bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C148: SC144: The first orally active small molecule gp130 inhibitor for the treatment of ovarian cancer.
Authors: Xu Shili , Grande Fedora , Garofalo Antonio , Neamati Nouri 
Published: June 2012

Abstract
Ovarian cancer is one of the leading causes of cancer-related death in women in the United States. The gp130/Stat3 signaling axis plays an important role in carcinogenesis and drug resistance in a wide variety of human cancers, including ovarian cancer. As a downstream effector of gp130, Stat3 is constitutively activated and plays a critical role in ovarian cancer progression. In this study, we showed that a novel selective small molecule gp130 inhibitor, SC144, suppressed ovarian cancer progression both in vitro and in vivo. SC144 treatment in vitro induced gp130 phosphorylation and deglycosylation, resulting in the downregulation of surface-bound gp130 and the abrogation of gp130-associated Stat3 activation. In addition, SC144 selectively inhibited the downstream signaling activation induced by gp130 substrates, including IL-6 and LIF, whereas SC144 did not exhibit detectable effects on the downstream signaling activation induced by non-gp130 substrates, including IFN-γ, SDF-1α, and PDGF. Protein expression regulated by the gp130/Stat3 axis in OVCAR-8 cells was also down-regulated after SC144 treatment, including Bcl-2, Bcl-XL, survivin, cyclin D1, MMP-7, gp130 and Ape1/Rel-1. In vivo, SC144 significantly inhibited tumor growth in a mouse xenograft model of human ovarian cancer via i.p. or p.o. administration. After SC144 treatment for two months, gp130, Bcl-2, Bcl-XL, MMP-7 and Ape1/Ref-1 protein levels were substantially decreased in the tumor site in the treatment group compared with the control group. Our results further suggest gp130 is a novel drug target for ovarian cancer therapy, and the development of small molecule inhibitors of gp130 can help interrogate this unique signaling pathway in human diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C148.
Abstract C158: Shoc2 gene induces chemotherapy sensitivity in acute lymphoblastic leukemia cell line.
Authors: Silveira Vanessa , Andrade Augusto , Cruzeiro Gustavo , Queiroz Rosane , Tone Luiz Gonzaga , Scrideli Carlos Alberto 
Published: June 2012

Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood and represents a heterogeneous disease regarding its biology and prognosis. Major improvements have been made in the ALL treatment, which achieved successful rates of approximately 80% of long-terms survival. Despite the significant percentage of success, the remaining 20% still presents treatment failure and the molecular mechanisms involved in the resistance process remains unclear. The SHOC2 gene encodes a leucine-rich-repeats (LRR) protein which acts as a positive modulator of the RAS-MAPK signaling cascade. Its gene expression profile was previously related to daunorubicin sensibility in children with ALL, suggesting the correlation of SHOC2 with good prognostic factors. Thus, the present study was undertaken to better understand the possible mechanisms which involve SHOC2 gene to the chemotherapy response process.
Methods: Jurkat, ALL T-type cells, were cultured in standard RPMI medium supplemented with 10% of fetal calf serum (FCS) and transfected with siRNA using lipossomal transfection reagent to silence the gene SHOC2. Mock transfections were also performed. The silencing confirmation was done by real time quantitative PCR and Western blotting. Responsiveness of leukemia cells to vincristine, methotrexate and L-asparaginase was determined by the 4-day XTT in vitro drug resistance assay. The concentrations of L-asparaginase, methotrexate and vincristine were 2–12 IU/mL ASP, 0.25–2.0uM/mL MTX and 4.0–14.0 ng/mL VCR. SHOC2 effect on apoptosis was analyzed by Annexin V staining by flow cytometer. The t-test was conducted to determine statistical significance between two groups in triplicate of two independent experiments. The significance level was set at p ≤ 0.05.
Results: When treated with vincristine and methotrexate, the survival rates of Jurkat cell lines were significantly lower in non-transfected cells than in transfected group (p&lt;0.05). The cytotoxic effects of the chemotherapeutic agent I-asparaginase, however, were not significantly modified by SHOC2 silencing. The apoptosis's induction after 72 hours of chemotherapy agent vincristine treatment did not show significant differences between transfected and non-transfected cells.
Conclusions: this data suggests that the SHOC2 gene could play an important role in leukemic cell's sensibility to chemotherapy agents by modifying the cell proliferation and the apoptosis' processes. Thus, this gene could be considered as a target for developing new therapeutic interventions for ALL treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C158.
Abstract C185: Register trial of sorafenib (S) for patients (pts) with metastatic uveal melanoma (metUvMel).
Authors: Scheulen Max E. , Nokay Bahar , Richly Heike , Hoffmann Andreas C. , Kalkmann Janine , Stattaus Joerg , Bornfeld Norbert , Schuler Martin , Hense Joerg 
Published: June 2012

