bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1022: Carfilzomib demonstrates broad antitumor activity in preclinical lung cancer models.
Authors: Baker Amanda F. , Sands Barbara , Carbajal Lilliana , Anderl Janet , Chan Elena T. , Kirk Christopher J. , Garland Linda L. 
Published: August 2014

Abstract
Carfilzomib (CFZ), is an irreversible inhibitor of the chymotrypsin-like activity of the proteasome that was recently FDA approved for treatment of refractory and relapsed multiple myeloma. Early Phase 1B studies of CFZ showed signs of clinical activity in a number of solid tumors, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). We investigated the anti-tumor activity of CFZ monotherapy and in combination with cisplatin in NSCLC and SCLC cell lines and xenograft models. CFZ showed marked anti-proliferative activity in A549, H1993, H520, H460, H1299 NSCLC cell lines, with IC50 values after 96 hours of treatment ranging from 1.0 nM to 27 nM. CFZ + cisplatin resulted in antagonistic anti-proliferative activity in the NSCLC A549, H1993, and H520 cells, independent of sequence of drug administration. In vivo, CFZ monotherapy resulted in tumor growth inhibition in an A549 NSCLC murine xenograft model. In contrast, the SCLC cell lines SHP77 and H69 were more resistant to the anti-proliferative effects of CFZ, with IC50 values at 96 hours of 0.917 μM and &gt;30 μM, respectively. In vitro, in the SHP-77 SCLC cell line CFZ + Cisplatin showed synergistic activity. In vivo, in a SHP-77 SCLC SCID murine xenograft model CFZ monotherapy resulted in an 8-day tumor growth delay to reach 1500 mm3. No additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin in this model. Western blot analysis from SHP-77 cell lines grown in vitro and treated with CFZ showed an increase in cleaved PARP and p53, supporting activation of apoptosis. We will report on inhibition of the chymotrypsin-like proteasome activity in CFZ-treated lung cancer cell lines. Together, these pre-clinical studies support further preclinical and clinical investigations of CFZ in NSCLC and SCLC, including novel CFZ + anti-cancer drug combinations.
Citation Format: Amanda F. Baker, Barbara Sands, Lilliana Carbajal, Janet Anderl, Elena T. Chan, Christopher J. Kirk, Linda L. Garland. Carfilzomib demonstrates broad antitumor activity in preclinical lung cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1022. doi:10.1158/1538-7445.AM2013-1022
Abstract 1024: Therapeutic efficacy of RNA interference targeting focal adhesion kinase against orthotropic xenograft of human malignant pleural mesothelioma in SCID mice.
Authors: Huang Jun , Liu Dai-Shun , Kakiuchi Soji , Goto Hisatsugu , Hanibuchi Masaki , Nishioka Yasuhiko 
Published: August 2014

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive neop lasm of the pleura. The prognosis for MPM remains disappointing, although there have been some improvements in prognosis from newer chemotherapies and multimodality treatments. Focal adhesion kinase (FAK) is an important regulator of cellular signaling, migration, apoptosis, and cell cycle progression. We tested the hypothesis that FAK plays an important role in the pathogenesis of MPM and examined the effect of inhibiting FAK expression of MPM using small interfering RNA (siRNA) in vitro and in vivo. FAK expression was evaluated by Western and Northern blots. Knockdown of FAK resulted in detachment and proliferation inhibition of MPM cells in vitro. We assessed the therapeutic applicability of FAK siRNA in orthotopic xenograft model in SCID mice. FAK siRNA treatment inhibited the growth of MPM tumors and production of pleural effusion. These findings suggest that FAK may be a potential therapeutic target for human MPM and exogenous delivery of siRNA targeting FAK may be a useful strategy for MPM therapy.
Citation Format: Jun Huang, Dai-Shun Liu, Soji Kakiuchi, Hisatsugu Goto, Masaki Hanibuchi, Yasuhiko Nishioka. Therapeutic efficacy of RNA interference targeting focal adhesion kinase against orthotropic xenograft of human malignant pleural mesothelioma in SCID mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1024. doi:10.1158/1538-7445.AM2013-1024
Abstract 1028: Role of Hsp90 in the stability of EGFR from radiation and cisplatin-induced degradation.
Authors: Elaimy Ameer L. , Ahsan Aarif , Ray Dipankar , Lawrence Theodore S. , Nyati Mukesh K. 
Published: August 2014

