bluuebunny/crossref_metadata_2025_split huggingface dataset:
MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted DrugsIn vitroandIn vivo
Authors: Hirai Hiroshi , Sootome Hiroshi , Nakatsuru Yoko , Miyama Katsuyoshi , Taguchi Shunsuke , Tsujioka Kyoko , Ueno Yoko , Hatch Harold , Majumder Pradip K. , Pan Bo-Sheng , Kotani Hidehito 
Published: June 2010

AbstractThe serine/threonine kinase Akt lies at a critical signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents. Mol Cancer Ther; 9(7); 1956–67. ©2010 AACR.
Mcl-1 Stability Determines Mitotic Cell Fate of Human Multiple Myeloma Tumor Cells Treated with the Kinesin Spindle Protein Inhibitor ARRY-520
Authors: Tunquist Brian J. , Woessner Richard D. , Walker Duncan H. 
Published: June 2010

AbstractKinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors. Mol Cancer Ther; 9(7); 2046–56. ©2010 AACR.
Sensitivity of Cancer Cells to Plk1 Inhibitor GSK461364A Is Associated with Loss of p53 Function and Chromosome Instability
Authors: Degenhardt Yan , Greshock Joel , Laquerre Sylvie , Gilmartin Aidan G. , Jing Junping , Richter Mark , Zhang Xiping , Bleam Maureen , Halsey Wendy , Hughes Ashley , Moy Christopher , Liu-Sullivan Nancy , Powers Scott , Bachman Kurtis , Jackson Jeffrey , Weber Barbara , Wooster Richard 
Published: June 2010

AbstractPolo-like kinases are a family of serine threonine kinases that are critical regulators of cell cycle progression and DNA damage response. Predictive biomarkers for the Plk1-selective inhibitor GSK461364A were identified by comparing the genomics and genetics of a panel of human cancer cell lines with their response to a drug washout followed by an outgrowth assay. In this assay, cell lines that have lost p53 expression or carry mutations in the TP53 gene tended to be more sensitive to GSK461364A. These more sensitive cell lines also had increased levels of chromosome instability, a characteristic associated with loss of p53 function. Further mechanistic studies showed that p53 wild-type (WT) and not mutant cells can activate a postmitotic tetraploidy checkpoint and arrest at pseudo-G1 state after GSK461364A treatment. RNA silencing of WT p53 increased the antiproliferative activity of GSK461364A. Furthermore, silencing of p53 or p21/CDKN1A weakened the tetraploidy checkpoint in cells that survived mitotic arrest and mitotic slippage. As many cancer therapies tend to be more effective in p53 WT patients, the higher sensitivity of p53-deficient tumors toward GSK461364A could potentially offer an opportunity to treat tumors that are refractory to other chemotherapies as well as early line therapy for these genotypes. Mol Cancer Ther; 9(7); 2079–89. ©2010 AACR.
PS-341 and Histone Deacetylase Inhibitor Synergistically Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells
Authors: Kim JinKoo , Guan Jean , Chang Insoon , Chen Xiaohong , Han Demin , Wang Cun-Yu 
Published: June 2010

Abstract
Proteasome inhibitor PS-341 (also known as bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, although TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341–induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341–mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341–induced Noxa expression and caspase activation in HNSCC cells. The knockdown of Noxa significantly reduced apoptosis induced by cotreatment of PS-341 and TSA. Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of the PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients. Mol Cancer Ther; 9(7); 1977–84. ©2010 AACR.
The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
Authors: Joshi Sanket , Perera Swetha , Gilbert Jayne , Smith Charlotte M. , Mariana Anna , Gordon Christopher P. , Sakoff Jennette A. , McCluskey Adam , Robinson Phillip J. , Braithwaite Antony W. , Chircop Megan 
Published: June 2010

Abstract
The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer. Mol Cancer Ther; 9(7); 1995–2006. ©2010 AACR.
Tissue Inhibitor of Metalloproteinase-2 Regulates Matrix Metalloproteinase-2–Mediated Endothelial Barrier Dysfunction and Breast Cancer Cell Transmigration through Lung Microvascular Endothelial Cells
Authors: Shen Qiang , Lee Eugene S. , Pitts Robert L. , Wu Mack H. , Yuan Sarah Y. 
Published: June 2010

