bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3676: A selective small molecule inhibitor of c-Jun N-terminal kinase 1
Authors: Yao Ke , Cho Yong-Yeon , Bode Ann M. , Vammenthala Anuradha , Park Jewn Giew , Liu Kangdong 
Published: February 2011

Abstract
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family. The jnk1 and jnk2 genes are expressed ubiquitously, whereas jnk3 has a limited pattern of expression and is largely restricted to brain, heart, and testis. The JNKs signal transduction pathway was shown to play an important role in coordinating various cellular responses including apoptosis, proliferation, and neoplastic transformation. Indiscriminately suppressing the activity of all three c-Jun N-terminal kinase isoforms, JNK1, JNK2, and JNK3, is probably not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, and Parkinson's disease. However, until now, isoform selective inhibitors for JNK1 over JNK2 or JNK3 activities have not been developed. Therefore, using structure-based design, we developed (in-house) a selective isoform inhibitor that showed a selective inhibitory effect against JNK1, but not JNK2 or JNK3. We found that 7-(6-N-Phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) suppressed JNK1 activity, with no effect on either JNK2 or JNK3, in vitro. In cell culture systems, we also found that AV-7 inhibited JNK1 activity dose-dependently. In contrast to SP600125, a non-selective JNKs inhibitor, that binds to the ATP active site, AV-7 was designed to target the protein-protein interaction between JNK1 and its binding partner(s) rather than the ATP binding site. At 10 μM, AV-7 specifically inhibited JNK1 by about 50%. The phosphorylation of c-Jun by JNKs induces c-Jun transactivation and transcriptional activity through the formation of a protein complex with c-Fos or ATF1 (i.e., AP-1 complex). c-Jun/AP-1 enhances transcription by binding to the promoter region of many genes. We found that AV-7 inhibits UVB-induced c-Jun phosphorylation and sub-G1 accumulation in JNK2−/− MEFs, which express only JNK1, but had no effect on c-Jun in JNK1−/− MEFs, which only express JNK2. These results demonstrate that AV-7 is an isoform selective JNK1 inhibitor. In humans, JNKs play a key role in obesity-induced type 2 diabetes mellitus and the absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and an enhanced insulin receptor signaling capacity in mouse obesity models. Therefore, we suggest that because of JNK1's critical role in diabetes, AV-7 might have therapeutic potential against this devastating disease.
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 3676.
Abstract 3687: Expression of a Src-family kinase in CML cells induces resistance to imatinib in a kinase-dependent manner
Authors: Pene-Dumitrescu Teodora , Smithgall Thomas E. 
Published: February 2011

Abstract
Chronic Myelogenous Leukemia (CML) is characterized by the presence of Philadelphia Chromosome, which results in the expression of the 210 kDa Bcr-Abl tyrosine kinase. Bcr-Abl constitutively activates signaling pathways important for the proliferation, survival and cytokine independence of myeloid progenitors, including the Src family kinases (SFKs). Imatinib, an inhibitor of Bcr-Abl tyrosine kinase activity, is the frontline therapy for CML. Although imatinib is remarkably effective in the chronic phase of the disease, patients with accelerated or blast crisis CML often develop resistance. Several recent studies performed on clinical specimens from imatinib-resistant patients with wild-type Bcr-Abl found that the Src family kinase members Hck and Lyn are overexpressed or highly active, suggesting that Src kinases may play a role in imatinib resistance. While the role of Lyn has been addressed in some detail, the contribution of Hck to this type of imatinib resistance is less well understood. To test whether Hck overexpression in CML cells induces resistance to imatinib in a kinase-dependent manner, we employed a Hck mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. In vitro, Hck-T338A was 48 times more sensitive to NaPP1 than the wild-type kinase. Importantly, this “gatekeeper” mutation was functionally silent and did not confer a loss or gain of function on Hck in a control fibroblast transformation assay. Expression of wild-type Hck or the T338A mutant in K562 CML cells resulted in resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in a concentration-dependent manner only in cells expressing the Hck-T338A mutant. In contrast, cells expressing wild-type Hck were not affected by NaPP1, demonstrating the selectivity of NaPP1 for the Hck-T338A mutant. This result shows that Hck-induced imatinib resistance requires Hck kinase activity. In addition, NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib binding exclusively in cells expressing Hck-T338A. Together, these data establish a direct cause and effect relationship between Hck overexpression and imatinib resistance in CML cells. Furthermore, our results show that imatinib resistance requires Hck kinase function and may occur via direct Hck-induced trans-phosphorylation of Bcr-Abl. Selective drug targeting of Hck may be of therapeutic benefit in imatinib-resistant CML patients with increased Hck expression or activity.
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 3687.
Abstract 3688: A flexible kinase inhibitor assay for active, non-activated, and impure kinase preparations
Authors: Riddle Steven , Lebakken Connie , Ellefson Jason , Reichling Laurie , Wolken Jill 
Published: February 2011