Abstract
Heat-shock protein 90 (Hsp90) is an evolutionary conserved eukaryotic molecular chaperone that has a large number of clients including signaling molecules such as EGFR. Induction of Hsp90 upon cellular stress induced by radiation or chemotherapy can enhance stabilization of its clients which may lead to resistance to therapy and can often provide an environment for metastasis. Therefore, targeting Hsp90 has been shown to be a potential therapeutic approach to induce EGFR degradation and block metastatic spread. The aim of this study is to further understand the mechanism of Hsp90 induction and its post-translational modifications within cancer cells as well as its microenvironment and their significance in EGFR protein stability. We hypothesized that activation of Hsp90 upon cellular stress induced by radiation and chemotherapy provides stability to EGFR not only in cancer cells, but also in tumor-associated endothelial cells, which allows cancer cell survival and metastatic spread by increasing EGFR (and other clients) stability. Our preliminary data indicate that an enhancement in EGFR protein interaction with Hsp90 in both endothelial cells and head and neck cancer cell lines correlate with cell survival upon radiation or cisplatin treatment. Cisplatin treatment also caused an increase in Hsp90 activation as reflected by an increase in ATP binding activity. Increase in EGFR phosphorylation led to a decrease in its interaction with Hsp90. We also found that inhibition of Hsp90 activity reduced this interaction, which decreased EGFR half-life and promoted cell-death in cancer and endothelial cells. We are now extending our research efforts to understand the effects of radiation and cisplatin on the post-translational modifications of Hsp90 such as phosphorylation and its potential role in binding with EGFR. The long-term goal of this study is to develop a specific protein-protein interaction antagonist (PPI) to induce selective EGFR degradation and block the survival and metastatic spread regulated by EGFR.
Citation Format: Ameer L. Elaimy, Aarif Ahsan, Dipankar Ray, Theodore S. Lawrence, Mukesh K. Nyati. Role of Hsp90 in the stability of EGFR from radiation and cisplatin-induced degradation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1028. doi:10.1158/1538-7445.AM2013-1028
Abstract 1031: The effects of NT1014, a novel AMPK activator, on ovarian cancer cell proliferation and apoptosis.
Authors: Kilgore Joshua , Jackson Amanda L. , Qiu Haifeng , Zhou Chunxiao , Batchelor Kenneth , Gehrig Paola , Bae-Jump Victoria 
Published: August 2014

