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Autophagy CML

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
Hella Amdouni, Guillaume Robert, Mohsine Driowya, Nathan Furstoss, Camille Métier, Alix Dubois, Maeva Dufies, Marwa Zerhouni, François Orange, Sandra Lacas-Gervais, Khalid Bougrin, Anthony R Martin, Patrick Auberger, Rachid Benhida
A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy...
February 2, 2017: Journal of Medicinal Chemistry
Dan Shi, Yan Liu, Ronggang Xi, Wei Zou, Lijun Wu, Zhiran Zhang, Zhongyang Liu, Chao Qu, Baoli Xu, Xiaobo Wang
Chronic myelogenous leukemia (CML) is characterized by the t(9;22) (q34;q11)-associated Bcr-Abl fusion gene, which is an essential element of clinical diagnosis. As a traditional Chinese medicine, realgar has been widely used for the treatment of various diseases for >1,500 years. Inspired by nano-drug, realgar nanoparticles (NPs) have been prepared with an average particle size of <100 nm in a previous work. Compared with coarse realgar, the realgar NPs have higher bioavailability. As a principal constituent protein of caveolae, caveolin-1 (Cav-1) participates in regulating various cellular physiological and pathological processes including tumorigenesis and tumor development...
2016: International Journal of Nanomedicine
Silvia Bono, Matteo Lulli, Vito Giuseppe D'Agostino, Federico Di Gesualdo, Rosa Loffredo, Maria Grazia Cipolleschi, Alessandro Provenzani, Elisabetta Rovida, Persio Dello Sbarba
BCR/Abl protein drives the onset and progression of Chronic Myeloid Leukemia (CML). We previously showed that BCR/Abl protein is suppressed in low oxygen, where viable cells retain stem cell potential. This study addressed the regulation of BCR/Abl protein expression under oxygen or glucose shortage, characteristic of the in vivo environment where cells resistant to tyrosine kinase inhibitors (TKi) persist. We investigated, at transcriptional, translational and post-translational level, the mechanisms involved in BCR/Abl suppression in K562 and KCL22 CML cells...
November 12, 2016: Oncotarget
Ying Lu, Ling-Ling Liu, Shou-Sheng Liu, Zhi-Gang Fang, Yong Zou, Xu-Bin Deng, Zi-Jie Long, Quentin Liu, Dong-Jun Lin
BACKGROUND: Chronic myelogenous leukemia (CML) is a hematological stem cell disorder. Tyrosine kinase inhibitors (TKIs) are the standard treatments for CML, but a number of patients fail to respond effectively due to gene mutations. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to have anti-tumor effect on solid tumor whereas the anti-CML effect and its underlying mechanism have not been completely elucidated. METHODS: The cytotoxic effects of celecoxib and/or imatinib were evaluated by MTT assay...
2016: Journal of Translational Medicine
Sujuan Guo, Kevin J Pridham, Zhi Sheng
Autophagy is a catabolic process whereby cellular components are degraded to fuel cells for longer survival during stress. Hence, autophagy plays a vital role in determining cell fate and is central for homeostasis and pathogenesis of many human diseases including chronic myeloid leukemia (CML). It has been well established that autophagy is important for the leukemogenesis as well as drug resistance in CML. Thus, autophagy is an intriguing therapeutic target. However, current approaches that detect autophagy lack reliability and often fail to provide quantitative measurements...
2016: Methods in Molecular Biology
Antoine Millet, Magali Plaisant, Cyril Ronco, Michaël Cerezo, Patricia Abbe, Emilie Jaune, Elisa Cavazza, Stéphane Rocchi, Rachid Benhida
Cancer is the second cause of deaths worldwide and is forecasted to affect more that 22 million people in 2020. Despite dramatic improvement in its care over the last two decades, the treatment of resistant forms of cancer is still an unmet challenge. Thus, innovative and efficient treatments are still needed. In this context, we report herein the synthesis and the evaluation of a new class of bioactive molecules belonging to the N-(4-(3-aminophenyl(thiazol-2-yl)acetamide family. Structure-activity relationships could be driven and resulted in the discovery of lead compound 6b...