Abstract
Kinase activity-based assays are cost-effective and widely used to drive early drug discovery and lead identification, however, they typically require purified, active kinase preparations to be produced that are shown to phosphorylate a known substrate. While it is possible to satisfy these requirements for well-studied kinases, there are many kinases which lack one or more of these requirements, such as CDK8 and STK33, making drug discovery efforts difficult. To solve for these assay development problems, we have developed a TR-FRET binding assay platform which allows for characterization of compounds with kinases that are not sufficiently purified, completely lack activity, or do not have a known substrate. These new assay options for addressing kinase assay requirements in early drug discovery should enable more targets to be screened sooner, resulting in compounds being made available for lead optimization faster. The ability to detect and characterize binding of compounds to non-activated kinases is also a benefit to the lead optimization process, as compounds that bind preferentially to kinases in their non-activated state, such as Gleevec®, are generally preferred due to their selectivity. In this poster, we present solutions for kinases that are difficult to address with activity assays and provide a comparison of compound affinities for active and non-activated forms of a diverse set of kinases to enable faster lead optimization.
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 3688.
Abstract 3693: Small molecule microarray screens for inhibitors of oncogenic ETS factors
Authors: Pop Marius , Doug Katie , Bradner James , Koehler Angela , Garraway Levi 
Published: February 2011

Abstract
Members of the ETS transcription factors family are involved in many cancers and are often targeted by translocation events that result in oncogenic gene fusions or dysregulated ETS factor expression. For example, the vast majority of prostate cancers harbor translocations involving the ETS factors ERG, ETV1 and ETV4 (most commonly, these are fused to the TMPRSS2 androgen-regulated gene or other house keeping genes). Overexpression of ETS factor gene fusions can induce or sustain malignant characteristics of cancer cells such as survival or invasiveness. However transcription factors have often been deemed “undruggable” by conventional approaches.
The focus of this project is to employ novel screening approaches to identify and characterize small molecules that are able to bind and modulate the biological function of oncogenic ETS factors. Toward this end, we have performed Small Molecule Microarray (SMM) screens that involve a total of 80,000 distinct small molecules spanning several categories, including diversity-oriented synthesis (DOS) products, natural products, and other biologically active chemotypes. The SMM screens identified six compound that selectively bind the ETS factor ETV1 with a stringent Zscore. Two of these compounds have shown inhibitory activity in an ETV1-specific promoter-induced luciferase system. Surface Plasmon Resonance analysis has confirmed that each of the two lead compounds binds ETV1 directly, with one compound showing submicromolar binding kinetics. This compound in particular was able to reduce the expression of several ETV1 downstream targets such as MMP1 and MMP7. These efforts suggest that we have identified novel small molecule “perturbagens” of ETV1, an oncogenic ETS transcription factor. More generally, our results suggest that SMM-based screens may offer a robust approach to identify novel compounds that bind and perturb the function of cancer-associated proteins deemed poorly “druggable” by conventional methods.
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 3693.
Abstract 370: Characterization of human umbilical vein endothelial cell clones resistant to VEGFR2 tyrosine kinase inhibitor
Authors: Matsumoto Kazuko , Arao Tokuzo , Furuta Kazuyuki , Sakai Kazuko , Nagai Tomoyuki , Kudo Kanae , Kaneda Hiroyasu , Tamura Daisuke , Aomatsu Keiichi , Fujita Yoshihiko , Nishio Kazuto 
Published: February 2011

