bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C212: Pharmacological and pharmacokinetc characterization of RP1040, a novel and potent c-Met tyrosine kinase inhibitor
Authors: Viswanadha Srikant , Muthuppalaniappan Meyyappan , Varanasi Kanthikiran VS , Veeraraghavan Sridhar , Thainashmuthu Josephrajan , Murugan Sivan Perumal , Kakarla Prasad Babu , Kuppireddi Sumalatha , Vakkalanka Swaroop 
Published: June 2012

Abstract
Background: Receptor tyrosine kinases (RTK) represent a class of high affinity cell surface receptors that play a critical role in the development and progression of several types of cancers. Among the receptor tyrosine kinases, c-Met mediates diverse cellular responses critical for tumor progression, growth, and survival. Alteration of the c-Met signalling cascade represents an attractive approach aimed at blocking invasion and metastasis of cancer cells. The objective of this study was to investigate the pharmacological and pharmacokinetic properties of RP1040, a novel small-molecule inhibitor of c-Met kinase.
Methods: c-Met Kinase activity of RP1040 was determined using using an HTScan® recombinant human Met Kinase Assay Kit (Cell Signaling Technology, Beverly, MA) with modifications. Viability assay (MTT) was conducted to determine the growth inhibitory effect of the compound on the high c-Met expressing sk-LMS-1 cell line. Metabolic stability of the compound was evaluated in microsomes obtained from mouse, rat, dog, monkey, and human. Pharmacokinetic behaviour of RP1040 in plasma after single dose oral administration or IV injection was determined in male Wistar rats.
Results: RP1040 demonstrated remarkable potency against the purified Met kinase by inhibiting enzyme activity at low nanomolar concentrations (IC50 = 1.3 nM). In addition, the compound caused a significant reduction in viability of sk-LMS-1 cells stimulated with 100 ng/ml HGF (IC50 = 0.03 nM). Pharmacokinetic studies indicated good oral absorption of RP1040 with plasma concentrations above 100 nM up to 24 h post administration. The compound had an elimination half-life of 8.95 hr with a clearance value of 4.21 ml/min/kg indicating a propensity to act as a long acting drug in this class. Further, RP1040 was metabolically stable across the species studied.
Conclusions: Our results demonstrate that RP1040 is a potent c-Met kinase inhibitor with a favourable pharmacokinetic profile and superior IC50 values compared to existing c-Met kinase inhibitors in development. RP1040 is currently being tested for in vitro and in vivo efficacy across various cancer cell lines and xenograft models besides selectivity against other receptor tyrosine kinases.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C212.
Abstract C213: Sorafenib blocks tumor growth, angiogenesis, and metastatic potential in preclinical models of osteosarcoma through the inhibition of ERK1/2, MCL-1, and ezrin pathways
Authors: Pignochino Ymera , Grignani Giovanni , Cavalloni Giuliana , Tapparo Marta , Motta Manuela , Bruno Stefania , Bottos Alessia , Gammaitoni Loretta , Camussi Giovanni , Migliardi Giorgia , Alberghini Marco , Torchio Bruno , Ferrari Stefano , Picci Piero , Fagioli Franca , Aglietta Massimo 
Published: June 2012

Abstract
Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory.
We explored phospho-ERK 1/2, MCL-1, phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets. The activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS. While, BRAF gene was found mutated in 4/30 OS samples from patients. Based on these results we tested the multikinases inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell lines proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, P-ERM in a dose dependent manner. ERM dephosphorylation is not due to ERK inhibition. The downregulation of MCL-1 increased apoptosis in OS cell lines. In chick embryo chorioallantoic membrane the angiogenesis induced by OS supernatants was blocked by sorafenib treatments. Indeed, sorafenib reduced VEGF and MMP2 production. Sorafenib treatment dramatically reduced tumor volume of OS xenografts and lung metastasis in SCID mice.
In conclusion, ERK1/2, MCL-1 and ERM pathways are active in OS. Sorafenib is able to interrupt their routes in vitro and in vivo displaying antitumoral activity, antiangiogenic effect and reducing metastasis colonies formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients failing standard treatments.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C213.
Abstract C227: Doxorubicin induces AKT phosphorylation through activation of the aryl hydrocarbon receptor in the heart
Authors: Maria Volkova , Ozcan Cevher , Palmeri Monica , Russell Raymond 
Published: June 2012