Abstract
Background: There is no effective systemic therapy for patients (pts) with metastatic uveal melanoma (metUvMel). Due to the paucity of clinical trials pts are frequently offered individual treatment options. We have analyzed the outcome of pts treated for metUvMel with the oral multikinase inhibitor sorafenib (S) in an IEC-approved register trial of the West German Cancer Center, a national reference center for uveal melanomas.
Methods: Pts with metUvMel were treated with S [at a dose of 400 mg bid in the first group (G1) and of 200 mg bid in the second group (G2)]. Overall survival (OS) and time to symptomatic progression (TTPsymp) were studied as primary outcome parameters. Secondary outcomes included time to radiologic progression (TTPrad) according to CT and safety. In addition, digital contrast-enhanced NMR (DCE-NMR) and contrast-enhanced ultrasound (CEUS) of liver metastases were performed in selected pts.
Results: A total of 62 pts (median age 63 yrs, range 35–83 yrs; 31 female [50%], 31 male [50%], ECOG 0 44 pts [71%], ECOG 1 15 pts [26%], ECOG 2 2 pts [3%]) were included in the analysis on an intent to treat basis (ITT). Fortysix pts had no prior systemic treatment (74%). Metastatic sites included liver in 60 pts (97%) in addition to other organs in 20 pts (32%). Only two pts (3%) had exclusively extrahepatic metastases. Following 4 CTC-Grade 4 toxicities [hand-foot-syndrome (HFS) and/or diarrhea] in the first 31 pts (G1) (13%), the starting dose of S was reduced to 200 mg twice daily in the subsequent 31 pts (G2) effectively preventing further severe side effects. Median OS was 10.8 mths (CI 6.1–15.1 mths) in G1 and 14.0 mths (CI 6.4-nd mths) in G2, median TTPrad was 5.0 mths (CI 3.1–8.9 mths) in G1 and 4,5 mths (CI 1.5–6.0 mths) in G2 and TTPsymp was 4.1 mths (CI 3.1–5.2 mths) in G1 and 7.1 mths (CI 3.2–10.6 mths) in G2 (Wilcoxon 0.043), respectively.
Conclusions: S at a dose of 200 mg bid is safe in pts with metUvMel predominantly metastatic to the liver and seems to be effective with a median OS of more than 10 mths. Treatment results are encouraging in an orphan malignant disease without established palliative systemic treatment options. A multicenter randomized discontinuation trial with S in pts with metUvMel will be performed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C185.
Abstract C186: In vitro profiling and compare analysis of the novel HDAC6-selective inhibitor ST80 in 42 human tumor cell lines.
Authors: Kelter Gerhard , Metz Thomas , Diana Stolfa , Jung Manfred , Fiebig Heinz-Herbert 
Published: June 2012

Abstract
Inhibitors of histone deacetylases (HDAC) have been shown to be potent anti-proliferative agents mediated in part by induction of histone acetylation, resulting in growth arrest, cell differentiation and apoptosis. ST80, a novel HDAC inhibitor of the hydroxamate class was investigated for anti-tumor activity towards a panel of human tumor cell lines. At Oncotest a cellular profiling screen was developed in which new compounds are being tested in a standard cell line panel consisting of 42 cell lines from all major solid tumor types. The read-out of the assay is propidium iodide-based fluorescence, which is a measure of viable cell number. For the purpose of mechanism of action (MOA) analysis, the IC50 pattern of the new compounds is compared with the corresponding patterns of 118 agents with a known MOA. Additionally, Compare Analysis can indicate off-target effects of compounds for which targets have previously only been confirmed biochemically. Simultaneously, particularly sensitive and resistant cell lines are identified, helpful for the selection of cell lines and tumor xenografts for follow-up studies like the ex vivo tumor colony assay or in vivo studies using human tumor xenografts growing in nude mice.
Concentration-dependent antitumor activity was detected for ST80 towards all cell lines tested with a mean IC50 value of 26.8 μM. Compare Analysis revealed the highest correlations towards HDAC inhibitors M344 (spearman's rho=0.84) and SBHA (rho=0.80) of the hydroxamate class, followed by apicidin (cyclic peptide, rho=0.60) and SAHA (hdroxamate, rho=0.57). Only the 5th ranked compound in Compare Analysis (daunorubicin, rho=0.53) was not an HDAC inhibitor, underscoring ST80's highly specific activity towards HDAC. The relative HDAC inhibiting potential was compared against immunoprecipitated FLAG-tagged HDAC1 and 6. ST80 demonstrated a 31-fold higher catalytic inhibition of purified HDAC6 activity (IC50= 0.9 μM) relative to HDAC1 activity (IC50= 29 μM). HDAC6 selectivity of ST80 was confirmed by acetylation of alpha-tubulin, an HDAC6 specific substrate, relative to acetylation of lysine 12 on histone H4 by immunoblotting whole cell lysate from SKBR3 cells treated for 24 h with 50 μM of ST80.
In conclusion, by using Oncotest's Compare Analysis inhibition of HDAC by ST80 was clearly confirmed. Selective catalytic activity towards HDAC6 was demonstrated biochemically.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C186.
Abstract C187: Posttreatment with PI3-kinase inhibitor enhances the chemotherapeutic effect of cisplatin nanoparticles in breast cancer.
Authors: Pandey Ambarish , Roy Bhaskar , Sarangi Sasmit , Sengupta Poulomi , Kopparam Jawahar , Basu Sudipta , Sengupta Shiladitya 
Published: June 2012

