bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fas-mediated killing of primary prostate cancer cells is increased by mitoxantrone and docetaxel
Authors: Symes Juliane C. , Kurin Michael , Fleshner Neil E. , Medin Jeffrey A. 
Published: September 2008

Abstract
Therapies for prostate cancer based on Fas (CD95) modulation have been under active development at the preclinical stage using immortalized cell lines. To address clinical applicability, the potential of 11 cultures of primary prostate cancer cells to be killed by Fas-mediated apoptosis was investigated. In addition, the effect of the chemotherapeutic agents mitoxantrone and docetaxel on this killing was determined. Apoptosis was induced in patient-derived, primary prostate cancer cells using effector cells engineered by recombinant lentivirus infection to express Fas ligand (FasL) and measured by 51Cr release assays. All cultured prostate cells were found to undergo Fas-mediated killing; cytotoxicity ranged from 12% to 87% after 6 h. These cells were significantly more sensitive to FasL-mediated killing than PC-3 cells. The basal expression of Fas or the expression of five inhibitors of apoptosis (c-FLIP, survivin, cellular inhibitors of apoptosis protein 1 and 2, and bcl-2) was not found to correlate with susceptibility to Fas-mediated killing. Both mitoxantrone and docetaxel were able to induce Fas receptor expression on primary prostate cancer cells, which translated into a 1.5- to 3-fold enhancement of apoptosis mediated by FasL. Whereas mitoxantrone increased the Fas-induced apoptotic response of all cultured prostate cells tested, docetaxel pretreatment was found to preferentially enhance the killing of bcl-2-expressing cells. These findings show that cultured primary prostate cancer cells are sensitive to Fas-mediated apoptosis. Furthermore, the incidence of apoptosis was found to be improved by combining Fas-mediated therapy with standard chemotherapeutic agents. These findings may have significant implications for prostate cancer therapy. [Mol Cancer Ther 2008;7(9):3018–28]
17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
Authors: Bruno Robert D. , Gover Tony D. , Burger Angelika M. , Brodie Angela M. , Njar Vincent C.O. 
Published: September 2008

AbstractInhibitors of the enzyme 17α-hydroxylase/17,20 lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 lyase inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G0 phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]
AAV-HGFK1 and Ad-p53 cocktail therapy prolongs survival of mice with colon cancer
Authors: Nie Biao , Shen Zan , Wen Jun-Bao , Wong Oscar Gee-Wan , Hsueh Wayne D. , Huo Long-Fei , Kung Hsiang-Fu , Jiang Bo , Lin Marie C.M. 
Published: September 2008

Abstract
This study tried to evaluate the application of a novel cancer gene therapy using recombinant adeno-associated virus (AAV) carrying the kringle 1 domain of human hepatocyte growth factor (AAV-HGFK1) in combination with recombinant adenovirus carrying p53 gene (Ad-p53). BALB/c and nude mice models of colon cancer were established and the mice were treated with AAV-HGFK1 alone or in combination with Ad-p53. Combination of AAV-HGFK1 and Ad-p53 significantly prolonged the survival of the mice and also significantly inhibited primary and secondary tumor growth. Histochemical examination of the tumors revealed that AAV-HGFK1+Ad-p53 combinatorial treatment not only induced necrosis and apoptosis in the tumors but also suppressed tumor angiogenesis. The antiangiogenesis effect could likely be attributed to the ability of AAV-HGFK1+Ad-p53 viral cocktail to inhibit endothelial cell migration and proliferation. AAV-HGFK1+Ad-p53 also inhibited tumor cell growth in vitro by inhibiting epidermal growth factor receptor phosphorylation. Therefore, AAV-HGFK1+Ad-p53 cocktail therapy has a significantly higher therapeutic effect than AAV-HGFK1 or Ad-p53 alone and is a novel promising gene therapy for colon cancer. [Mol Cancer Ther 2008;7(9):2855–65]
Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway
Authors: Lioni Mercedes , Noma Kazuhiro , Snyder Andrew , Klein-Szanto Andres , Diehl J. Alan , Rustgi Anil K. , Herlyn Meenhard , Smalley Keiran S.M. 
Published: September 2008

