bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3554: The fungal metabolite galiellalactone inhibits ALDH positive prostate cancer cells
Authors: Hellsten Rebecka , Dahlman Anna , Culig Zoran , Johansson Martin , Sterner Olov , Bjartell Anders 
Published: February 2011

Abstract
Introduction: Tumor stem cells have shown resistance to conventional cancer therapy and may be a cause for recurrent cancer, making tumor stem cell targeted therapy attractive. The fungal metabolite galiellalactone is suggested to be a Stat3 specific inhibitor and we have previously shown that galiellalactone inhibits prostate cancer (PCa) cell growth, both in vitro and in vivo, in PCa cells expressing phosphorylated Stat3 (Hellsten et al, 2008). Aldehyde dehydrogenase (ALDH) has shown promise as a marker of cancer stem cells and in this study we investigated the ALDH activity in human PCa cell lines and the effects of galiellalactone on ALDH+ PCa cells.
Methods: The human PCa cell lines DU145, LNCaP, and long-term interleukin-6 stimulated LNCaP (LNCaP-IL6) cells were used. Galiellalactone was prepared by synthesis (Johansson & Sterner, 2002). PCa cells were subjected to Aldefluor assay followed by flow cytometry to detect ALDH+ subpopulations. WST-1 proliferation assay was performed to study the effect of galiellalactone on proliferation of ALDH+ and ALDH- cells sorted from LNCaP-IL6 cells.
Results: In DU145 cells 2 ± 0.25% of the cells were ALDH+ and in LNCaP-IL6 cells, 2 ± 0.36% were ALDH+. No ALDH+ cells were detected in LNCaP cells. Treatment with 5, 10, 25 or 50 µM galiellalactone for 24h decreased the ALDH+ cell population in DU145 and LNCaP-IL6 cells in a dose dependent manner: 25 µM galiellalactone decreased the ALDH+ population in DU145 cells by 40% and by 75% in LNCaP-IL6 cells. In LNCaP-IL6 cells a dose dependent decrease in ALDH+ cells was observed after 72h (65% decrease at 25 µM galiellalactone). However, in DU145 cells no difference in the relative amount of ALDH+ cells was observed in galiellalactone treated DU145 cells compared to untreated control cells after 72h. The proliferation was decreased by galiellalactone in a dose dependent manner in all cell populations isolated from LNCaP-IL6 cells. The proliferation of ALDH+ cells isolated from LNCaP-IL6 cells was inhibited by 75%, ALDH- cells by 75% and unsorted LNCaP-IL6 cells by 80% after treatment with 25 µM galiellalactone for 48h.
Conclusions: ALDH+ subpopulations, possibly representing tumor stem cell populations were detected in human PCa cell lines, and were clearly inhibited by galiellalactone. ALDH is associated with cell growth and drug resistance, and targeting ALDH+ PCa cells with galiellalactone may be a novel potent treatment against therapy resistant PCa. The effect and mechanism of galiellalactone treatment of ALDH+ PCa cells will be further investigated.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3554.
Abstract 3559: Celastrol, a unique multifunctional pharmacophore with multiple targets as an effective therapeutic against ErbB2-overexpressing cancers
Authors: Raja Srikumar M. , Clubb Robert J. , Ortega-Cava Cesar , Duan Lei , Bailey Tameka A. , Band Vimla , Band Hamid 
Published: February 2011

