bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3530: Chemicals that stimulate iron uptake: a novel approach to cancer treatment
Authors: Li Zhen 
Published: June 2012

Abstract
Cancer cells have increased levels of transferrin receptor and lower levels of ferritin, an iron deficient phenotype that has led to the use of iron chelators to further deplete cells of iron to limit growth. Chelators have not proven, however, to be successful anti-cancer agents. As cancer cells also have increased reactive oxygen species (ROS) we hypothesized that a contrarian approach of enhancing iron entry would allow for further increased generation of ROS causing oxidative damage and cell death. Molecules that accelerate iron uptake were identified using high through-put screening of a reporter system of K562 cells loaded with the divalent metal chelator calcein whose fluorescence is quenched with chelation of Fe2+. A small molecule library consisting of ∼11,000 compounds was screened and a class of compounds identified that stimulated iron-induced quenching of calcein fluorescence. The stimulation was verified by dose-dependent 55Fe uptake in various cancer cell lines. The lead compound LS081 exhibited an IC50 = 1.22 ± 0.48 μM and also increased the uptake of Fe from transferrin (Tf). LS081 decreased PC-3 cell growth in the presence of Fe2+ by 64 ± 8% compared to 14 ± 1% decrease with LS081 alone (mean decrease ± SEM, n = 3) with minimal effects on the immortalized, non-malignant prostate cell line 267B1 cells. LS081 plus Fe increased DNA strand breaks and induced cell cycle arrest at the G1 phase of PC-3 cells. In addition, LS081 markedly decreased HIF-1α and HIF-2α levels in the DU-145 prostate cancer and the MDA-MB-231 breast cancer cell lines. LS081 also stimulated ROS production by nearly 3-fold and decreased clonogenicity by greater than 50% in PC-3 cells. In summary, we have developed a high through-put screening technique that identified small molecules that stimulate iron uptake both from ferri-Tf and non-Tf bound iron. These molecules have properties that suggest that these iron facilitator compounds may serve as anti-cancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3530. doi:10.1158/1538-7445.AM2011-3530
Abstract 3532: Antitumor activity of SR16388 on multiple myeloma targets factors needed for adaptation to bone marrow microenvironment
Authors: Chao Wan-Ru , Dinh Dominic H. , Shi Yihui , Hou Carol , Sato Barbara , Alt Carsten , Collins Nathan , Sambucetti Lidia 
Published: June 2012

Abstract
Multiple myeloma (MM) is a B-cell malignancy that is characterized by accumulation of clonal plasma cells in the bone marrow. The bone marrow microenvironment plays a critical role in MM cell pathogenesis and progression. In the bone marrow milieu, MM cells adhere to the bone marrow stromal cells and trigger the secretion of growth factors such as vascular endothelial growth factor (VEGF). VEGF in turn upregulates the secretion of interleukin-6 (IL-6), the major cytokine that mediates MM cell growth and survival in part through the activation of Janus kinase (Jak)/signal transducers and activators of transcription 3 (STAT3). VEGF also stimulates the proliferation of endothelial and stromal cells and induces angiogenesis via its receptors. Thus, targeting both myeloma cells and bone marrow microenvironment is a valid approach for the development of therapeutic agents for MM. At SRI International, we have developed an antiestrogen, SR16388, that binds to ER-α, ER-β and ERR-α with potent antitumor and antiangiogenic properties. We have previously reported that SR16388 inhibited MM cell proliferation in vitro and MM tumors in vivo. In the current study, we are presenting data to show that the inhibitory effect of SR16388 on MM cell proliferation was achieved by inducing apoptosis, and arresting cells at the G2 phase. Furthermore, at nanomolar concentrations SR16388 inhibited IL-6-induced cell proliferation and blocked the activation of STAT3 induced by IL-6 in RPMI-8226 human MM cells. In human endothelial cells, SR16388 inhibited VEGF-induced cell proliferation and VEGF-induced phosphorylation of STAT3. In a RPIM-8226 tumor xenograft model, the microvessel density in the tumor tissue was markedly reduced by treatment with SR16388. We are currently investigating the effect of SR16388 in combination with known therapeutic agents on the growth of MM tumors in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3532. doi:10.1158/1538-7445.AM2011-3532
Abstract 3541: Combination of the ruthenium compound KP1339 with the tyrosine kinase inhibitor sorafenib: A promising approach for the treatment of human hepatoma
Authors: Heffeter Petra , Atil Bihter , Kryeziu Kushtrim , Jungwirth Ute , Gal Elisabeth , Keppler Bernhard K. , Berger Walter 
Published: June 2012