Abstract
Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate &lt;5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens. [Mol Cancer Ther 2008;7(9):2866–75]
Polyethylene glycol-mediated colorectal cancer chemoprevention: roles of epidermal growth factor receptor and Snail
Authors: Wali Ramesh K. , Kunte Dhananjay P. , Koetsier Jennifer L. , Bissonnette Marc , Roy Hemant K. 
Published: September 2008

AbstractPolyethylene glycol (PEG) is a clinically widely used agent with profound chemopreventive properties in experimental colon carcinogenesis. We reported previously that Snail/β-catenin signaling may mediate the suppression of epithelial proliferation by PEG, although the upstream events remain unclear. We report herein the role of epidermal growth factor receptor (EGFR), a known mediator of Snail and overepressed in ∼80% of human colorectal cancers, on PEG-mediated antiproliferative and hence antineoplastic effects in azoxymethane (AOM) rats and HT-29 colon cancer cells. AOM rats were randomized to either standard diet or one with 10% PEG-3350 and euthanized 8 weeks later. The colonic samples were subjected to immunohistochemical or Western blot analyses. PEG decreased mucosal EGFR by 60% (P &lt; 0.001). Similar PEG effects were obtained in HT-29 cells. PEG suppressed EGFR protein via lysosmal degradation with no change in mRNA levels. To show that EGFR antagonism per se was responsible for the antiproliferative effect, we inhibited EGFR by either pretreating cells with gefitinib or stably transfecting with EGFR-short hairpin RNA and measured the effect of PEG on proliferation. In either case, PEG effect was blunted, suggesting a vital role of EGFR. Flow cytometric analysis revealed that EGFR-short hairpin RNA cells, besides having reduced membrane EGFR, also expressed low Snail levels (40%), corroborating a strong association. Furthermore, in EGFR silenced cells, PEG effect on EGFR or Snail was muted, similar to that on proliferation. In conclusion, we show that EGFR is the proximate membrane signaling molecule through which PEG initiates antiproliferative activity with Snail/β-catenin pathway playing the central intermediary function. [Mol Cancer Ther 2008;7(9):3103–11]
AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
Authors: Zabludoff Sonya D. , Deng Chun , Grondine Michael R. , Sheehy Adam M. , Ashwell Susan , Caleb Benjamin L. , Green Stephen , Haye Heather R. , Horn Candice L. , Janetka James W. , Liu Dongfang , Mouchet Elizabeth , Ready Shannon , Rosenthal Judith L. , Queva Christophe , Schwartz Gary K. , Taylor Karen J. , Tse Archie N. , Walker Graeme E. , White Anne M. 
Published: September 2008

Abstract
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955–66]
Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase
Authors: Zhong Jieying , Chau Ying 
Published: September 2008

Abstract
Membrane lytic peptides are a novel class of anticancer agents that have the potential to overcome drug resistance. The limited selectivity against cancer cells, however, presents a major hurdle for the application. We aim to exploit the proteolytic activity of tumor-associated matrix metalloproteinases (MMP) to mediate the cytotoxicity of these peptides. We designed a membrane lytic peptide cyclized with a linker cleavable by membrane type 1-MMP (MT1-MMP). We showed that the cyclic peptide could be restored to the linear state on MT1-MMP digestion, and it preferentially killed MMP-overexpressing cells above a threshold concentration. Circular dichroism indicated that cyclization resulted in a more rigid structure, making it more difficult for the lytic peptide to transit from random coil to α-helix in a membrane-mimicking environment. Selective membrane activity of the cyclic peptide was shown by comparing cytotoxicity results on RBC and two human breast cancer cell lines of different malignancy and MT1-MMP expression: highly invasive MDA-MB-435 and noninvasive MCF-7. Above a concentration of 5 μmol/L, suppressed activity to MCF-7 and RBC was observed, whereas the toxicity against MDA-MB-435 was maintained. MMP inhibition experiments further showed that the membrane-lysing activity was enzyme dependent. [Mol Cancer Ther 2008;7(9):2933–40]
Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters
Authors: Okabe Mitsunori , Szakács Gergely , Reimers Mark A. , Suzuki Toshihiro , Hall Matthew D. , Abe Takaaki , Weinstein John N. , Gottesman Michael M. 
Published: September 2008

AbstractMolecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells. [Mol Cancer Ther 2008;7(9):3081–91]
Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells
Authors: Fan Fan , Gray Michael J. , Dallas Nikolaos A. , Yang Anthony D. , Van Buren George , Camp E. Ramsay , Ellis Lee M. 
Published: September 2008

AbstractVascular endothelial growth factor (VEGF) is induced by stress. We determined whether chemotherapy (genotoxic stress) could induce expression of VEGF and VEGF receptors (VEGFR) in human colorectal cancer cells. The colorectal cancer cell lines HT29, RKO, and HCT116 were acutely exposed to increasing doses of oxaliplatin or 5-fluorouracil for 2, 6, and 24 h in vitro. Expression of VEGF ligand family members, VEGFRs, and signaling intermediates was determined by reverse transcription-PCR and Northern and Western blotting. The effect of oxaliplatin on VEGF-A transcriptional activity was determined by promoter assays. Acute exposure of human colorectal cancer cells to oxaliplatin led to a marked induction of VEGF-A mRNA and protein, whereas 5-fluorouracil alone or when added to oxaliplatin did not cause a further increase in VEGF levels. VEGF-A promoter activity was induced by oxaliplatin exposure. Expression of VEGF-C, placental growth factor, VEGFR-1, and neuropilin-1 levels were also increased when cells were treated with oxaliplatin. Oxaliplatin led to an increase in Akt and Src activation in HT29 cells. In contrast, Akt activation did not change in RKO cells whereas phospho-Src and phospho-p44/42 mitogen-activated protein kinase was dramatic increased by oxaliplatin. Inhibition of Akt or Src activation with wortmannin or PP2 blocked induction of VEGF-A by oxaliplatin in HT29 or RKO cells, respectively. VEGFRs may reflect the adaptive stress responses by which tumor cells attempt to protect themselves from genotoxic stress. Neutralization of prosurvival responses with anti-VEGF therapy might explain, in part, some of the beneficial effects of anti-VEGF therapy when added to chemotherapy. [Mol Cancer Ther 2008;7(9):3064–70]
Subseasonal SST Variability in the Tropical Eastern North Pacific during Boreal Summer
Authors: Maloney Eric D. , Chelton Dudley B. , Esbensen Steven K. 
Published: September 2008

Abstract
Boreal summer intraseasonal (30–90-day time scale) sea surface temperature (SST) variability in the east Pacific warm pool is examined using Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) sea surface temperatures during 1998–2005. Intraseasonal SST variance maximizes at two locations in the warm pool: in the vicinity of 9°N, 92°W near the Costa Rica Dome and near the northern edge of the warm pool in the vicinity of 19°N, 108°W. Both locations exhibit a significant spectral peak at 50–60-day periods, time scales characteristic of the Madden–Julian oscillation (MJO). Complex empirical orthogonal function (CEOF) and spectra coherence analyses are used to show that boreal summer intraseasonal SST anomalies are coherent with precipitation anomalies across the east Pacific warm pool. Spatial variations of phase are modest across the warm pool, although evidence exists for the northward progression of intraseasonal SST and precipitation anomalies. Intraseasonal SSTs at the north edge of the warm pool lag those in the vicinity of the Costa Rica Dome by about 1 week.
The MJO explains 30%–40% of the variance of intraseasonal SST anomalies in the east Pacific warm pool during boreal summer. Peak-to-peak SST variations of 0.8°–1.0°C occur during MJO events. SST is approximately in quadrature with MJO precipitation, with suppressed (enhanced) MJO precipitation anomalies leading positive (negative) SST anomalies by 7–10 days. Consistent with the CEOF and coherence analyses, MJO-related SST and precipitation anomalies near the Costa Rica Dome lead those at the northern edge of the warm pool by about 1 week.
Turbulent Condensation of Droplets: Direct Simulation and a Stochastic Model
Authors: Paoli Roberto , Shariff Karim 
Published: September 2008