Abstract
Celastrol, a novel triterpene natural product, has shown immense promise against various cancer models including prostate cancer, pancreatic cancer, leukemia, and melanoma. A unique property of Celastrol is its ability to affect multiple oncogenic cellular targets that include the proteasome, HSP90, I Kappa B Kinase and the cellular redox-balance system. Celastrol could therefore be viewed as a multifunctional pharmacophore simultaneously affecting multiple targets within oncogenically transformed cell. In this paper we explore the properties of this unique pharmacophore as therapeutic agent for treating ErbB2-overexpressing breast cancers. Celastrol not only induced ubiquitinylation and degradation of ErbB2 and other HSP90 client proteins; it also increased cellular ROS levels, and killed ErbB2-overexpressing cells with higher selectivity. Comparison of IC50 values amongst a panel of breast cancer cell lines indicated a strong correlation of basal ROS-levels to sensitivity to killing. ErbB2-overexpression led to increase in basal ROS and consequently ErbB2-high cells were more sensitive to Celastrol than ErbB2-low cells. Celastrol also strongly synergized with ErbB2-targeted therapeutics, Trastuzumab and Lapatinib, resulting in enhanced ErbB2-specific cellular cytotoxicity at substantially reduced doses of Celastrol. Pharmacogenomic expression analysis comparing 17-AAG and Celastrol confirmed several common signatures and revealed unique signatures. Celastrol, but not 17-AAG, could potently induce depletion of Aurora A Kinase at both the transcript as well as protein level, adding to the spectrum of targets, given the importance of Aurora Kinase as a target in development of anti-cancer therapeutics. In vivo xenograft experiments using ErbB2-overexpressing breast cancer model confirmed the potential of Celastrol as a therapeutic agent for the treatment of ErbB2-overexpressing breast cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3559.
Abstract 3601: Evaluation of a mathematical modeling framework to describe combination therapy with Gemcitabine
Authors: Spilker Mary E. , Yamazaki Shinji , Blasina Alessandra , Hallin Jill , Bartkowski Darian M. , Vicini Paolo 
Published: February 2011

Abstract
The quantitative assessment of the effectiveness of chemotherapeutic combinations is of increasing interest. This is especially true given the complexities of different dosing schedules and animal model systems. This work evaluates a recently proposed mathematical modeling framework (Koch et al., J Pharmacokinet Pharmacodyn 36:179-197, 2009), and modifications thereof, for quantifying synergisms between drugs used in combination therapy based on preclinical data. In this study, we evaluated published NSCLC (H460a) tumor growth inhibition (TGI) data following treatment with Erlotinib and Gemcitabine (Higgins et al., Anticancer Drugs 15: 503-512, 2004), administered both alone and in combination. We simultaneously modeled the pharmacodynamic data from all therapeutic regimens. TGI data from both monotherapy and combination therapy were adequately described. The results suggest that Erlotinib and Gemcitabine at sub-maximal doses work in a synergistic manner to reduce tumor growth. This modeling framework may prove useful in the design and optimization of preclinical experiments involving drug combinations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3601.
Abstract 3602: Radiation pharmacogenomics: an integrative analysis approach to identify biomarkers using the human lymphoblastoid cell lines
Authors: Hou Junmei , Niu Nifang , Qin Yuxin , Fridley Brooke L. , Kalari Krishna , Jenkins Gregory , Batzler Anthony , Wang Liewei 
Published: February 2011