Abstract
Acquired resistance to anti-angiogenetic drugs have emerged as a potentially important problem in clinical settings, however, the underlying mechanism remains largely unclear. In this study, we established human umbilical vein endothelial cell (HUVEC) clones that are resistant to VEGFR tyrosine kinase inhibitor (VEGFR-TKI, Ki8751) using MNNG and VEGFR-TKI.
In growth inhibition assay, VEGFR-TKI resistant HUVEC clones were significantly decreased cellular sensitivity to Ki8751 about 4-10 fold compared with that in the parental cells. VEGF-mediated cellular proliferations of resistant clones were also decreased. Interestingly, VEGFR2 expression was down-regulated and the phosphorylation levels of Akt were up-regulated in resistant clones. Finally, microarray analysis revealed that several angiogenesis-related or -specific genes including CD31 were remarkably down-regulated in resistant clones compared with the parental cells. In conclusion, these results suggest that the mechanism of VEGFR-TKI resistant is closely involved in “escape phenomenon” from VEGF-VEGFR system and our findings provide a novel insight into the drug resistant to VEGFR-TKI in vascular endothelial cells.
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 370.
Abstract 3704: Gemtuzumab ozogamicin conjugated gold nanoparticles induce cell death in D1.1 leukemia cells when exposed to a radiofrequency field
Authors: Willborn Katherine A. , Glazer Evan S. , Briggs Katrina L. , Curley Steven A. 
Published: February 2011

Abstract
Introduction: Acute T-cell leukemia cells may express the marker CD33. Gemtuzumab is a monoclonal antibody against CD33, used clinically in combination with ozogamicin, a cytotoxic antibiotic, for treatment of acute leukemias. It has been previously demonstrated that gold nanoparticles delivered intracellularly and exposed to nonionizing radiofrequency (RF) fields induce hyperthermic cytotoxicity. RF fields are not cytotoxic without the presence of nanoparticles. The purpose of this experiment is to investigate cell death in cells treated with gemtuzumab ozogamicin conjugated to gold nanoparticles after RF field exposure.
Methods: D1.1 (acute T-cell leukemia) cells were plated in 60mm cell culture dishes. Two groups (n=3 in each group) of plated cells were treated for two hours with gemtuzumab ozogamicin conjugated to 10nm solid gold nanoparticles in media. One group of cells was then exposed to a radiofrequency field for a total generator energy of 1500 W-minutes. The control cells were treated with the same gold conjugate, but were not exposed to an RF field. Two days later, cell viability, apoptosis, and death was determined by flow cytometry. The groups were compared with Student's t-test.
Results: RF fields induced apoptosis in 58.7% ± 3.95% of treated cells, compared with 8.66% ± 0.56% of the controls (p=0.002). The viability after RF exposure was 13.9% ± 6.11% while gemtuzumab ozogamicin gold conjugate alone decreased viability to 74.2% ± 0.85% (p=0.003). The temperature of the media was kept below 40°C to avoid nonspecific cell injury.
Conclusions: Multimodality therapy (chemotherapy and nanoparticle-mediated hyperthermia) induced significantly more death in acute T-cell leukemia cells than antibody-chemotherapy alone. Antibodies specific to molecular targets on cells permit targeting of the heat mediator (nanoparticles) while preventing non-specific delivery of both nanoparticles and chemotherapeutic agent. The use of non-invasive RF fields to specifically induce cell death by hyperthermia with nanoparticles may present new options for the treatment of leukemias.
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 3704.
Abstract 3710: Facile Synthesis and Characterization of Pyropheophorbide-a -Taxol Conjugate
Authors: Kim Hyo Jun , Gantumur Battogtokh , Kim Sook Hee , Bae Sumi , Ahn Woong Shick 
Published: February 2011