Abstract
Doxorubicin (DOX) is one of the most effective anticancer drugs in treating different types of tumors. However, cumulative cardiotoxicity is a significant side effect of this therapy resulting in clinical heart failure through the production of reactive oxygen species (ROS). However, the protective responses of the heart to DOX treatment are still unknown. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is primarily involved in the detoxification of xenobiotic agents that generate ROS. Activation of AhR results in its migration to the nucleus where it dimerizes with ARNT1 to form a transcription factor for genes coding many phase I drug metabolizing enzymes, such as the cytochrome P450, CYP1A1. We hypothesize that DOX treatment activates AhR and triggers Akt phosphorylation as a protective mechanism against oxidant stress. H9C2 cells incubated with 2.5 M DOX for 4 hours showed a significant increase of AhR protein levels in the nuclear fraction, which then decreased to baseline levels by 24 hours of treatment. The same pattern of change was seen for CYP1A1 expression. Immunoprecipitation of the nuclear protein fraction with AhR antibodies and subsequent immunoblotting with ARNT1 antibodies showed increased binding between these proteins after 4 hours of DOX treatment. Similar results were shown when ARNT1 immunoprecipitation and AhR immunoblotting were performed. Increased phosphorylation of Akt at Ser473 was detected at 4 hours of DOX treatment, which decreased by 24 hours. A similar temporal pattern of phosphorylation was identified for known downstream targets of Akt (pSer9-GSK3 and pSer136-BAD). Transfection with either AhR or ARNT1 siRNAs blocked the phosphorylation of Akt following DOX treatment in H9C2 cells, increased ROS production as well as cytotoxicity. DOX treatment of isolated adult rat cardiomyocytes showed similar pattern of changes in Akt phosphorylation and its downstream targets as well as increased oxidative stress. In mice injected with 10 mg/kg DOX, AhR translocated into the nucleus by 4 hours after injection, which was associated with ARNT1 binding and increased CYP1A1 expression. Phosphorylation of Akt, GSK3 and BAD increased by 24 hours after DOX injection. Oxidative stress was significantly higher in mice injected with DOX after 4 hours. We conclude that the early cardiac response to DOX treatment involves Akt phosphorylation through AhR activation.Moreover, silencing of AhR might lead to higher oxidative stress and increased cellular toxicity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C227.
Abstract C231: A great mime produced by nature: The case of paclitaxel
Authors: Ferlini Cristiano , Raspaglio Giuseppina , Cicchillitti Lucia , Bartollino Silvia , Gallo Daniela , Persico Marco , Fattorusso Caterina , Scambia Giovanni 
Published: June 2012