Abstract
Background Radiation therapy is used to treat half of the all cancer patients. Response to radiation therapy varies widely, in terms of both response and toxicity related events. Previous studies suggested almost 80% of the variation in normal tissue response to radiation treatment was likely to be due to genetic factors. Therefore, we performed a genome-wide association study (GWAS) to identify biomarkers that might help predict radiation response using a the “Human Variation Panel” lymphoblastoid cell lines (LCLs) that consists 287 ethnically defined cell lines.
Method Basal gene expression level, 1.3 million genome-wide SNP data were obtained for 287 human LCLs using Affymetrix U133 plus 2.0 GeneChip, Illumina HumanHap 550K, 510S BeadChips and Affymetix SNP Array 6.0. Radiation cytotoxicity assay was also performed to obtain the area under radiation dose response curve (AUC), a summary measure for cytotoxicity for the same cell lines. Functional validation of candidate genes, selected based on the integrated analysis of SNP, expression and AUC data, was performed in multiple cancer cell lines using specific siRNAs followed by MTS and colony formation assays.
Results 27 loci, containing at least 2 SNPs of p values &lt;10−4 within 50kb were associated with radiation AUC. 270 expression probe sets were associated with radiation AUC (p&lt; 10−3). The integrated analysis of 27 loci, 54,000 basal expression probe sets and radiation AUC identified 50 unique SNPs associated with AUC were also associated with gene expression of 39 unique annotated genes. In addition, these 39 genes were associated with radiation AUC with p values &lt;10−3. Based on the GWAS and integrated analysis of SNP, expression array and radiation AUC data, 22 genes were selected for functional validation studies using siRNA knock down followed by MTS and colony formation assays in multiple tumor cell lines. C13orf34 (Bora), MAD2L1, PLK4, TPD52 significantly altered the radiation sensitivity in at least 2 cancer cell lines for both MTS and colony formation assays (p&lt;0.05). Knock down of DEPDC1B, a gene containing 2 SNPs at the 3′-end that was significantly related with Bora gene expression level (p&lt;10−4) significantly desensitized cancer cells to radiation treatment. Both microarray data and QRT-PCR analysis indicated that expression levels for those two genes were significantly correlated. Conclusion Our results using the lymphoblastoid cell lines might help identify novel biomarkers that contribute to variation in response to radiation therapy and help understand the mechanisms underlying the association.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3602.
Abstract 3605: Enterohepatic circulation of indolecarboxamide ML-970 (NSC 716970), an investigative anticancer agent
Authors: Rayburn Elizabeth , Wang Wei , Grau Silvana , Li Haibo , Xu Hongxia , Zhang Xu , Li Mao , Sommers Charnell , Jia Lee , Lee Moses , Zhang Ruiwen 
Published: February 2011

Abstract
ML-970 (NSC 716970), an analog of CC-1065 (a DNA minor-groove binding agent) is under preclinical investigation as a novel anticancer agent. The compound has shown in vitro and in vivo anti-cancer activity. As part of the preclinical evaluation of this agent, we carried out pharmacokinetic studies of ML-970 in CD-1 and nude mice. Of interest, we observed that there was minimal urinary and fecal excretion of the agent within the first 24 hr and relatively low concentrations of the compound in tissues examined (lungs, kidneys, heart, spleen, brain). Additionally, the compound was still detectable at low levels in the plasma for at least 8 hr, and in tissues for at least 24 hr after administration, regardless of the routes of administration. Although high levels of plasma protein binding of the compound may be partially responsible, it was apparent that other factors might be contributing. To examine the underlying mechanism, we performed a pharmacokinetic study evaluating the distribution of the compound in tissues, organs, and organ contents (plasma, liver, lungs, kidneys, spleen, heart, brain, stomach, stomach contents, small intestine, small intestine contents, large intestine, large intestine contents, gallbladder, muscle, urine and feces) after i.v. and oral administration. We found the highest levels of the compound in the gallbladder, small intestine, small intestine contents, large intestine contents and liver, regardless of route of administration. Concentrations of 314.7μg/g, 1383.5μg/g, and 392.6μg/g for 0.5, 2, and 8 hr after i.v. injection, and 28.0μg/g, 313.1μg/g, and 123.7μg/g for 0.5, 2, and 8 hr after oral administration, respectively, were observed for the gallbladder. Average concentrations higher than 19 μg/g were found in the other tissues for at least one time point (range: 19.3μg/g to 286.2μg/g). The high concentrations present in gastrointestinal and hepato-biliary organs, persistence of the compound, and relatively low levels of urinary and fecal excretion during the first 24 hr, indicate that the compound undergoes enterohepatic circulation. These results should be useful for interpretation of future preclinical and clinical developmental studies of ML-970. (This work was supported by NCI Contract N01-CM-52207.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3605.
Abstract 3607: The effect of gefitinib on the expression of c-MYC and TSP-1 in cancer cells
Authors: Suenaga Mitsuhiro , Tei Chuwa , Akiyama Shin-ichi 
Published: February 2011