Abstract
Nanoformulations of chemotherapeutic drugs are increasingly being studied for their potential to improve efficacy and safety. However, limited studies have been done on sequential dosing of nanochemotherapeutics and signal transduction inhibitors. In this study, pre-treatment and post-treatment dosing of PI-3 kinase inhibitor PI828 was used with cisplatin nanoparticles in murine breast cancer model. In vitro cell proliferation assay showed an enhanced cytotoxic capacity of cisplatin nanoparticle when used in combination with PI828. Moreover, post-treatment with the signal transduction inhibitors was found to be significantly more effective than pre-treatment. Western blot analysis showed a time dependent upregulation of phospho- AKT expression after administration of cisplatin nanoparticles, which was efficiently suppressed by PI828 in the post-treatment schedule. The upregulation of piAKT dependent signalling was mediated by both an EGFR dependent downstream activation of PI3 kinase pathway and an increased nuclear transcription of Akt gene. Post treatment with EGFR inhibitor (Erlotinib) showed similar enhancement in cytotoxicity of cisplatin nanoparticle.
In a 4T1 syngenic murine cancer in-vivo model, post-treatment with PI828 and Erlotinib following cisplatin nanoparticles treatment significantly suppressed tumor growth as compared to the pre-treatment or nanoparticles alone. These results indicate that sequence of administration of signal transduction inhibitors can impact the outcome of treatment with cisplatin nanotherapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C187.
Abstract C210: Microregional distribution and activity of camptothecins in tumor xenografts.
Authors: Kyle Alastair H. , Baker Jennifer H.E. , Gandolfo Maria-Jose , Minchinton Andrew I. 
Published: June 2012

Abstract
Background: The tumor microenvironment plays an important role in determining the activity of many anticancer drugs and one critically important factor that has recently garnered considerable interest is the micro-regional distribution of anticancer drugs within tumors. One of the key issues being whether chemotherapy drugs reach all the cells within a tumor at concentrations high and long enough to exert a therapeutic effect. Irinotecan and topotecan are two camptothecin analogues with differing pharmacological and physicochemical properties, both exhibit clinical activity though are not curative. In this study the micro-regional distribution of the two analogues was compared to their pattern of activity with tumor cryosections.
Methods: Using whole tissue section mapping and multiplexed immunostaining techniques irinotecan and topotecan fluorescence was detected in relation to tumor vasculature in cryosections from HCT116 xenografts 1, 2, 4, 8 & 24 hours following their administration. The tissue sections were subsequently stained to map drug activity via apoptosis and proliferation status at early (1–24 hours) and late (1–14 days) times after treatment.
Results: Topotecan exhibited a faster and more uniform tissue distribution than irinotecan but experienced significant wash-out within the first 2 hours following treatment. Irinotecan exhibited a larger concentration gradient in relation to tumor blood vessels but appeared to benefit from a longer retention within the tissue, with significant exposure occurring out to 8–24 hours following treatment. Interestingly, irinotecan did not appear to permeate equally from all vessels within the tumors. Some areas of the tumors received much higher exposure than others. At 50 mg/kg irinotecan and 10 mg/kg topotecan, both agents were able to exert a uniform block of cycling tumor cells within 4 hours of treatment but by 24 hours tumor proliferation status had returned to near normal levels indicating neither drug was retained long enough to exert activity on cells that were out of cycle at time of treatment.
Conclusions: Development of new camptothecin analogues might benefit from design strategies to increase tumor retention and uniformity in tissue distribution. While both irinotecan and topotecan were able to exert a significant and uniform cell cycle block within 4 hours of treatment in the HCT116 xenografts, due to their short retention proliferation was seen to recover by 24 hours. Irinotecan appeared to distribute less uniformly within the tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C210.
Abstract C217: Aneuploidy induction by the microtubule-stabilizing agent peloruside A involves the cell cycle checkpoint proteins MAD2 and p55CDC.
Authors: Chan Ariane , Miller John H. 
Published: June 2012

