bluuebunny/crossref_metadata_2025_split huggingface dataset:
THEORETICAL STUDIES OF THE TETRACHLOROCUPRATE(II) ANION: ADF GEOMETRY OPTIMIZATION, AND CALCULATION OF THE PES, EPR PARAMETERS, AND VIBRATIONAL FREQUENCIES
Authors: RAHEMI H. , TAYYARI S. F. , RILEY M. J. 
Published: January 2008

PES as functions of the trans-angle (θ) and the dihedral angle (ε) for optimized bond length is calculated. It is found that the most unstrained stable conformation of the [Formula: see text] is D2d at θ = 129.45° and ε = 90.0°. Calculated EPR g values change smoothly and in a logarithmic manner in the experimental range. The g33 value varies from 2.1287 (D4h) to 2.2836 (Td), and g11 = g22 from 2.035 to 2.1001. The Cu hyperfine values of the D4h are A11 = -196.455 and A22 = A33 = -17.533. At the most stable D2d conformation, the values are A11 = -177.606 and A22 = A33 = 2.6266, all in the 10-4 cm-1 unit. The variation of EPR g values with molecular charge in the range of -2.0 to -2.8 were studied, and it was found that by increasing molecular charge, both components of g values are increased. For the D2d conformation with molecular charge of -2.6, g⊥ = 2.085 (expt. = 2.094) and g|| = 2.243 (expt. = 2.238). For the D4h conformation, calculated g|| values with increasing molecular charge improved, but g⊥ values deviated increasingly from experimental values. Frequencies are also calculated in the range of D2d to D4h.
Phytochemistry and pharmacogenomics of natural products derived from traditional chinese medicine and chinese materia medica with activity against tumor cells
Authors: Efferth Thomas , Kahl Stefan , Paulus Kerstin , Adams Michael , Rauh Rolf , Boechzelt Herbert , Hao Xiaojiang , Kaina Bernd , Bauer Rudolf 
Published: January 2008

Abstract
The cure from cancer is still not a reality for all patients, which is mainly due to the limitations of chemotherapy (e.g., drug resistance and toxicity). Apart from the high-throughput screening of synthetic chemical libraries, natural products represent attractive alternatives for drug development. We have done a systematic bioactivity-based screening of natural products derived from medicinal plants used in traditional Chinese medicine. Plant extracts with growth-inhibitory activity against tumor cells have been fractionated by chromatographic techniques. We have isolated the bioactive compounds and elucidated the chemical structures by nuclear magnetic resonance and mass spectrometry. By this strategy, we identified 25-O-acetyl-23,24-dihydro-cucurbitacin F as a cytotoxic constituent of Quisqualis indica. Another promising compound identified by this approach was miltirone from Salvia miltiorrhiza. The IC50 values for miltirone of 60 National Cancer Institute cell lines were associated with the microarray-based expression of 9,706 genes. By COMPARE and hierarchical cluster analyses, candidate genes were identified, which significantly predicted sensitivity or resistance of cell lines to miltirone. [Mol Cancer Ther 2008;7(1):152–61]
Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of Integrin-linked kinase (ILK)
Authors: Edwards Lincoln A. , Woo Janet , Huxham Lynsey A. , Verreault Maite , Dragowska Wieslawa H. , Chiu Gigi , Rajput Ashish , Kyle Alastair H. , Kalra Jessica , Yapp Donald , Yan Hong , Minchinton Andrew I. , Huntsman David , Daynard Tim , Waterhouse Dawn N. , Thiessen B. , Dedhar Shoukat , Bally Marcel B. 
Published: January 2008

Abstract
Integrin-linked kinase (ILK) was assesed as a therapeutic target in glioblastoma xenograft models through multiple endpoints including treatment related changes in the tumor microenvironment. Glioblastoma cell lines were tested in vitro for sensitivity toward the small-molecule inhibitors QLT0254 and QLT0267. Cell viability, cell cycle, and apoptosis were evaluated using MTT assay, flow cytometry, caspase activation, and DAPI staining. Western blotting and ELISA were used for protein analysis (ILK, PKB/Akt, VEGF, and HIF-1α). In vivo assessment of growth rate, cell proliferation, BrdUrd, blood vessel mass (CD31 labeling), vessel perfusion (Hoechst 33342), and hypoxia (EF-5) was done using U87MG glioblastoma xenografts in RAG2-M mice treated orally with QLT0267 (200 mg/kg q.d.). ILK inhibition in vitro with QLT0254 and QLT0267 resulted in decreased levels of phospho-PKB/Akt (Ser473), secreted VEGF, G2-M block, and apoptosis induction. Mice treated with QLT0267 exhibited significant delays in tumor growth (treated 213 mm3 versus control 549 mm3). In situ analysis of U87MG tumor cell proliferation from QLT0267-treated mice was significantly lower relative to untreated mice. Importantly, VEGF and HIF-1α expression decreased in QLT0267-treated tumors as did the percentage of blood vessel mass and numbers of Hoechst 33342 perfused tumor vessels compared with control tumors (35% versus 83%). ILK inhibition with novel small-molecule inhibitors leads to treatment-associated delays in tumor growth, decreased tumor angiogenesis, and functionality of tumor vasculature. The therapeutic effects of a selected ILK inhibitor (QLT0267) should be determined in the clinic in cancers that exhibit dysregulated ILK, such as PTEN-null glioblastomas. [Mol Cancer Ther 2008;7(1):59–70]
Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression
Authors: Aird Katherine M. , Ding Xiuyun , Baras Aris , Wei Junping , Morse Michael A. , Clay Timothy , Lyerly Herbert K. , Devi Gayathri R. 
Published: January 2008

