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Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice  [PDF]
Mahesh Hegde, Subhas S. Karki, Elizabeth Thomas, Sujeet Kumar, Kuppusamy Panjamurthy, Somasagara R. Ranganatha, Kanchugarakoppal S. Rangappa, Bibha Choudhary, Sathees C. Raghavan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043632
Abstract: Background Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyan?ato-imidazo[2,1-b][1], [3], [4]thiadiazole). Materials and Methods ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. Results We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 μM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. Conclusion Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.
ZNF367 Inhibits Cancer Progression and Is Targeted by miR-195  [PDF]
Meenu Jain, Lisa Zhang, Myriem Boufraqech, Yi Liu-Chittenden, Kimberly Bussey, Michael J. Demeure, Xiaolin Wu, Ling Su, Karel Pacak, Constantine A. Stratakis, Electron Kebebew
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101423
Abstract: Background Several members of the zinc finger protein family have been recently shown to have a role in cancer initiation and progression. Zinc finger protein 367 (ZNF367) is a member of the zinc finger protein family and is expressed in embryonic or fetal erythroid tissue but is absent in normal adult tissue. Methodology/Principal Findings We show that ZNF367 is overexpressed in adrenocortical carcinoma, malignant pheochromocytoma/paraganglioma and thyroid cancer as compared to normal tissue and benign tumors. Using both functional knockdown and ectopic overexpression in multiple cell lines, we show that ZNF367 inhibits cellular proliferation, invasion, migration, and adhesion to extracellular proteins in vitro and in vivo. Integrated gene and microRNA expression analyses showed an inverse correlation between ZNF367 and miR-195 expression. Luciferase assays demonstrated that miR-195 directly regulates ZNF367 expression and that miR-195 regulates cellular invasion. Moreover, integrin alpha 3 (ITGA3) expression was regulated by ZNF367. Conclusions/Significance Our findings taken together suggest that ZNF367 regulates cancer progression.
A Phthalimide Derivative That Inhibits Centrosomal Clustering Is Effective on Multiple Myeloma  [PDF]
Hirokazu Shiheido, Fukiko Terada, Noriko Tabata, Ichigo Hayakawa, Nobutaka Matsumura, Hideaki Takashima, Yoko Ogawa, Wenlin Du, Taketo Yamada, Mitsuru Shoji, Takeshi Sugai, Nobuhide Doi, Shiro Iijima, Yutaka Hattori, Hiroshi Yanagawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038878
Abstract: Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.
N-(3-Chlorophenyl)maleimide  [cached]
Rodolfo Moreno-Fuquen,Zulay Pardo-Botero,Javier Ellena
Acta Crystallographica Section E , 2008, DOI: 10.1107/s1600536808011604
Abstract: The title compound, C10H6ClNO2, has a dihedral angle of 46.46 (5)° between the benzene and maleimide rings. A short intermolecular halogen–oxygen contact is observed, with a Cl...O distance of 3.0966 (13) . Both CO groups are involved in two C—H...O interactions, which gives rise to sheets parallel to (100). In addition, these sheets exhibit a π–π stacking interaction between the benzene and maleimide rings [mean interplanar distance of 3.337 (3) ].
MicroRNA-149 Inhibits Proliferation and Cell Cycle Progression through the Targeting of ZBTB2 in Human Gastric Cancer  [PDF]
Ying Wang, Xiushan Zheng, Zhiyong Zhang, Jinfeng Zhou, Guohong Zhao, Jianjun Yang, Limin Xia, Rui Wang, Xiqiang Cai, Hao Hu, Cailin Zhu, Yongzhan Nie, Kaichun Wu, Dexin Zhang, Daiming Fan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041693
Abstract: An increasing body of evidence indicates that miR-149 can both suppress and promote tumor growth depending on the tumor type. However, the role of miR-149 in the progression of gastric cancer (GC) remains unknown. Here we report that miR-149 is a tumor suppressor in human gastric cancer. miR-149 expression is decreased in GC cell lines and clinical specimens in comparison to normal gastric epithelial cell and tissues, respectively. The expression levels of miR-149 also correlate with the differentiation degree of GC cells and tissues. Moreover, ectopic expression of miR-149 in gastric cancer cells inhibits proliferation and cell cycle progression by down-regulating ZBTB2, a potent repressor of the ARF-HDM2-p53-p21 pathway, with a potential binding site for miR-149 in its mRNA's 3′UTR. It is also found that ZBTB2 expression increases in GC cells and tissues compared to normal gastric epithelial cell and tissues, respectively. Silencing of ZBTB2 leads to suppression of cell growth and cell cycle arrest in G0/G1 phase, indicating that ZBTB2 may act as an oncogene in GC. Furthermore, transfection of miR-149 mimics into gastric cancer cells induces down-regulation of ZBTB2 and HDM2, and up-regulation of ARF, p53, and p21 compared to the controls. In summary, our data suggest that miR-149 functions as a tumor suppressor in human gastric cancer by, at least partially through, targeting ZBTB2.
N-(4-Chlorophenyl)maleimide  [cached]
Rodolfo Moreno-Fuquen,Zulay Pardo-Botero,Javier Ellena
Acta Crystallographica Section E , 2008, DOI: 10.1107/s160053680803016x
Abstract: In the title compound, C10H6ClNO2, the dihedral angle between the benzene and maleimide rings is 47.54 (9)°. Molecules form centrosymmetric dimers through C—H...O hydrogen bonds, resulting in rings of graph-set motif R22(8) and chains in the [100] direction. Molecules are also linked by C—H...Cl hydrogen bonds along [001]. In this same direction, molecules are connected to other neighbouring molecules by C—H...O hydrogen bonds, forming edge-fused R44(24) rings.
Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis  [PDF]
Jing Xu,Laurent Lecanu,Matthew Tan,Janet Greeson,Vassilios Papadopoulos
Molecules , 2009, DOI: 10.3390/molecules14093392
Abstract: Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer’s disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-1-(tert-butyl-1H-indol-3-yl-methyl)-2-oxo-ethyl]-4-nitrobenzamide (SP-10) inhibits dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI) expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F-) and monomeric (G-) actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10-induced changes in actin distribution might prevent the formation of microvilli–cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells.
Targeted Knockdown of IQGAP1 Inhibits the Progression of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo  [PDF]
Xiao-Xia Wang, Kang Wang, Xiao-Zhong Li, Li-Qin Zhai, Chong-Xiao Qu, Yan Zhao, Zhi-Rong Liu, Hui-Zhen Wang, Qi-Jun An, Li-Wei Jing, Xu-Hong Wang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096501
Abstract: IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways. The accumulating evidence has demonstrated that IQGAP1 plays an important role in tumorigenesis and tumor progression. However, the function of IQGAP1 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly investigated. In the present study, we showed that IQGAP1 was overexpressed in ESCC tumor tissues, and its overexpression was correlated with the invasion depth of ESCC. Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice. Furthermore, Knockdown of IQGAP1 expression in ESCC cell lines led to a reversion of epithelial to mesenchymal transition (EMT) progress. These results suggest that IQGAP1 plays crucial roles in regulating ESCC occurrence and progression. IQGAP1 silencing may therefore develop into a promising novel anticancer therapy.
Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model  [cached]
Beatriz Pagán,Angel A Isidro,Myrella L Cruz,Yuan Ren
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i44.4858
Abstract: AIM: To investigate the role of epidermal growth factor receptor (EGFR) in colitis-associated dysplasia using the EGFR tyrosine kinase inhibitor erlotinib. METHODS: Sprague-Dawley rats received trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol, ic), followed 6 wk later by reactivation with TNBS (5 mg/kg, iv) for 3 d. To induce colitis-associated dysplasia, rats then received TNBS (iv) twice a week for 10 wk. One group received erlotinib (10 mg/kg, ip) for 1 wk before the start of the reactivation of the colitis and 2 wk after (21 d); the rest received the vehicle. After rats were euthanized, the colons were removed and analyzed for damage and expression of the EGFR downstream effectors Erk1/2 and c-Myc. RESULTS: Ninety percent of the vehicle-treated animals had dysplasia in any region of the colon. Erlotinib-treated animals had a significant decrease in the incidence of dysplasia compared to vehicle-treated animals in all regions of the colon (50.00% ± 11.47% vs 90.00% ± 10.00% in proximal, P < 0.05; 15.00% ± 8.19% vs 50.00% ± 16.67% in mid, P < 0.05; and 20.00% ± 9.17% vs 70.00% ± 15.28% in distal, P < 0.01). Erlotinib-treated animals also had reduced cell proliferation, reduced active Erk1/2, and reduced c-Myc in colon epithelium compared with the vehicle-treated animals. In vitro, erlotinib treatment was shown to markedly decrease c-Myc and pErk1/2 levels in rat epithelial cells. Proliferation of rat epithelial cells was stimulated by epidermal growth factor and inhibited by erlotinib (P < 0.05). CONCLUSION: Erlotinib can decrease the development of colitis-associated dysplasia, suggesting a potential therapeutic use for erlotinib in patients with long-standing colitis.
A Protoberberine Derivative HWY336 Selectively Inhibits MKK4 and MKK7 in Mammalian Cells: The Importance of Activation Loop on Selectivity  [PDF]
Namil Kim, Jeongyeon Park, Changdev G. Gadhe, Seung Joo Cho, Youngjin Oh, Donghyun Kim, Kiwon Song
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091037
Abstract: A protoberberine derivative library was used to search for selective inhibitors against kinases of the mitogen-activated protein kinase (MAPK) cascades in mammalian cells. Among kinases in mammalian MAPK pathways, we identified a compound (HWY336) that selectively inhibits kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4 and MKK7). The IC50 of HWY336 was 6 μM for MKK4 and 10 μM for MKK7 in vitro. HWY336 bound to both kinases reversibly via noncovalent interactions, and inhibited their activity by interfering with access of a protein substrate to its binding site. The binding affinity of HWY336 to MKK4 was measured by surface plasmon resonance to determine a dissociation constant (Kd) of 3.2 μM. When mammalian cells were treated with HWY336, MKK4 and MKK7 were selectively inhibited, resulting in inhibition of c-Jun NH2-terminal protein kinases in vivo. The structural model of HWY336 bound to either MKK4 or MKK7 predicted that HWY336 was docked to the activation loop, which is adjacent to the substrate binding site. This model suggested the importance of the activation loop of MKKs in HWY336 selectivity. We verified this model by mutating three critical residues within this loop of MKK4 to the corresponding residues in MKK3. The mutant MKK4 displayed similar kinase activity as wild-type kinase, but its activity was not inhibited by HWY336 compared to wild-type MKK4. We propose that the specific association of HWY336 to the activation loop of MKK4/MKK7 is responsible for its selective inhibition.
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