September 22, 2016: Journal of Medicinal Chemistry
Yu-Jen Chen, Li-Wen Fang, Wen-Chi Su, Wen-Yi Hsu, Kai-Chien Yang, Huey-Lan Huang
Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells...
2016: OncoTargets and Therapy
Antonella Rigo, Fabrizio Vinante
The sesquiterpene α-bisabolol (α-BSB) has been shown to be an effective cytotoxic agent for a variety of human cancer cells in culture and animal models. However, much of its intracellular action remains elusive. We evaluated the cytotoxic action of α-BSB against CML-T1, Jurkat and HeLa cell lines, as preclinical models for myeloid, lymphoid and epithelial neoplasias. The approach included single cell analysis (flow cytometry, immunocytology) combined with cytotoxicity and proliferation assays to characterize organelle damage, autophagy, cytostatic effect, and apoptosis...
August 2016: Apoptosis: An International Journal on Programmed Cell Death
Maria Karvela, Pablo Baquero, Elodie M Kuntz, Arunima Mukhopadhyay, Rebecca Mitchell, Elaine K Allan, Edmond Chan, Kamil R Kranc, Bruno Calabretta, Paolo Salomoni, Eyal Gottlieb, Tessa L Holyoake, G Vignir Helgason
A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells are able to survive TKI-mediated BCR-ABL inhibition, leading to disease persistence in patients. Investigation of strategies aiming to inhibit alternative survival pathways in CML is therefore critical. We have previously shown that a nonspecific pharmacological inhibition of autophagy potentiates TKI-induced death in Philadelphia chromosome-positive cells. Here we provide further understanding of how specific and pharmacological autophagy inhibition affects nonmitochondrial and mitochondrial energy metabolism and reactive oxygen species (ROS)-mediated differentiation of CML cells and highlight ATG7 (a critical component of the LC3 conjugation system) as a potential specific therapeutic target...
June 2, 2016: Autophagy
Juan Liu, Yujing Zhang, Aichun Liu, Jinghua Wang, Lianqiao Li, Xi Chen, Xinyu Gao, Yanming Xue, Xiaomin Zhang, Yao Liu
Although dasatinib is effective in most imatinib mesylate (IMT)-resistant chronic myeloid leukemia (CML) patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562R(IMT)). Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling and autophagic activity were increased significantly in K562R(IMT) cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells...
April 8, 2016: International Journal of Molecular Sciences
Alix Dubois, Clemence Ginet, Nathan Furstoss, Amine Belaid, Mohamed Amine Hamouda, Wedjene El Manaa, Thomas Cluzeau, Sandrine Marchetti, Jean Ehrland Ricci, Arnaud Jacquel, Frederic Luciano, Mohsine Driowya, Rachid Benhida, Patrick Auberger, Guillaume Robert
Differentiation-inducing factor (DIF) defines a group of chlorinated hexaphenones that orchestrate stalk-cell differentiation in the slime mold Dictyostelium discoideum (DD). DIF-1 and 3 have also been reported to have tumor inhibiting properties; however, the mechanisms that underlie the effects of these compounds remain poorly defined. Herein, we show that DIF-3 rapidly triggers Ca2+ release and a loss of mitochondrial membrane potential (MMP) in the absence of cytochrome c and Smac release and without caspase activation...
May 3, 2016: Oncotarget
Shanshan Jiang, Jiajun Fan, Qian Wang, Dianwen Ju, Meiqing Feng, Jiyang Li, Zhong-Bin Guan, Duopeng An, Xin Wang, Li Ye
BACKGROUND: Diosgenin, a steroidal saponin isolated from legumes and yams, has been confirmed to possess potent anticancer effect on multifarious tumors including chronic myeloid leukemia (CML). PURPOSE: We aimed to further determine the anti-cancer activity of diosgenin and its mechanisms in CML cells. METHODS: The cell vitality was detected by MTT assay. Autophagic flux and reactive oxygen species (ROS) production were analyzed by laser scanning confocal microscope...