Abstract
Inflammatory breast cancer (IBC) patients show poor survival and a significant incidence of epidermal growth factor receptor-2 (ErbB2) overexpression. A distinct mechanism involving increased expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin, key members of the inhibitor of apoptosis protein (IAP) family, was observed post-trastuzumab (an ErbB2 monoclonal antibody) treatment in an ErbB2-overexpressing, estrogen receptor negative, IBC cellular model, SUM190PT, isolated from a primary IBC tumor. In contrast, a decrease in the IAP expression was observed in the non-IBC, ErbB2-overexpressing SKBR3 cells in which trastuzumab treatment also decreased p-AKT and cell viability. Further, in SUM190PT cells, therapeutic sensitivity to GW583340 (a dual epidermal growth factor receptor/ErbB2 kinase inhibitor) corresponded with XIAP down-regulation and abrogation of XIAP inhibition on active caspase-9 release. Specific small interfering RNA–mediated XIAP inhibition in combination with trastuzumab caused decrease in inactive procaspase-9 and inhibition of p-AKT corresponding with 45% to 50% decrease in cell viability in the SUM190PT cells, which have high steady-state p-AKT levels. Further, embelin, a small-molecule inhibitor that abrogates binding of XIAP to procaspase-9, caused significant decrease in SUM190PT viability. However, embelin in combination with trastuzumab failed to affect SUM190PT viability because it has no direct effect on XIAP, which is induced by trastuzumab treatment. These data have identified a novel functional link between ErbB2 signaling and antiapoptotic pathway mediated by XIAP. Blockade of the IAP antiapoptotic pathway alone or in combination would be an attractive strategy in IBC therapy. [Mol Cancer Ther 2008;7(1):38–47]
Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κB
Authors: Sung Bokyung , Pandey Manoj K. , Nakajima Yuki , Nishida Hiroshi , Konishi Tetsuya , Chaturvedi Madan M. , Aggarwal Bharat B. 
Published: January 2008

Abstract3,4-Dihydroxybenzalacetone (DBL) is a polyphenol derived from the medicinal plant Chaga [Inonotus obliquus (persoon) Pilat]. Although Chaga is used in Russia folk medicine to treat tumors, very little is known about its mechanism of action. Because most genes involved in inflammation, antiapoptosis, and cell proliferation are regulated by the transcription factor nuclear factor-κB (NF-κB), we postulated that DBL activity is mediated via modulation of the NF-κB activation pathway. We investigated the effects of DBL on NF-κB activation by electrophoretic mobility shift assay and on NF-κB-regulated gene expression by Western blot analysis. We found that DBL suppressed NF-κB activation by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, epidermal growth factor, okadaic acid, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific and inhibited both inducible and constitutive NF-κB activation. DBL did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase activity, IκBα phosphorylation and degradation, p65 phosphorylation, and translocation. DBL also suppressed the expression of TNF-induced and NF-κB-regulated proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of TNF-induced apoptosis and suppression of TNF-induced invasion. Together, our results indicate that DBL inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of DBL to enhance apoptosis and inhibit invasion. [Mol Cancer Ther 2008;7(1):191–201]
Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α
Authors: Koh Mei Y. , Spivak-Kroizman Taly , Venturini Sara , Welsh Sarah , Williams Ryan R. , Kirkpatrick D. Lynn , Powis Garth 
Published: January 2008