Abstract
Paclitaxel is widely used in the medical treatment of solid tumors. Despite the clinical success still now the exact mechanism(s) through which the drug kills cancer cells are unknown. In this work we provide evidence, through Surface Plasmon Resonance technology, that paclitaxel beside to microtubules is able also to target mitochondria by directly interacting with the disordered loop of Bcl-2, thereby stimulating the opening of the permeability transition pore channel and ultimately reverting Bcl-2 function from antiapoptotic to proapoptotic. Studying the paclitaxel binding site in Bcl-2, we discovered through molecular modeling that it is positioned in the disordered loop domain and is extraordinarily similar to that experimentally defined in beta-tubulin, thereby prompting us to speculate that paclitaxel is a peptidomimetic factor. Since to our knowledge, the only factor able to revert the Bcl-2 function from protector to cell killer is Nur77, we tested the hypothesis that paclitaxel mimics the activity of Nur77. To address this issue, coimmunoprecipitation experiments demonstrated that like paclitaxel Nur77 interacts with Bcl-2 in the disordered loop domain and with beta-tubulin. Moreover, stably transformed cells with Nur77 show the classical slow band isoform of Bcl-2 detectable in cells treated with paclitaxel. Finally, interaction between Nur-77 and Bcl-2 was inhibited by paclitaxel, thus demonstrating that the drug and Nur77 compete for the binding to Bcl-2. The discovery of the molecular component mimicked by paclitaxel could promote the development of novel agonists of the paclitaxel receptor with a nontaxane structure.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C231.
Abstract C232: ALB-109564, a novel tubulin inhibitor with improved efficacy over vinorelbine, is better tolerated when dosed iv versus ip, leading to improved activity in human tumor xenograft studies
Authors: Wolf Mark A. , Johnson Randall K. , Xie Deijian , Avrutskaya Anna , Mullin Robert , Godfrey Beverly , Mead Mary Ann , Trachet Erin E. , Leopold Wilbur R. , Guzzo Peter , Scott Ian 
Published: June 2012

Abstract
Purpose: ALB-109564 is a novel semi-synthetic Vinca alkaloid which is currently in a Phase I clinical trial. The antitumor activity of ALB-109564 was compared to vinorelbine in human tumor xenograft studies when dosed ip and iv.
Methods: The maximum tolerated dose (MTD) of ALB-109564 and vinorelbine was determined in athymic nude mice using both ip and iv dosing on q4dx4 and q7dx4 schedules. Athymic nude mice (n = 10) were implanted sc with a number of human tumor cell lines. Following establishment of measurable tumors, mice received equivalent therapeutic doses, based on their MTDs, of vinorelbine and ALB-109564. Vinorelbine and ALB-109564 were compared by dosing ip (q4dx4) in a panel of five xenografts (H460 NSCLC, Colo205 colon cancer, PC3 prostate cancer, H69 SCLC, and MX-1 breast cancer). Additionally, a comparison of ALB-109564 and vinorelbine was run dosing iv on a q7dx4 schedule in two xenograft models (PC3 and H460).
Results: It was discovered that ALB-109564 and vinorelbine were better tolerated when dosed iv rather than ip, allowing higher dose levels of both agents. For example, the MTD for ALB-109564 using the q4dx4 schedule was 6 mpk ip compared with 14 mpk iv. ALB-109564 demonstrated antitumor activity superior to vinorelbine when dosed at their respective MTDs ip. Statistically significant tumor growth delays (TGDs) were observed with ALB-109564 in four of the five xenografts studied while vinorelbine did not significantly delay tumor growth in any of the models when dosing ip. A comparison of the two agents dosed iv in the PC3 and H460 xenograft models showed that both agents induced significant TGDs in both models with ALB-109564 showing superior efficacy in the H460 study (35.7 days TGD vs. 15.7 days at respective MTDs).
Conclusions: Preclinical evaluation of tubulin inhibitor ALB-109564 (12′-methylthiovinblastine dihydrochloride) demonstrated in vivo oncolytic activity against several human tumor cell types in xenograft models greater than that seen with vinorelbine. These results demonstrate that minor structural modifications of vinca alkaloids can have a large impact on activity. Based on these results a Phase I clinical study with ALB-109564 was initiated in August 2008 and is ongoing through dose-escalation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C232.
Abstract C235: OXi4503: A novel vascular disrupting agent that enhances radiation-induced local tumor control when given alone or as part of a trimodality therapy
Authors: Horsman Michael R. , Nomura Miwako , Hokland Steffen 
Published: June 2012