AbstractMatrix metalloproteinases (MMP) have been implicated in multiple stages of cancer metastasis. Tissue inhibitor of metalloproteinase-2 (TIMP-2) plays an important role in regulating MMP-2 activity. By forming a ternary complex with pro-MMP-2 and its activator MMP-14 on the cell surface, TIMP-2 can either initiate or restrain the cleavage and subsequent activation of MMP-2. Our recent work has shown that breast cancer cell adhesion to vascular endothelial cells activates endothelial MMP-2, promoting tumor cell transendothelial migration (TEME). However, the mechanism of MMP-2 regulation during TEME remains unclear. In the current study, we present evidence that MMP-14 is expressed in both invasive breast cancer cells (MDA-MB-231 and MDA-MB-436) and lung microvascular endothelial cells (HBMVEC-L), whereas TIMP-2 is exclusively expressed and released from the cancer cells. The tumor cell–derived TIMP-2 was further identified as a major determinant of endothelial MMP-2 activity during tumor cell transmigration in the presence of MMP-14. This response was associated with endothelial barrier dysfunction because coculture of MDA-MB-231 or MDA-MB-436 with HBMVEC-L caused a significant decrease in transendothelial electrical resistance concomitantly with endothelial cell-cell junction disruption and tumor cell transmigration. Knockdown of TIMP-2 or inhibition of TIMP-2/MMP-14 attenuated MMP-2–dependent transendothelial electrical resistance response and TEME. These findings suggest a novel interactive role of breast cancer cells and vascular endothelial cells in regulating the TIMP-2/MMP-14/MMP-2 pathway during tumor metastasis. Mol Cancer Res; 8(7); 939–51. ©2010 AACR.
The Predominant WT1 Isoform (+KTS) Encodes a DNA-Binding Protein Targeting the Planar Cell Polarity Gene Scribble in Renal Podocytes
Authors: Wells Julie , Rivera Miguel N. , Kim Woo Jae , Starbuck Kristen , Haber Daniel A. 
Published: June 2010

Abstract
WT1 encodes a tumor suppressor first identified by its inactivation in Wilms' Tumor. Although one WT1 splicing variant encodes a well-characterized zinc finger transcription factor, little is known about the function of the most prevalent WT1 isoform, whose DNA binding domain is disrupted by a three–amino acid (KTS) insertion. Using cells that conditionally express WT1(+KTS), we undertook a genome-wide chromatin immunoprecipitation and cloning analysis to identify candidate WT1(+KTS)–regulated promoters. We identified the planar cell polarity gene Scribble (SCRB) as the first WT1(+KTS) target gene in podocytes of the kidney. WT1 and SCRB expression patterns overlap precisely in developing renal glomeruli of mice, and WT1(+KTS) binds to a 33-nucleotide region within the Scribble promoter in mouse and human cell lines and kidneys. Together, our results support a role for the predominant WT1(+KTS) isoform in transcriptional regulation and suggest a link between the WT1-dependent tumor suppressor pathway and a key component of the planar cell polarity pathway. Mol Cancer Res; 8(7); 975–85. ©2010 AACR.
Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia
Authors: Kuroda Junya , Yamamoto Mio , Nagoshi Hisao , Kobayashi Tsutomu , Sasaki Nana , Shimura Yuji , Horiike Shigeo , Kimura Shinya , Yamauchi Akira , Hirashima Mitsuomi , Taniwaki Masafumi 
Published: June 2010

Abstract
Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl–related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl–unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC50s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant AblT315I, or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics. Mol Cancer Res; 8(7); 994–1001. ©2010 AACR.
Epidermal Growth Factor Receptor Expression and Gene Copy Number in the Risk of Oral Cancer
Authors: Taoudi Benchekroun Mohammed , Saintigny Pierre , Thomas Sufi M. , El-Naggar Adel K. , Papadimitrakopoulou Vassiliki , Ren Hening , Lang Wenhua , Fan You-Hong , Huang Jianhua , Feng Lei , Lee J. Jack , Kim Edward S. , Hong Waun Ki , Johnson Faye M. , Grandis Jennifer R. , Mao Li 
Published: June 2010