Abstract
We have reported previously that PX-478 (S-2-amino-3-[4′-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1α (HIF-1α) within the tumor. We now report that PX-478 inhibits HIF-1α protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1α inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1α mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5′ untranslated region of HIF-1α. Moreover, to a lesser extent, PX-478 also inhibits HIF-1α deubiquitination resulting in increased levels of polyubiquitinated HIF-1α. The inhibitory effect of PX-478 on HIF-1α levels is primarily due to its inhibition of translation because HIF-1α translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1α at multiple levels that together or individually may contribute to its antitumor activity against HIF-1α-expressing tumors. [Mol Cancer Ther 2008;7(1):90–100]
Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth
Authors: Clem Brian , Telang Sucheta , Clem Amy , Yalcin Abdullah , Meier Jason , Simmons Alan , Rasku Mary Ann , Arumugam Sengodagounder , Dean William L. , Eaton John , Lane Andrew , Trent John O. , Chesney Jason 
Published: January 2008

Abstract6-Phosphofructo-1-kinase, a rate-limiting enzyme of glycolysis, is activated in neoplastic cells by fructose-2,6-bisphosphate (Fru-2,6-BP), a product of four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isozymes (PFKFB1-4). The inducible PFKFB3 isozyme is constitutively expressed by neoplastic cells and required for the high glycolytic rate and anchorage-independent growth of ras-transformed cells. We report herein the computational identification of a small-molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which suppresses glycolytic flux and is cytostatic to neoplastic cells. 3PO inhibits recombinant PFKFB3 activity, suppresses glucose uptake, and decreases the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD+, and NADH. 3PO markedly attenuates the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines (IC50, 1.4-24 μmol/L) and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. The PFKFB3 enzyme is an essential molecular target of 3PO because transformed cells are rendered resistant to 3PO by ectopic expression of PFKFB3 and sensitive to 3PO by heterozygotic genomic deletion of PFKFB3. Importantly, i.p. administration of 3PO (0.07 mg/g) to tumor-bearing mice markedly reduces the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo. Taken together, these data support the clinical development of 3PO and other PFKFB3 inhibitors as chemotherapeutic agents. [Mol Cancer Ther 2008;7(1):110–20]
A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
Authors: Zhang Tao , Hamza Adel , Cao Xianhua , Wang Bing , Yu Shuwen , Zhan Chang-Guo , Sun Duxin 
Published: January 2008

Abstract
Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 μmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 μmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 μmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):162–70]
2-[(1-Methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation
Authors: Huber Kelly , Patel Poulam , Zhang Lei , Evans Helen , Westwell Andrew D. , Fischer Peter M. , Chan Stephen , Martin Stewart 
Published: January 2008

Abstract2-[(1-Methylpropyl)dithio]-1H-imidazole (IV-2) is a known inhibitor of the thioredoxin system. It causes the oxidation of cysteine residues from both thioredoxin reductase and thioredoxin, with only the latter leading to irreversible inhibition of protein function. Although IV-2 is considered to be the first specific inhibitor of thioredoxin to undergo evaluation in cancer patients (under the name PX-12), it is unclear whether the oxidative ability of IV-2 is limited to proteins of the thioredoxin family. The current study investigated the specificity of IV-2 by examining its interaction with tubulin, a protein in which cysteine oxidation causes loss of polymerization competence. The cellular effects of IV-2 were examined in MCF-7 breast cancer and endothelial cells (human umbilical vein endothelial cells). Immunocytochemistry revealed a loss of microtubule structure with Western blot analysis confirming that treated cells contained a higher proportion of unpolymerized tubulin. Cell-free tubulin polymerization assays showed a dose-dependent inhibition of tubulin polymerization and depolymerization of preformed microtubules, confirming a direct interaction between IV-2 and tubulin. Further investigation of the tubulin interaction, through analysis of sulfhydryl reactivity and disulfide bond formation, suggested that IV-2 acts through the oxidation of cysteines in tubulin. Biochemical assays indicated that the oxidative properties of IV-2 are not limited to thioredoxin and tubulin, as cysteine-dependent proteases were also inhibited. Breast cancer cells with thioredoxin silenced by short interfering RNA remained sensitive to IV-2, albeit at higher antiproliferative GI50 values than in cells with normal thioredoxin function. These findings show that modulation of targets other than thioredoxin contribute to the effects of IV-2 on proliferating cells. [Mol Cancer Ther 2008;7(1):143–51]
β-Ionone inhibits colonic aberrant crypt foci formation in rats, suppresses cell growth, and induces retinoid X receptor-α in human colon cancer cells
Authors: Janakiram Naveena B. , Cooma Indranie , Mohammed Altaf , Steele Vernon E. , Rao Chinthalapally V. 
Published: January 2008