Abstract
Chlorin-based photosensitizers are considered the ideal photosensitizer (second generation) in photodynamic therapy (PDT). They have improved efficacy and have lesser side effects compared to porphyrin-based photosensitizers (first generation). Paclitaxel (PTX) is one of the most effective and widely used anticancer a drug. Although chemotherapy is a powerful and important modality in cancer treatment, the effectiveness of the chemotherapy is limited due to systemic toxicity and side effects.
For the improvement of photosensitizers (chlorin; apoptosis, necrosis, local immune response) and increased anticancer drug (PTX; apoptosis), we combined photosensitizer and PTX.
For the synthesis, naturally occurring chlorin derivative was used as a starting material. It was prepared with the acidic treatment of methyl pyropheophorbide-a from Spirulina maxima algae according to the previously reported methods [1-2]. PTX should contain three hydroxyl groups at 21-position and 1-position and 7-position, respectively. A hydroxyl group at 21-position has more reactivity than others. To the synthesize target compound, we carried out an esterification reaction between the hydroxyl group at 21-position for the PTX moiety and carboxyl group at 173-position for the pyropheophorbide-a. The conjugate was performed as reaction the pyropheophorbide-a and the commercial PTX by using DMAP/DCC coupling agent.
The structure of chlorin- based PTX conjugate was fully characterized by 1D and 2D NMR techniques and also by MALDI-MS and UV-Vis. As well as, the conjugate was determined the purity of 99.45% by analytical reversed phase HPLC at 660 nm.
This conjugate can be applied as anticancer agent and photosensitizer for PDT. This compound is promising to be able to afford some synergistic effects in tumor cell.
References:
1. Smith, K. M.; Goff, D. A.; Simpson, D. J.; J. Am. Chem. Soc. 1985, 107, 4946-4954.
2. Galindev, O.; Badraa, N.; Dalantai, M.; Sengee, G.; Dorjnamjin, D.; Shim, Y. K. Photochem. Photobiol. Sci. 2008, 7, 1273-1281.
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 3710.
Abstract 3722: Ovarian suppression with gonadotropin-releasing hormone analogues (Gn-RH) in high risk premenopausal breast cancer patients (PM-HR-BC): decrease of T regulatory cells (T-regs) and of vascular endothelial growth factor (VEGF)
Authors: Recchia Francesco , Candeloro Giampiero , Necozione Stefano , Desideri Giovambattista , D'Andrea Maurizio S. , Recchia Cornelia O.C. , Rea Silvio 
Published: February 2011