AbstractLeukoplakia is the most common premalignant lesion of the oral cavity. Epidermal growth factor receptor (EGFR) abnormalities are associated with oral tumorigenesis and progression. We hypothesized that EGFR expression and gene copy number changes are predictors of the risk of an oral premalignant lesion (OPL) progressing to oral squamous cell carcinoma (OSCC). A formalin-fixed, paraffin-embedded OPL biopsy specimen was collected from each of 162 patients in a randomized controlled clinical trial. We assessed EGFR expression by immunohistochemistry with two methods: a semiquantitative analysis (145 evaluable specimens) and an automated quantitative analysis (127 evaluable specimens). EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) in a subset of 49 OPLs with high EGFR expression defined by the semiquantitative analysis. We analyzed EGFR abnormalities for associations with OSCC development. High EGFR expression occurred in 103 (71%) of the 145 OPLs and was associated with a nonsignificantly higher risk of OSCC (P = 0.10). Twenty (41%) of 49 OPLs assessed by FISH had an increased EGFR gene copy number (FISH-positive). Patients with FISH-positive lesions had a significantly higher incidence of OSCC than did patients with FISH-negative (a normal copy number) lesions (P = 0.0007). Of note, 10 of 11 OSCCs that developed at the site of the examined OPL were in the FISH-positive group, leaving only one FISH-negative OPL that did so (P &lt; 0.0001). Our data indicate that an increased EGFR gene copy number is common in and associated with OSCC development in patients with OPLs expressing high EGFR, particularly OSCC developing at the site of a high-expression OPL; they also suggest that EGFR inhibitors may prevent oral cancer in patients with OPLs having an increased EGFR gene copy number. Cancer Prev Res; 3(7); 800–9. ©2010 AACR.
The Epidermal Growth Factor Receptor Axis: Support for a New Target for Oral Premalignancy
Authors: Rosin Miriam P. , Califano Joseph A. 
Published: June 2010

Abstract
This perspective on the report by Benchekroun et al. in this issue of the journal (beginning on page 800) examines new studies of factors in the epidermal growth factor receptor (EGFR) axis (including copy number alterations at the EGFR locus) that potentially predict the development of oral cancer; this work was conducted in a chemoprevention trial cohort of patients with oral premalignant lesions. The new data raise the possibility that a subset of oral premalignant lesions may benefit from specific therapeutic targeting of the EGFR axis. Cancer Prev Res; 3(7); 797–9. ©2010 AACR.
Mutational Heterogeneity, Modifier Genes, and Environmental Influences Contribute to Phenotypic Diversity of Arrhythmogenic Cardiomyopathy
Authors: Sen-Chowdhry Srijita , Syrris Petros , Pantazis Antonios , Quarta Giovanni , McKenna William J. , Chambers John C. 
Published: June 2010

Background—
Arrhythmogenic cardiomyopathy is one of the leading causes of sudden cardiac death in the ≤35-year age group. The broad phenotypic spectrum encompasses left-dominant and biventricular subtypes, characterized by early left ventricular involvement, as well as the classic right-dominant form, better known as arrhythmogenic right ventricular cardiomyopathy. Mendelian inheritance patterns are accompanied by incomplete penetrance and variable expressivity, the latter manifesting as diversity in morphology, arrhythmic burden, and clinical outcomes.

Methods and Results—
To investigate the role of mutational heterogeneity, genetic modifiers and environmental influences in arrhythmogenic cardiomyopathy, we studied phenotype variability in 9 quantitative traits among an affected-only sample of 231 cases from 48 families. Heritability was estimated by variance component analysis as a guide to the combined influence of mutational and genetic background heterogeneity. Nested ANOVA was used to distinguish mutational and genetic modifier effects. Heritability estimates ranged from 20% to 77%, being highest for left ventricular ejection fraction and right–to–left ventricular volume ratio and lowest for the ventricular arrhythmia grade, suggesting differing genetic and environmental contributions to these traits. ANOVA models indicated a predominant mutation effect for the left ventricular lesion score, an indicator of the extent of fat and late enhancement on cardiovascular magnetic resonance. In contrast, the modifier genetic effect appeared significant for right ventricular end-diastolic volume, ejection fraction, and lesion score; left ventricular ejection fraction; ventricular volume ratio; and arrhythmic events.