Abstract
Background: OXi4503 is a novel vascular disrupting agent (VDA) with single agent activity against solid tumors. However, its potential application in cancer therapy lies in its combination with more conventional therapies. The aim of this study was to determine its interaction with radiation when given alone or as part of a trimodality treatment schedule that also included cisplatin or mild temperature hyperthermia.
Material and Methods: Restrained non-anaesthetised CDF1 mice, with a 200 cubic mm C3H mammary carcinoma grown in the right rear foot, were used. Tumors were locally irradiated (240 kV x-rays) with single graded radiation doses. OXi4503 (50 mg/kg) and cisplatin (6 mg/kg) were prepared fresh before each experiment and injected intraperitoneally in a saline mixture at 0.02 ml/g body weight. Previous tumor growth studies had shown that the combination of OXi4503 with radiation was independent of timing and sequencing, thus it was always given within the first 60 minutes after irradiating. But, for cisplatin the optimal effect with radiation and/or OXi4503 was when the cisplatin was administered 3-hours later. Mild temperature hyperthermia (41.5°C; 1-hour) involved immersing the tumor bearing foot in a water bath and was always started 4-hours after irradiating. The response endpoint was the percentage of mice in each treatment group showing local tumor control 90 days after irradiating. From full radiation dose response curves, the TCD50 values (radiation dose to control 50% of tumors) were estimated. A Chi-squared test (significance level of p&lt;0.05) was used to statistically compare the TCD50 results.
Results: The TCD50 value (with 95% confidence interval) for radiation alone was 53 Gy (50–56). Irradiating tumors and then injecting OXi4503 significantly reduced this to 43 Gy (40–44). Injecting cisplatin 3-hours after irradiating had absolutely no effect on radiation response; the TCD50 being 53 Gy (50–56), but combining all 3 modalities gave the lowest TCD50 value of 41 Gy (38–43). Mild temperature hyperthermia produced a small yet significant reduction in the radiation TCD50 value to 47 Gy (45–50), But, the greatest enhancement was obtained when radiation, OXi4503 and heat were combined. With this combination the TCD50 was significantly reduced to 37 Gy (34–41).
Conclusions: OXi4503 on its own significantly enhanced the response of this C3H mammary carcinoma to radiation. Although cisplatin and mild hyperthermia had little or no effect on radiation-induced local tumor control, combining these therapies with OXi4503 resulted in the greatest enhancement of radiation response. This VDA clearly has a role to play in combination with radiation therapy whether used on its own or as part of a multimodality schedule.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C235.
Abstract C236: A novel oxime-containing flavone anticancer agent, WTC01, exhibits potent microtubule disruption ability
Authors: Juang Shin-Hun , Lee Chao-Hsun , Lin Yu-Chin , Chaing Chang-Ying , Wang Tai-Chi 
Published: June 2012

Abstract
Flavonoids and its derivatives are common components found in human diet. Several studies indicated flavonoids could benefit in cancer prevention or therapy, but their structure-activity relationships (SAR) remain poorly defined. In order to further understand the SAR, a series of oxime-containing flavone derivatives were designed, synthesized and evaluated for their biological anti-cancer potential. The anti-proliferative ability of these compounds was measured by several human cancer cell lines from different origins including nasopharyngeal cancer (NPC-TW01), leukemia (MT-2) and lung carcinoma (H661). Among over 30 different oxime-containing flavone derivatives, (Z)-6-[2-hydroxyimino-2-(4-methoxyphenyl)ethoxy]-2-phenyl -4H-1- benzopyran-4-one (WTC01) possessed potent activity against NPC-TW01 growth with IC50 of 400 nM. As determined by flow cytometry, WTC01 treatment results in an accumulation of NPC-TW01 cells in G2-M phase following a 6-h exposure with amaximum accumulation observed by 18 h. Furthermore, Annexin-V/propidium iodide (PI) binding assay, Hoechst 33258/PI double staining, and PARP cleavage indicates that cell death proceeded through an apoptotic pathway. Interestingly,WTC01 also causes mitochondrial transmembrane potential loss and activation of caspase-9 and caspase-3 without noticeable activation of the caspase-8. These results suggest that the WTC01-mediated apoptotic signaling pathway depends on the mitochondria and caspase-9/-3 cascades. Further studies showed that WTC01 inhibits microtubule assembly in a concentration-dependent manner, this data suggests that tubulin may serve as the cellular target for WTC01. Taken together, these findings indicated that WTC01, a novel synthetic oxime-containing flavone, exhibits potent activity against cancer growth through the disruption of microtubule and has potential for management of nasopharyngeal malignancies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C236.
Abstract C24: Methylation of AKAP12 promoter in lung cancer
Authors: Kim Yeul Hong , Jo Uk Hyun , Whang Young Mi , Sung Jae Sook , Park Kyong Hwa 
Published: June 2012