Abstract
The effect of turbulent mixing on droplet condensation is studied via direct numerical simulations of a population of droplets in a periodic box of homogeneous isotropic turbulence. Each droplet is tracked as a fluid particle whose radius grows by condensation of water vapor. Forcing of the small wavenumbers is used to sustain velocity, vapor, and temperature fluctuations. Temperature and vapor fluctuations lead to supersaturation fluctuations, which are responsible for broadening the droplet size distribution in qualitative agreement with in situ measurements. A model for the condensation of a population of cloud droplets in a homogeneous turbulent flow is presented. The model consists of a set of Langevin (stochastic) equations for the droplet area, supersaturation, and temperature surrounding the droplets. These equations yield corresponding ordinary differential equations for various moments and correlations. The statistics predicted by the model, for instance, the droplet area–supersaturation correlation, reproduce the simulations well.
The Vertical Structure of Mesoscale Convective Vortices
Authors: Davis Christopher A. , Galarneau Thomas J. 
Published: September 2008

Abstract
Simulations of two cases of developing mesoscale convective vortices (MCVs) are examined to determine the dynamics governing the origin and vertical structure of these features. Although one case evolves in strong vertical wind shear and the other evolves in modest shear, the evolutions are remarkably similar. In addition to the well-known mesoscale convergence that spins up vorticity in the midtroposphere, the generation of vorticity in the lower troposphere occurs along the convergent outflow boundary of the parent mesoscale convective system (MCS). Lateral transport of this vorticity from the convective region back beneath the midtropospheric vorticity center is important for obtaining a deep column of cyclonic vorticity. However, this behavior would be only transient without a secondary phase of vorticity growth in the lower troposphere that results from a radical change in the divergence profile favoring lower-tropospheric convergence. Following the decay of the nocturnal MCS, subsequent convection occurs in a condition of greater relative humidity through the lower troposphere and small conditional instability. Vorticity and potential vorticity are efficiently produced near the top of the boundary layer and a cyclonic circulation appears at the surface.
A New Look at Stratospheric Sudden Warmings. Part III: Polar Vortex Evolution and Vertical Structure
Authors: Matthewman N. J. , Esler J. G. , Charlton-Perez A. J. , Polvani L. M. 
Published: September 2008

Abstract
The evolution of the Arctic polar vortex during observed major midwinter stratospheric sudden warmings (SSWs) is investigated for the period 1957–2002, using 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40) Ertel’s potential vorticity (PV) and temperature fields. Time-lag composites of vertically weighted PV, calculated relative to the SSW onset time, are derived for both vortex-displacement SSWs and vortex-splitting SSWs, by averaging over the 15 recorded displacement and 13 splitting events. The evolving vertical structure of the polar vortex during a typical SSW of each type is clearly illustrated by plotting an isosurface of the composite PV field, and is shown to be very close to that observed during representative individual events. Results are verified by comparison with an elliptical diagnostic vortex moment technique.
For both types of SSW, little variation is found between individual events in the orientation of the developing vortex relative to the underlying topography; that is, the location of the vortex during SSWs of each type is largely fixed in relation to the earth’s surface. During each type of SSW, the vortex is found to have a distinctive vertical structure. Vortex-splitting events are typically barotropic, with the vortex split occurring near simultaneously over a large altitude range (20–40 km). In the majority of cases, of the two daughter vortices formed, it is the “Siberian” vortex that dominates over its “Canadian” counterpart. In contrast, displacement events are characterized by a very clear baroclinic structure; the vortex tilts significantly westward with height, so that the top and bottom of the vortex are separated by nearly 180° longitude before the upper vortex is sheared away and destroyed.