Abstract
Peloruside A (PelA) is a novel secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli. It is a potent microtubule-stabilizer and binds to a distinct site on -tubulin compared to the widely used anti-cancer drug paclitaxel. PelA has clear potential benefits over paclitaxel, including increased solubility, reduced sensitivity to multiple drug resistance in cancer cell lines, and improved tolerability and efficacy in non-small cell lung cancer xenografts in mice. Previous chemical genetics studies have indicated that MAD2 (mitotic arrest deficiency-2), a spindle-assembly checkpoint (SAC) protein, could potentially be a secondary target of PelA. Premature dissociation of MAD2 from the SAC protein, p55CDC, has been implicated in the induction of aneuploidy in response to low concentrations of paclitaxel; thus, we sought to validate and investigate MAD2 as an additional target of PelA. Flow cytometric analysis of 1A9 (human ovarian carcinoma) cells confirmed that low concentrations of PelA (&lt; 40 nM) induced chromosome mis-segregation in up to 15% of cells. Western blot analyses detected minimal changes in the abundance levels of MAD2, BUBR1 and p55CDC at both high (100 nM) and low (40 nM) PelA concentrations. However, differences in the association between MAD2 and BUBR1 with p55CDC were observed after cells were released from synchronization and assessed by co-immunoprecipitation. The mitotic arrest seen at 100 nM PelA was accompanied by a sustained formation of MAD2/p55CDC and BUBR1/p55CDC complexes; whereas, 40 nM PelA resulted in a similar dissociation profile of these complexes compared to controls. Given that PelA-induced aneuploidy coincides with G2-M progression, it is likely that dissociation of these complexes occurs despite aberrant microtubule-kinetochore attachments. Studies are currently underway to determine whether this increase in aneuploidy is due to the presence of erroneous attachments that are not detected by the SAC, such as merotelically oriented chromosomes. Aneuploidy is important because of its link to apoptosis and cancer cell death, and these experiments will help to elucidate some of the underlying signalling pathways. Additionally, these studies improve our understanding of the molecular actions of PelA during the cell cycle and highlight the importance of characterizing the concentration-dependent effects of drug interactions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C217.
Abstract C218: Novel therapeutic potential in targeting micro tubules by naturally occurring anti cancer agent withaferin A in human cancers.
Authors: Ghosh Kamalini , Sengupta Sumita 
Published: June 2012

Abstract
Background: Chemical compounds from natural sources continue to serve as important pharmacological tools for the understanding of biological pathways and also provide chemical platform for new drug discovery. The utility of various anti-microtubule agents from natural origins are the best examples that continuously serve these two purposes. In this study, we have identified a novel tubulin-targeting activity of a natural product Withaferin-A. Though several groups have already shown that Withaferin-A is a potent anti-cancer agent, can kill variety of carcinomas by inducing apoptosis, but not much is known about its molecular targets inside the cell. This study is to evaluate the therapeutic efficacy of WA towards human cancer, in relation to its ability to directly targeting microtubule dynamics within cell.
Methods: The IC-50 value of WA was determined by MTT assay, apoptosis and cell cycle assay was performed by FACS analysis, wound healing assay was done to see cellular migration, immune fluorescent detection was done to check microtubular network of WA treated cells. Effect of WA on tubulin polymerization in cell free system was studied by light scattering assay, binding measurements of WA to tubulin was determined by flurometric assay and probable WA-tubulin interaction site was proposed by molecular modeling method.
Results: We have identified WA as a novel anti-microtubule agent that inhibits proliferation, migration and cellular progression by affecting mitosis in HeLa and MCF-7 cells. Brief incubation with nontoxic concentrations of WA induced significant depolymerization of interphase and mitotic spindle microtubules. It inhibits tubulin polymerization, induces conformational changes in tubulin by directly binding to purified tubulin. Both in silico and in-vitro studies indicated that WA preferably binds to a novel site on tubulin.
Conclusion: It is evident that WA suppresses microtubule dynamics by directly binding to tubulin which sheds light on mechanisms behind its anti-proliferative activity towards cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C218.