Abstract
Aim of this study was to test the in vitro and in vivo activity of KP1339, a promising ruthenium-based anti-cancer compound, in combination with the tyrosine kinase inhibitor sorafenib against human hepatoma cells. As a first approach, the drugs were tested together against a hepatoma cell line panel (n=7) by MTT assay. Combination of KP1339 with sorafenib induced additive to synergistic effects in all cell lines tested. Especially at higher sorafenib concentrations (10 µM) strong synergism with CI values between 0.1 and 0.5 were observed. Notably, synergistic activity with KP1339 was found in sorafenib-resistant as well as sorafenib-responsive cell lines. Recently, we have presented that KP1339 treatment induced phosphorylation of P38, JNK and erk and led to cell cycle arrest in G2/M Phase. Consequently, the effects of sorafenib on KP1339-induced P38 phosphorylation were investigated. Western blot analyses revealed that sorafenib strongly reduced phosphorylation of P38 and erk after KP1339 treatment. Moreover, addition of sorafenib reduced KP1339-induced G2/M arrest. Finally, the activity of the KP1339/sorafenib combination was evaluated in xenograft experiments (Hep3B cells). KP1339 monotreatment led to a 2.4-fold increase in life span (mean survival 80 days vs. 33 days in control) and thus was superior to sorafenib monotherapy, which induced a 1.9-fold survival increase (60 days). Combination of KP1339 with sorafenib increased the mean survival by 3.9-fold to 96 days. Together, our data indicate that the combination of KP1339 with Sorafenib is very promising in vitro and in vivo especially against human hepatoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3541. doi:10.1158/1538-7445.AM2011-3541
Abstract 356: Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer
Authors: Park Yun-Yong , Kim Kyoungjyun , Kim Sang-Bae , Hennessy Bryan , Kim Soo Mi , Park Eun Sung , Lim Jae Yun , Li Jane , Lu Yiling , Gonzalez-Angulo Ana , Mills Gordon , Safe Stephen , Lee Ju-Seog 
Published: June 2012

Abstract
ESR1 is one of the most important oncogenes and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and favorable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insight into how ESR1 is regulated by NR2E3 and clinical relevance of NR2E3 in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2011-356
Abstract 3591: Discovery of SB1317: A novel small molecule macrocycle with a unique kinase inhibitory spectrum in phase 1 clinical trials for hematological malignancies
Authors: William Anthony , Blanchard Stephanie , Lee Angeline , Poulsen Anders , Sun Eric , Teo Ee Ling , Nagaraj Harish , Goh Kay Lin , Ong Wai Chung , Goh Kee Chuan , Pasha Mohammed K. , Jayaraman Ramesh , Wood Jeanette M. , Ethirajulu Kantharaj , Dymock Brian W. 
Published: June 2012