Abstract
Gefitinib is a selective inhibitor of epidermal growth factor receptor tyrosine kinase, and is known to suppress tumor angiogenesis. We previously reported that gefitinib suppressed E2F-1 expression and telomerase activity in A431 and A549 cells. The expression of hTERT was increased by c-MYC, whereas we found that 5-FU decreased the expression of c-MYC and increased Thrombospondin-1 (TSP-1) expression. In the present study, we examined the effects of gefitinib on the expression of c-MYC and TSP-1 in human epidermmoid carcinoma A431 and lung adenocarcinoma A549 cells. Gefitinib suppressed the expression of c-MYC in both of two cell lines within 12 hours after gefitinib exposure, however, the expression of c-MYC mRNA was reduced only in A431 cells. A549 cells are known to have K-RAS mutation but A431 cells do not. We suppose that post-transcriptional inhibition or degradation of c-MYC had been induced by the treatment with gefitinib. MG132, a proteasome inhibitor, could inhibit the suppression of c-MYC expression by gefitinib exposure in both of these cells. Thus, the promotion of c-MYC degradation may be one of the mechanisms of the suppression of c-MYC expression by gefitinib exposure on these cells.
On the other hand, in A549 cells, 5-20μM of gefitinib suppressed the expression of c-MYC after incubation for 96 hours too, while TSP-1 expression was increased by gefitinib. In A431 cells, 0.12-1.0μM of gefitinib affected the expression of c-MYC and TSP-1. As in A549 cells, TSP-1 expression was up-regulated but the expression of c-MYC was attenuated by gefitinib. Our findings suggest that the anti-angiogenic effects of gefitinib might be, at least in part, due to TSP-1 expression augmented by gefitinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3607.
Abstract 361: Large scale virtual screening to identify novel inhibitors of Fyn as potential drugs for cancer treatment
Authors: Mottamal Madhusoodanan , Kim Jong-Eun , Kang Nam Joo , Lee Ki Won , Sosa Carlos P. , Bode Ann M. , Dong Zigang 
Published: February 2011

Abstract
Protein kinases are involved in a number of signaling cascades and they are considered as one of the major classes of potential drug targets. Overexpression of protein kinases is often found in many human cancers. Fyn, a member of the Src family of tyrosine kinases, plays a critical role in T-cell receptor signaling, brain function, and cell adhesion-mediated signaling. More importantly, Fyn has oncogenic potential and is involved in carcinogenesis processes, including skin cancer development. These properties make Fyn an ideal molecular target for chemoprevention of skin cancer and other diseases. Molecular docking-based virtual screening has become an important tool in the drug discovery process, and it significantly reduces the number of possible chemical compounds to be investigated. In the present study, we carried out virtual screening of chemical databases to find potential inhibitors of Fyn by targeting the ATP-binding pocket. Because binding of ATP to a protein kinase is essential for the phosphotransferase activity of kinases, the ATP-binding pocket is often considered as the first potentially effective target of most inhibitor screens. Potential Fyn kinase activity inhibitors were identified based on the docking score and selected compounds were subjected to in vitro and cellular assays. The in vitro kinase assay has resulted in the identification of a compound with strong (&lt;50 nM) inhibition of Fyn kinase activity. The same compound was found to suppress UVB-induced Fyn kinase activity in JB6 P+ cells. The inhibitor also suppressed UVB-induced cyclooxygenase-2 expression in JB6 P+ cells, indicating its involvement in skin carcinogenesis. Thus, by using virtual screening, we have identified a potential drug candidate to prevent UVB-induced skin cancer. Studies are in progress to validate our observations in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 361.
Abstract 3611: LY2801653, an orally available small molecule inhibitor of c-Met, demonstrated broad antitumor efficacy in patient derived xenograft models
Authors: Yang Wei J. , Credille Kelly , Gao Hong , Uhlik Mark , Pomeroy Julie , Walgren Richard , Shih Chuan , Baltes Steffen , Beckers Thomas , Yingling Jonathan M. 
Published: February 2011