Abstract
AKAP12 play an important role in tumor growth suppression by inducing apoptosis with the regulation of multiple molecules in the cell cycle progression. This function of AKAP12 gene might be inhibited by epigenetic repression like other tumor suppressor genes. In the previous report, we showed that AKAP12 inactivation was associated with the promoter methylation in the lung cancer. In the present study, to investigate whether the promoter methylation of AKAP12 gene affects the expression of AKAP12 protein, we carried out in vitro methylation assay and protein analysis. We also performed methylation profiling of AKAP12 promoter using the bisulfite-sequencing in the additional matched normal and lung cancer tissue DNA, and serum DNA samples. The expression of the AKAP12 protein was down-regulated in lung cancer cells. The reduced expression of AKAP12 protein was restored by the treatment of the DNA methyltransferase inhibitor. AKAP12 fragments pGL3-837 M (methylated) and pGL3-443 M (methylated) showed low luciferase activities compared to the unmethylated constructs. CpG islands of the AKAP12 promoter were frequently methylated in tumor samples compared with normal tissue samples. Furthermore, CpG islands methylation of AKAP12 was more frequently found in non-relapse patients after surgery compared to early relapse patients within 2 years after surgery.
In conclusion, our results demonstrated that AKAP12 expression was regulated by DNA methylation and AKAP12 promoter methylation was associated with lung cancer development and prognosis after surgery. This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A010250) and Seoul Research and Business Development Program (10574)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C24.
Abstract C247: Noninvasive optical imaging of the tumor microenvironment within the hollow fibre assay: A model for the evaluation of novel anticancer agents
Authors: Whelband Elisabeth , Kumari Rajendra , Grabowska Anna M. , Argent Richard H. , Shams-Nateri Abdol , Watson Susan A. 
Published: June 2012

Abstract
The hollow fibre assay (HFA) facilitates the short-term assessment of cancer drug efficacy in vivo, bridging in vitro screening methods and more complex xenograft in vivo models. However a drawback of this model is the need for end-stage cell recovery and assessment in order to determine the test compound effects. An additional limitation of this system is the use of a homogenous population of epithelial cells, which is not representative of the solid tumor micro-environment, a critical component in tumor progression and the development of drug resistance. The aims of our current research were to recapitulate the human tumor micro-environment within the hollow fibre model and apply a real-time bio-imaging component to enable the non-invasive analysis of drug responsiveness and toxicity in addition to evaluate markers of tumor progression, which was confirmed histologically.
Using epithelial tumor cells stably expressing fluorescent/bioluminescent reporter genes, we have investigated cell viability and the response to cytotoxic treatment in the presence and absence of human mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) both within in vitro cell cultures and the HFA. Real-time imaging of bioluminescent tumor cells demonstrated that these cells can actively proliferate for up to 16 days within the hollow fibres. In the presence of MSCs or CAFs tumor growth was significantly enhanced compared with tumor cells alone and immuno—staining analysis revealed stromal deposits around the periphery of the fibre with MSCs acquiring a ‘myofibroblastic’ phenotype with prolonged culture, resulting in growth promoting effects similar to CAFs. Tumor cells expressing dual reporters with luciferase under the control of 3 hypoxia response elements (HREs) and RFP driven by a CMV promoter confirmed the development of hypoxia within the HFA and enabled further investigation of cancer stem cell development and epithelial:mesenchymal transition. This re-capitulation of the human tumor micro-environment provides a relevant model by which to identify and characterise novel anti-cancer compounds.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C247.