Abstract
Introduction: Anti-diabetic biguanide drugs, such as metformin, have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. NT1014 (NovaTarg Therapeutics) is a novel AMPK activator that enters cells specifically through the organic cation transporter, OCT1. Thus, we sought to assess the effect of NT1014 on cell proliferation and apoptosis in human ovarian cancer cell lines.
Methods: Ovarian cancer cell proliferation was assessed by MTT assay after exposure to NT1014. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by Cellometer. Phosphorylated-S6, pan-S6, and OCT1 were evaluated by Western immunoblotting analysis.
Results: NT1014 significantly inhibited proliferation in a dose-dependent manner in both ovarian cancer cell lines (IC50 1000 μM for SKOV3, 500 μM for IGROV1), within 48 hours of exposure. Treatment with NT1014 resulted in G1 cell cycle arrest in both cell lines. Apoptosis occurred in IGROV1 cells exposed to NT1014, but not in SKOV3 cells. Western immunoblot analysis demonstrated that NT1014 decreased phosphorylation of the S6 protein, a key downstream target of the mTOR pathway. Expression of OCT1 was also decreased in a dose-dependent fashion.
Conclusion: NT1014 suppressed ovarian cancer cell growth, predominantly through G1 cell cycle arrest, and resulted in inhibition of the mTOR pathway. More work is needed to determine if metformin and related novel agents, such as NT1014, will be beneficial in the treatment of women with ovarian cancer.
Citation Format: Joshua Kilgore, Amanda L. Jackson, Haifeng Qiu, Chunxiao Zhou, Kenneth Batchelor, Paola Gehrig, Victoria Bae-Jump. The effects of NT1014, a novel AMPK activator, on ovarian cancer cell proliferation and apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2013-1031
Abstract 1034: Induction of miR183 and miR21 is associated with down regulation of cellular signaling in nitrogen mustard mediated inhibition of tumor cell proliferation.
Authors: Kim Hong Duck , Shakarjian Michael P. , Vetrano Anna M. , Laskin Jeffrey D. , Heck Diane E. 
Published: August 2014

Abstract
Nitrogen mustard (HN2) is a chemotherapeutic agent used to treat skin cancers and lymphomas including squamous cell carcinomas (SCC) and cutaneous T cell lymphoma. Although HN2 non-selectively alkylates DNA, many tumors exhibit resistance to HN2 therapy. To evaluate additional mechanisms potentially underlying the activity of HN2 we tested the effects of HN2 on Pam 212 murine squamous cell carcinoma cells. We found that mustard treatment reduced cell viability, and that this result was associated with an increase in PKCδ phosphorylation. Furthermore, cytotoxicity was antagonized by the PKCδ selective inhibitor, rottlerin, implicating this PKC isoform in HN2 action. The p38MAPK inhibitor, SB203580, acted in a similar manner to rottlerin, increasing viability 30% in HN2-treated Pam 212 cells. In contrast, PI3kinase inhibitor, wortmannin, enhanced HN2-mediated cytotoxicity, suggesting a protective role for this signaling pathway. Recent reports indicate that the activity of the p38MAPK and PKCδ signaling cascades, pathways involved in regulating glucose uptake and metabolism, growth, motility, and other essential functions for cell survival, is hallmarked by increases in levels of miRNAs 21 and 183. Therefore we next evaluated the effects of HN2 on microRNA (miR) levels using microRNA PCR arrays. In these experiments we found that HN2 treatment enhanced levels of miR21 and miR183 in Pam 212 keratinocytes, effects that were time and dose-dependent dependent. In additional studies we found that transfection of PAM cells with miR21 and miR183 resulted in enhanced sensitivity to inhibitors of PI3 kinase and p38MAPK regulated mTOR activity. Using techniques in real time PCR we observed that HN2-mediated increases in miRNA 21 and 183 levels were inhibited by the mTOR inhibitors 3-MA, rapamycin and LY294002 in PAM cells. Taken together these data indicate that signaling pathways play significant roles in HN2-mediated inhibition of tumor cell proliferation. We speculate that PKCδ, PI3 kinase, p38MAPK and mTOR pathways are important in the anti-cancer activities of HN2 and may be modified in tumors resistant to this agent.
Citation Format: Hong Duck Kim, Michael P. Shakarjian, Anna M. Vetrano, Jeffrey D. Laskin, Diane E. Heck. Induction of miR183 and miR21 is associated with down regulation of cellular signaling in nitrogen mustard mediated inhibition of tumor cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1034. doi:10.1158/1538-7445.AM2013-1034
Abstract 1036: Cbl-independent degradation of Met: Ways to avoid agonism of bivalent Met targeting antibody.
Authors: Lee Ji Min , Kim Bogyou , Kim Kyung-Ah 
Published: August 2014