Abstract
The receptor tyrosine kinase c-Met and its ligand hepatocyte growth factor (HGF) play important roles in cell growth, migration, and survival. Dysregulation of the c-Met/HGF signaling pathway has been found in many human malignancies. LY2801653 was identified and developed as a novel, potent, and orally active small molecule inhibitor of human c-Met. It demonstrated dose dependent inhibition of c-Met phosphorylation in xenograft tumors with a long lasting PD effect. In the current study, the anti-tumor activity of LY2801653 was evaluated in a panel of human patient derived xenograft models. LY2801653 displayed potent anti-tumor efficacy in a number of non small cell lung, renal, pancreatic, and breast tumor models. Examination of c-Met expression in these tumors by immunohistochemistry (IHC) revealed a good correlation between response and c-Met expression in the tumor tissue. Interestingly, the two non small cell lung adenocarcinoma models LXFA526 and LXFA1647 that were resistant to EGFR inhibitors Cetuximab and Erlotinib, displayed high sensitivity towards LY2801653. High level of genomic amplification of c-Met locus was found in these models, consistent with the hypothesis that c-Met activation represents one of the resistant mechanisms to EGFR inhibition. LY2801653 treatment led to increase in functional vessel areas, and decrease in tumor hypoxia. Enhanced anti-tumor efficacy was achieved when Erlotinib was combined with LY2801653. In summary, these results demonstrated the promising therapeutic potential of LY2801653 in mono and combination therapy of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3611.
Abstract 3614: Multi-targeted kinase inhibitor E7080 showed anti-tumor activity against medullary thyroid carcinoma and squamous thyroid carcinoma cell line based on RET and VEGFR2 tyrosine kinase inhibition
Authors: Matsui Junji , Minoshima Yukinori , Tsuruoka Akihiko , Funahashi Yasuhiro 
Published: February 2011

Abstract
There are about 37,000 and 8,000 new cases of thyroid cancer each year in the US and JP respectively, according to reports of the National Cancer Institute and National Cancer Center in Japan. Thyroid cancer is one of most common cancers after age 30, and its aggressiveness increases significantly in older patients. VEGFR tyrosine kinase inhibitors showed anti-tumor activity against thyroid carcinoma in early clinical study and some of inhibitors have been tested in late stage of clinical trial.
E7080, a multi-targeted kinase inhibitor, potently inhibits VEGFR1-3, FGFR1-4 and RET tyrosine kinases and has been tested in several PhII trials including thyroid carcinoma trial. In this study, we report the efficacy of E7080 as an anti-cancer agent for thyroid carcinoma, based on both anti-tumorigenic activity and anti-angiogenic activity.
E7080 inhibit RET kinase and VEGFR2 kinase with Ki values of 1.5 and 0.74 nmol/L, respectively, in cell free kinase assays. E7080 inhibited proliferation and phosphorylation of RET as well that of downstream Erk1/2 in medullary thyroid carcinoma (MTC) cell lines, TT and MTC-M, which expressed RET kinase in a dose dependent manner. E7080 showed significantly anti-tumor activity at the dose of 10-100 mg/kg in TT xenograft and 1-100 mg/kg in MTC xenograft without affecting microvessel density, suggesting that anti-tumor activity was caused by anti-tumorigenic activity based on RET kinase inhibition. On the other hand, E7080 did not show anti-proliferative activity against thyroid squamous carcinoma cell line, SW579, which did not expressed RET kinase, even at 10 µmol/L of E7080. While E7080 significantly inhibited in vivo growth of SW579 tumor in nude mice, accompanied by decreased of microvessel density within xenografted tumors at 3 - 100 mg/kg.
These results demonstrated that the blockage of RET and VEGFR2 was a promising therapeutic strategy against several types of thyroid carcinoma and E7080, a dual inhibitor of both VEGFR2 and RET tyrosine kinase, is warranted to be examined for thyroid cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3614.