Abstractβ-Ionone, an end-ring analogue of β-carotenoid, which is a constituent of vegetables and fruits, has been analyzed for colon cancer chemoprevention and treatment. β-Ionone induced cell growth inhibition and apoptosis in human colon cancer HCT116 cell line. We tested the in vivo chemopreventive efficacy in rat colon carcinogenesis model using aberrant crypt foci (ACF) as endpoint marker. HCT116 cells treated with subtoxic concentrations of β-ionone resulted dose-dependent cell growth suppression with G1-S-phase growth arrest and significant induction of apoptosis. β-Ionone up-regulated expression of retinoid X receptor-α mRNA dose-dependently in HCT116 cells. To evaluate inhibitory properties of β-ionone on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.1%, or 0.2% β-ionone. After 1 week, rats received s.c. injections of azoxymethane, 15 mg/kg body weight, once weekly for 2 weeks. Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.1% and 0.2% β-ionone significantly suppressed total colonic ACF formation up to 34% to 38% (P &lt; 0.0002 to P &lt; 0.0009), respectively, when compared with control group. Importantly, rats fed β-ionone showed &gt;55% inhibition (P &lt; 0.0001) of foci containing four or more aberrant crypts. Results from in vitro and in vivo bioassay clearly suggest that β-ionone could be further developed for prevention and treatment of colon cancer. [Mol Cancer Ther 2008;7(1):181–90]
Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro
Authors: Schayowitz Adam , Sabnis Gauri , Njar Vincent C.O. , Brodie Angela M.H. 
Published: January 2008

Abstract
This study was carried out to determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer. We investigated the role of the androgen receptor and its relationship to other signal transduction proteins. A hormone-refractory prostate cancer cell line [high-passage LNCaP (HP-LNCaP)] was established in vitro. Cells were treated with inhibitors of mammalian target of rapamycin and tyrosine kinase receptors. Expression of these proteins and the androgen receptor were measured by Western immunoblotting. Analysis of the model and various treatments was also assessed through proliferation assays, luciferase activation assays, binding assays, and ELISA. Our novel antiandrogen, VN/124-1, effectively inhibited proliferation of hormone-resistant prostate cancer cell lines (HP-LNCaP), which were no longer sensitive to bicalutamide and had increased expression of the androgen receptor. Treatment with everolimus or gefitinib resulted in an increase in protein expression and activation of the androgen receptor. Conversely, inhibition of the androgen receptor resulted in increased expression of IGFR1β, pHER2, pmTOR, and pAkt. The addition of bicalutamide to everolimus or gefitinib inhibited cell proliferation in HP-LNCaP cells. However, the addition of VN/124-1 has proven to be superior to bicalutamide, and the combination was synergistic (P &lt; 0.05) compared with either agent alone. This study suggests that compensatory cross-talk between the androgen receptor and various signaling pathways may account for decreased sensitivity to androgen receptor antagonists and the progression to hormone-resistant prostate cancer. Furthermore, these findings suggest that inhibition of both pathways may provide effective control in hormone-resistant prostate cancer and restore sensitivity to androgen antagonists in hormone-refractory patients. [Mol Cancer Ther 2008;7(1):121–32]
Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib
Authors: Ma Jie , Waxman David J. 
Published: January 2008

AbstractThe promising but still limited efficacy of angiogenesis inhibitors as monotherapies for cancer treatment indicates a need to integrate these agents into existing therapeutic regimens. Presently, we investigate the antitumor activity of the small-molecule angiogenesis inhibitor axitinib (AG-013736) and its potential for combination with metronomic cyclophosphamide. Axitinib significantly inhibited angiogenesis in rat 9L tumors grown s.c. in scid mice but only moderately delayed tumor growth. Combination of axitinib with metronomic cyclophosphamide fully blocked 9L tumor growth on initiation of drug treatment. In contrast, metronomic cyclophosphamide alone required multiple treatment cycles to halt tumor growth. However, in contrast to the substantial tumor regression that is ultimately induced by metronomic cyclophosphamide, the axitinib/cyclophosphamide combination was tumor growth static. Axitinib did not inhibit hepatic activation of cyclophosphamide or export of its activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), to extrahepatic tissues; rather, axitinib selectively decreased 9L tumor uptake of 4-OH-CPA by 30% to 40%. The reduced tumor penetration of 4-OH-CPA was associated with a decrease in cyclophosphamide-induced tumor cell apoptosis and a block in the induction of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells, which may contribute to the absence of tumor regression with the axitinib/cyclophosphamide combination. Finally, axitinib transiently increased 9L tumor cell apoptosis, indicating that its effects are not limited to the endothelial cell population. These findings highlight the multiple effects that may characterize antiangiogenic agent/metronomic chemotherapy combinations and suggest that careful optimization of drug scheduling and dosages will be required to maximize antitumor responses. [Mol Cancer Ther 2008;7(1):79–89]