March 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Alessandra Chiarenza, Fabrizio Manetti, Elena Petricci, Martial Ruat, Antonella Naldini, Maurizio Taddei, Fabio Carraro
The most relevant therapeutic approaches to treat CML rely on the administration of tyrosine kinase inhibitors (TKIs) like Imatinib, which are able to counteract the activity of Bcr-Abl protein increasing patient's life expectancy and survival. Unfortunately, there are some issues TKIs are not able to address; first of all TKIs are not so effective in increasing survival of patients in blast crisis, second they are not able to eradicate leukemic stem cells (LSC) which represent the major cause of disease relapse, and third patients often develop resistance to TKIs due to mutations in the drug binding site...
2016: PloS One
Lu Cao, Jishi Wang, Dan Ma, Ping Wang, Yaming Zhang, Qin Fang
Heme oxygenase-1 (HO-1) has been verified to play an important role in imatinib (IM)-resistant chronic myeloid leukemia (CML) cells, but the mechanism remains unclear. In drug resistant CML cells, HO-1 expression abnormally increased and that of autophagy-related protein LC-3I/II also increased, so we herein postulated HO-1 was associated with autophagy. HO-1 expressions in IM-sensitive/resistant K562/K562R cells were regulated through lentiviral mediation. K562 cells transfected with HO-1 resisted IM and underwent obvious autophagy...
March 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Wei He, Xiujin Ye, Xianbo Huang, Wen Lel, Liangshun You, Lei Wang, Xiaohui Chen, Wenbin Qian
Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells...
April 2016: International Journal of Oncology
Claudio Marcelo Fader, Betiana Nebaí Salassa, Rubén Adrián Grosso, Agustín Nicolás Vergara, María Isabel Colombo
BACKGROUND INFORMATION: In eukaryotic cells, autophagy is considered a lysosomal catabolic process which participates in the degradation of intracellular components in a vacuolar structure termed autolysosome. This pathway plays a significant role in the erythropoiesis process, contributing to the clearance of some organelles (such as mitochondria) that are not necessary in the mature red blood cells. Nevertheless, the role of autophagy in erythrocyte maturation has not been fully established...
April 2016: Biology of the Cell
Mei-Chen Lo, Ming-Hong Chen, Wen-Sen Lee, Chin-I Lu, Chuang-Rung Chang, Shu-Huei Kao, Horng-Mo Lee
Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic β-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGE-damaged tissues were evaluated...
November 15, 2015: American Journal of Physiology. Endocrinology and Metabolism
David Colecchia, Matteo Rossi, Federica Sasdelli, Sveva Sanzone, Angela Strambi, Mario Chiariello
A reciprocal translocation of the ABL1 gene to the BCR gene results in the expression of the oncogenic BCR-ABL1 fusion protein, which characterizes human chronic myeloid leukemia (CML), a myeloproliferative disorder considered invariably fatal until the introduction of the imatinib family of tyrosine kinase inhibitors (TKI). Nonetheless, insensitivity of CML stem cells to TKI treatment and intrinsic or acquired resistance are still frequent causes for disease persistence and blastic phase progression experienced in patients after initial successful therapies...
2015: Autophagy
Rui Shi, Juan Lin, Yuping Gong, Tianyou Yan, Fangfang Shi, Xi Yang, Xuehua Liu, Duolan Naren
In recent years, there have been considerable research advances on the antileukemic mechanisms of the antidiabetic drug metformin. Our current studies have shown that metformin suppresses cell viability, induces apoptosis, and downregulates the mTORC1 signaling pathway both in the Ph+ALL cell line and primary blasts from Ph+ ALL patients, as well as the CML cell lines K562 (imatinib-sensitive) and K562R (imatinib-resistance). We have also shown that metformin activates the ERK pathway in Ph+ALL cells, SUP-B15, a side effect that can be overcome by U0126 (MEK1/2 inhibitor) or imatinib...
October 2015: Anti-cancer Drugs
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