Abstract
Background: In a previous phase II study we have shown an improvement of disease-free survival and overall survival of 180 premenopauseal high-risk early breast cancer patients (PM-HR-BC) treated with ovarian suppression with Gn-RH and a chemotherapy tailored to the peculiar clinical situation. Aim of this study was the evaluation of VEGF and T-regs in a group of PM-HR-BC patients treated with the above mentioned therapy.
Methods: From 01/2006 to 12/2008 54 patients with PM-HR-BC were entered into this study. At baseline, one week before chemotherapy, patients received a Gn-RH analogue which was continued for five years. Tailored adjuvant chemotherapy, included anthracycline and taxane based regimens. 11 patients with triple negative tumors, received a platinum-based consolidation high-dose chemotherapy with (n. 7) or without (n. 4) autologous peripheral blood progenitor cell transplantation, respectively. Radiation therapy was administered to all patients that had received breast conserving surgery. Patients received a strong psychological support, biphosphonates, and after the end of chemotherapy, estrogen receptor positive (ER+) patients received an aromatase inhibitor.
Results: Characteristics of patients. Median age was 41 years (range, 26-44 yrs). 79% of patients were ER+, while 21% were estrogen receptor negative. Total number of positive nodes was 145, with a mean of 2,7 for each patient (range 0-25). G3 tumors were observed in 33% of patients, C-erB-2 status (FISH) was positive in 17% of patients, while mean Ki-67 value was 27%. Serum estradiol was suppressed to values &lt; 40 pg/mL in all patients. After six months and one year, a statistically significant decrease was observed in T-regs number (p&lt; 0.005) and VEGF (p&lt; 0.005) with respect to baseline values. No impairement of cognitive function was observed with respect to baseline conditions. After a median follow-up of 26 months, 4 years progression-free survival and overall survival rate were 97% and 100%, respectively. Conclusions: These data show that ovarian suppression with a Gn-RH analogue decreases T-regs and VEGF, and seems to improve the expected outcome of PM-HR-BC patients through immunologic mechanisms.
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 3722.
Abstract 3725: Bortezomib-induced neuropathic pain: Evaluation of anti nociceptive effect of a new analgesic compound
Authors: Canta Annalisa , Meregalli Cristina , Carozzi Valentina Alda , Oggioni Norberto , Chiorazzi Alessia , Tredici Giovanni , Lanza Marco , Letari Ornella , Caselli Gianfranco 
Published: February 2011

Abstract
Bortezomib (Btz) is a highly effective and widely used antineoplastic drug for the treatment of many tumors, primarily multiple myeloma. Despite its effectiveness, the use of this proteasome inhibitor is limited by its toxicity. Among Btz side effects, peripheral neurotoxicity is a major and clinically relevant problem. In fact, since the earliest Phase I and Phase II studies, sensory peripheral neuropathy emerged as a dose-limiting side effect. Moreover, a significant proportion of Btz-treated patients developed severe neuropathic pain. The treatment of Btz-induced neuropathic pain is extremely difficult with the currently available drugs and still remains a major challenge for oncologists and neurologists. Aim of this study was to demonstrate if the new analgesic compound CR4056 could reverse the neuropathic pain induced by a chronic treatment with Btz in the rat. The anti-nociceptive and dose-dependent effect of CR4056 was assessed in a well-established experimental rat model in which Btz was administered to Wistar rats (0.20 mg/kg three times/week for 8 weeks) followed by treatment with CR4056 (6, 20 or 60 mg/kg daily p.o.) or buprenorphine administered 28,8 µg/kg/day p.o. for 2 weeks. Body weight change, hematological and histopathological parameters, nerve conduction velocity (NCV) and sensory behavioral tests were evaluated during the experiment. No remarkable effect of Btz administration or of any dose of CR4056 was observed in the hematological parameters and blood chemistry. After 8 weeks of treatment, Btz induced a severe reduction in NCV; this impairment was not reversed by CR4056 or by buprenorphine. The behavioral assessment showed a significant mechanical allodynia in rats treated with Btz for 8 weeks (delta vs. controls −6 g). Buprenorphine significantly reduced Btz-induced allodynia during the fist day by about 63%. However, this effect was lost during the following days of treatment (i.e 20% reduction on the 3rd day). The mid and high dose of CR4056 (20 and 60 mg/kg) showed a significant (i.e &gt; 80 %) reduction of allodynia till the 3rd day of administration, afterwards a slight reduction in efficacy was recorded. On the contrary, the oral daily administration of 6 mg/kg CR4056 persistently counteracted Btz-induced allodynia, showing an even complete reversion after 2 weeks of treatment. The present study gives evidence for a relevant and persistent anti-allodynic effect of CR4056, suggesting a role for CR4056 in the management of neuropathic pain in patients treated with Btz.
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 3725.