Abstract
The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met down-regulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Cbl E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met over-expressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met targeting antibody demonstrated intrinsic agonistic activity while capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to down-regulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.
Citation Format: Ji Min Lee, Bogyou Kim, Kyung-Ah Kim. Cbl-independent degradation of Met: Ways to avoid agonism of bivalent Met targeting antibody. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2013-1036
Abstract 1041: Sorafenib in combination with rottlerin show an additive effects in renal cell carcinoma (RCC) cells.
Authors: Joeckel Matthias W. , Schneider Elke , Roos Frederik C. , Hampel Christian , Thueroff Joachim W. , Brenner Walburgis 
Published: August 2014

Abstract
Introduction: RCC is a tumor entity with poor outcome. Targeted therapies with tyrosine kinase inhibitors (TKI) are promising agents for combating progression in RCC. We investigated the effect of the TKI sorafenib and sunitinib on cancer progression in vitro. We additionally analysed a coadministration of rottlerin, inhibiting PKCdelta, with sorafenib or sunitinib.
Methods: Four clear cell RCC cell lines were treated with sorafenib or sunitinib alone (5 μM) or in combination with rottlerin (10 μM). Proliferation (BrdU incorporation), apoptosis (caspase 3) and expression of PKCdelta in nuclei (pro-apoptitic), cytoplasm (inactive) and membranous (active) was quantified. The activity of PKCdelta was analysed by detection of phosphorylated PKCdelta (Western blot).
Results: Cell proliferation was reduced by sorafenib and rottlerin, but not by sunitinib. Combination of sorafenib and rottlerin showed an additive effect in proliferation inhibition. Rottlerin and sunitinib induced apoptosis. Althougth sorafenib alone did not induce apoptosis, in combination with rottlerin, apoptosis was more intensely induced than with rottlerin alone. All agents induced an enhanced expression of PKCdelta in the nuclei. Sunitinib in combination with rottlerin reduced membrane -bound PKCdelta. Analogue, expression of activated PKCdelta was reduced after cell treatment with sunitinib in combination with rottlerin.
Conclusion: Coadministration of sorafenib and rottlerin showed an additive effect on proliferation and apoptosis of RCC cells. The expression and activity of PKCdelta was reduced most by sorafenib in comibation with rottlerin. This indicates an improvement in RCC therapy with sorafenib by coadministration of rottlerin.
Citation Format: Matthias W. Joeckel, Elke Schneider, Frederik C. Roos, Christian Hampel, Joachim W. Thueroff, Walburgis Brenner. Sorafenib in combination with rottlerin show an additive effects in renal cell carcinoma (RCC) cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1041. doi:10.1158/1538-7445.AM2013-1041
Abstract 1043: Connexin might be involved in anti-cancer combination effect of sunitinib and sodium butyrate.
Authors: Uzu Miaki , Sato Hiromi , Suzuki Rina , Okuzawa Hiroko , Siddig Sana , Tuerdi Guligena , Suzuki Sayumi , Nomura Yuki , Sekine Yuko , Yano Tomohiro , Ueno Koichi 
Published: August 2014