Conclusions—
Systematic investigation of modifier genes and environmental influences will be pivotal to understanding clinical diversity in arrhythmogenic cardiomyopathy, refining prognostication, and developing targeted therapies.
Using Insulin Pump Therapy in Poorly Controlled Type 2 Diabetes
Authors: Wolff-McDonagh Phyllis , Kaufmann Judith , Foreman Stephen , Wisotsky Steven , Wisotsky Jo Ann , Wexler Craig 
Published: June 2010

Purpose The purpose of this pilot/feasibility study was to evaluate the use of insulin regimens among individuals with poorly controlled type 2 diabetes. In addition, a secondary aim was to build the body of evidence regarding the use of insulin pumps in patients with type 2 diabetes. Methods The setting was a suburban private endocrinology practice. Patients were a convenience sample of 15 adults, aged 40 to 64 years with poorly controlled type 2 diabetes, as defined by a hemoglobin A1C (A1C) of 8% or higher when continuous subcutaneous insulin infusion (CSII) was initiated. Baseline, 3-month, 6-month, and 1-year A1C, body mass index (BMI), basal and bolus insulin use, and number of office visits were collected through medical record review. Descriptive, independent, and paired t tests were used to evaluate data. Results A significant reduction in basal insulin use was found. Significant reductions in A1Cs were found at 3 months, 6 months, and 1 year. A significant increase in BMI was noted. Conclusions Results indicated improvement in glycemic control with CSII for some patients with an associated increase in BMI. Reduction of basal insulin use was significant and, for some, cost effective using CSII. Current policies regarding CSII use in patients with type 2 diabetes need to be re-evaluated.
Insights from the conduct of a device trial in older persons: low magnitude mechanical stimulation for musculoskeletal health
Authors: Kiel Douglas P , Hannan Marian T , Barton Bruce A , Bouxsein Mary L , Lang Thomas F , Brown Kathleen M , Shane Elizabeth , Magaziner Jay , Zimmerman Sheryl , Rubin Clinton T 
Published: June 2010

Background Osteoporosis is a common complication of aging. Alternatives to pharmacologic treatment are needed for older adults. Nonpharmacologic treatment with low magnitude, high frequency mechanical stimulation has been shown to prevent bone loss in animal and human studies. Methods The VIBES (Vibration to Improve Bone Density in Elderly Subjects) study is a randomized, double-blind, sham-controlled trial of the efficacy of low magnitude, high frequency mechanical stimulation in 200 men and women aged 60 years and older with bone mineral density T-scores by dual X-ray absorptiometry between —1 and —2.5 at entry. Participants are healthy, cognitively intact residents of independent living communities in the Boston area who receive free calcium and Vitamin D supplements. They are randomly assigned to active or sham treatment and stand on their assigned platform once daily for 10 min. All platforms have adherence data collection software downloadable to a laptop computer. Adverse events are closely monitored. 174 participants were randomized and will be followed for 2 years. Almost all active subjects have attained 1 year of follow-up. Bone mineral density is measured by both dual X-ray absorptiometry and quantitative computed tomography at baseline and annually. The main analysis will compare mean changes from baseline in volumetric bone density by quantitative computed tomography in active and sham groups. Adherence and treatment effect magnitude will also be evaluated. Secondary analyses will compare changes in two biochemical markers of bone turnover as well as longitudinal comparisons of muscle and balance endpoints. Results The VIBES trial has completed its first year of data collection and encountered multiple challenges leading to valuable lessons learned about the areas of recruitment from independent living communities, deployment of multiuser mechanical devices using radio frequency identification cards and electronic adherence monitoring, organization of transportation for imaging at a central site, and the expansion of study aims to include additional musculoskeletal outcomes. Conclusions These lessons will guide future investigations in studies of individuals of advanced age. Clinical Trials 2010; 7: 354—367. http://ctj.sagepub.com