Clark, Mark Wunderlich, Cuiqing Fan, Ashley Davis, Song Chen, Jun-Lin Guan, James C Mulloy, Ashish Kumar, Yi Zheng
Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28278721/sertraline-exerts-its-antitumor-functions-through-both-apoptosis-and-autophagy-pathways-in-acute-myeloid-leukemia-cells
#19
Di Xia, Ying-Ting Zhang, Gui-Ping Xu, Wei-Wei Yan, Xiao-Rong Pan, Jian-Hua Tong
It has been found that sertraline, a widely used antidepressant drug, possessed antitumor roles in a variety of cancers including liver cancer, colorectal cancer and lymphoma. In this study, we provided evidences that sertraline had potent antiproliferative activity not only in acute myeloid leukemia (AML) cell lines but also in the fresh leukemia cells from AML patients, and could induce cell death through both apoptosis and autophagy pathways. Moreover, we found that inhibiting autophagy pathway could partially attenuate sertraline-induced apoptosis and cell growth inhibition, indicating that sertraline-induced autophagy process could facilitate AML cell apoptosis to some degree...
February 13, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28251795/quercetin-simultaneously-induces-g0-g1-phase-arrest-and-caspase-mediated-crosstalk-between-apoptosis-and-autophagy-in-human-leukemia-hl-60-cells
#20
Junn-Liang Chang, Jyh-Ming Chow, Jer-Hwa Chang, Yu-Ching Wen, Yung-Wei Lin, Shun-Fa Yang, Wei-Jiunn Lee, Ming-Hsien Chien
Quercetin is a plant-derived bioflavonoid with high anticancer activity in various tumors. Herein, the molecular mechanisms by which quercetin exerts its anticancer effects against HL-60 acute myeloid leukemia (AML) cells were investigated. Results showed that quercetin suppressed cell proliferation in the HL-60 cell line in vitro and in vivo. Quercetin-induced G0 /G1 -phase arrest occurred when expressions of cyclin-dependent kinase (CDK)2/4 were inhibited and the CDK inhibitors, p16 and p21, were induced...
March 2, 2017: Environmental Toxicology
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