Abstract
Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor (TKI). It is more effective for renal cell carcinoma (RCC) treatment than conventional immunotherapy, but it causes the resistance and severe side effects in some cases. As a combination therapy might be one solution for them, we paid attention to sodium butyrate (NaBu). It is classified into histone deacetylase (HDAC) inhibitor and it is reported HDAC inhibitors can enhance anti-cancer effect of existent drugs including TKI. So, we examined combination effect of SU and NaBu. And to reveal the target of this combination, we examined effects of SU and NaBu on connexin (Cx), which is a component of gap junction (GJ) and tumor suppressors.
We assessed effect of SU and NaBu combination on ACHN (human RCC cell line) cell proliferation by MTT assay and this combination exhibited a synergistic anti-proliferative effect. By real-time PCR, we detected up-regulation of Cx32 mRNA by NaBu. Moreover, NaBu depicted the up-regulated Cx32 protein expression, which was observed by confocal fluorescence microscope. Hemi-channel (Cx hexamer) function was assessed by propidium iodide (PI) uptake into cells. We found both SU and NaBu enhanced PI uptake significantly. GJ function was assessed by scrape-loading. It was confirmed GJ didn't function in ACHN cells and neither SU nor NaBu affected its function. So, it was suggested NaBu could up-regulate Cx32 expression and both SU and NaBu could enhance hemi-channel function. However, we couldn't reveal whether GJ was related to enhancing SU sensitivity. So, we used GJ positive or negative H28 (human malignant mesothelioma cell line) to reveal this matter. As a result, GJ positive cells were more sensitive to SU than negative ones. On the other hand, inhibition of GJ function didn't restore viability of GJ positive cells.
In conclusion, we demonstrated the combination therapy of SU and NaBu had synergistic anti-proliferative effect, so it could be a prominent therapy for RCC. Furthermore, we found Cx could be involved in this combination effect, which might be performed in GJ-independent manner.
Citation Format: Miaki Uzu, Hiromi Sato, Rina Suzuki, Hiroko Okuzawa, Sana Siddig, Guligena Tuerdi, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomohiro Yano, Koichi Ueno. Connexin might be involved in anti-cancer combination effect of sunitinib and sodium butyrate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1043. doi:10.1158/1538-7445.AM2013-1043
Abstract 1046: AS1411 activity is regulated by epidermal growth factor receptor signaling pathway.
Authors: Reyes-Reyes Elsa M. , Salipur Francesca R. , Bates Paula J. 
Published: August 2014

Abstract
The anticancer AS1411 agent is a G-rich phosphodiester oligodeoxynucleotide, which forms a stable quadruplex structure and binds specifically to nucleolin as an aptamer. It efficiently inhibits proliferation and induces cell death in many types of cancer cells, but has little effect on normal cells. We have also shown that AS1411 is taken up by macropinocytosis and stimulates further macropinocytosis by a nucleolin-dependent mechanism in several cancer cells. AS1411 activity correlates with stimulated macropinocytosis, suggesting this hyperstimulation of macropinocytosis may explain the unusual cancer cell death caused by AS1411. Macropinocytosis is a ligand-independent endocytic pathway that is normally activated by growth factor receptor stimulation. On the other hand, nucleolin has been reported that can enhance growth factor signaling by binding directly to some growth factor receptors. Therefore in this study, we determine the participation of growth factor signaling pathway in AS1411-induced macropinocytosis and cell death. Pre-incubation of DU145 cells with a specific EGFR inhibitor, but not PDGFR or JAK2 inhibitors, significantly inhibited the stimulation of AS1411-mediated macropinocytosis, suggesting that AS1411 activates EGFR signaling pathways. This was confirmed by observing that DU145 cells treated with AS1411 induced tyrosine phosphorylation of EGFR and activation of its downstream effectors, including p38, PI3K and Rac1. Furthermore, AS1411 seem to induce the interaction between EGFR and nucleolin in accord with EGFR activation. We also found that the activation of EGFR signaling pathway by AS1411 might regulate its cancer cellular response. Simulation of macropinocytosis by AS1411 was significantly inhibited in DU145 cells pre-treated with pharmacological inhibitors of Rac1 or PI3K, but not by Src inhibitor. Moreover the ability of AS1411 to inhibit cell proliferation and induce cell death was reduced by an EGFR-neutralizing antibody (cetuximab) or by downregulating the expression of Rac1 using siRNAs. These results indicate that AS1411 mediates the activation of EGFR signaling pathway to induce cancer cell death, and suggest that AS1411 might redirect EGFR signaling pathway from a cell survival signal to a cell death signal.
Citation Format: Elsa M. Reyes-Reyes, Francesca R. Salipur, Paula J. Bates. AS1411 activity is regulated by epidermal growth factor receptor signaling pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1046. doi:10.1158/1538-7445.AM2013-1046