Abstract
Introduction: During our quest to find novel kinase inhibitor motifs for our protein kinase research projects we discovered a novel series of macrocyclic structures which possess unique but tunable kinase inhibitory profiles. Here we present the chemical structure of SB1317 and the SAR studies leading to the discovery of this novel CDK/FLT3/JAK2 inhibitor, currently in clinical trials for hematological malignancies.
Methods/Results: The unusual structure of SB1317 is characterized by a biaryl connection to the hinge-binding 2-anilinopyrimidine and an allylic tertiary amine – homo allylic ether linker forming an 18-membered macrocyclic ring. Combination of the biaryl motif and unsaturation in the linker confers limited conformational freedom and may explain the specific biological activity observed with this series. Following extensive SAR studies a single preferred compound, SB1317, emerged with potent CDK (IC50 against CDKs 1, 2 and 9 = 9, 5 and 3 nM, respectively), FLT3 (IC50 = 19nM) and JAK2 (IC50 = 19nM) potency. SB1317 has low molecular weight and good physicochemical properties conferring good oral exposure and prompting its further evaluation in vitro and in in vivo cancer models. Following promising efficacy data in these studies, SB1317 was nominated as the preferred candidate for progression to the clinic. SB1317 was synthesized via a ring-closing metathesis (RCM) strategy where the macrocycle was formed from coupling the two halves of the molecule to provide a diene which was then closed by RCM using either Grubbs or Zhan catalysts. Crucially the RCM reaction requires acidic conditions to neutralize the basic centre to allow the metathesis to proceed.
Conclusions: SB1317 is a low molecular weight compact macrocyclic structure with a unique spectrum of kinase activity suggesting it may have particular utility in the treatment of hematological malignancies and potential for solid tumor therapy as well. SB1317 is currently being developed in the clinic by Tragara Pharmaceuticals (San Diego, CA) under the name TG02.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3591. doi:10.1158/1538-7445.AM2011-3591
Abstract 3593: Generation of a potent and selective inhibitor of ALK, CH5424802, showing superior oral bioavailability, PK profile and in vivo efficacy
Authors: Oikawa Nobuhiro , Kinoshita Kazutomo , Asoh Kohsuke , Furuichi Noriyuki , Itoh Toshiya , Kawada Hatsuo , Hara Sosuke , Miyagi Takuho , Ohwada Jun , Taniguchi Saori , Hattori Kazuo , Tsukuda Takuo , Takanashi Kenji , Sakamoto Hiroshi , Tsukaguchi Toshiyuki , Ishii Nobuya , Aoki Yuko , Shimma Nobuo 
Published: June 2012

Abstract
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in some cancers, due to gene alterations such as chromosomal translocation, amplification, or point mutation. It has been recognized as an attractive solid tumor target since the discovery in 2007 of the fusion gene, comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene, which is detected in ca. 6.7% of non-small-cell lung cancer (NSCLC) patients. We have identified a lead compound as an ALK inhibitor through kinase panel screening of in-house kinase-oriented library. The lead compound had a unique scaffold but showed a rather broad kinase inhibition profile. Therefore, we examined structure-activity relationship from the viewpoint of the kinase selectivity as well as ALK inhibition potency. Finally, we identified CH5424802 as a clinical candidate having high selectivity over other kinases including c-Met, c-Kit and KDR. CH5424802 has a preferable PK profile and good oral bioavailability in rats and monkeys. CH5424802 showed preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion both in vitro and in vivo. CH5424802 is currently being investigated in Phase I/II clinical trials for patients with ALK-positive NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3593. doi:10.1158/1538-7445.AM2011-3593
Abstract 3599: Aurora kinase inhibitors as a novel targeted drug therapy for bladder cancer
Authors: Zhou Ning , Singh Kamini , Almasan Alexandru , Hansel Donna 
Published: June 2012

Abstract
Introduction: Conventional chemotherapy for invasive bladder cancer has limited efficacy and is generally associated with poor patient prognoses. This study aims to evaluate the potential of targeting the aurora kinases, a family of mitotic regulators, with pharmacologic inhibitors as a novel treatment for bladder cancer.
Materials and Methods: RNA microarray and reverse-transcriptase polymerase chain reaction (RT-PCR) were utilized to evaluate expression of genes associated with the mitotic spindle checkpoint, including aurora kinases A and B, in clinical tissue samples of urothelial carcinomas of the bladder and normal urothelium. Human urothelial carcinoma cell lines UM-UC-3 and T24 were treated with the nonspecific aurora kinase inhibitor ZM447439 and the aurora kinase A inhibitor MLN8237, either alone or in combination with gemcitabine or paclitaxel. Effects of drug treatments were evaluated by flow cytometry with propidium iodide staining, immunofluorescence microscopy, MTS proliferation assay, and TUNEL labeling.
Results: RNA microarray analysis comparing human tissue specimens of urothelial carcinomas of the bladder (N=10) to normal urothelium (N=8) identified overexpression of 13 gene transcripts related to the mitotic spindle checkpoint, including aurora kinases A and B, in the cancer specimens. Upregulation of these genes was validated by RT-PCR on a separate set of clinical samples (N=4 for each group). Next, the impact of aurora kinase inhibitors on bladder cancer cell lines was assessed. ZM447439 and MLN8237 treatment of UM-UC-3 and T24 cell lines at concentrations of 10 nM to 1 uM induced G2/M cell cycle arrest and aneuploidy in a dose dependent manner. Immunofluorescence microscopy showed abnormal mitotic figures with multipolar spindle apparatuses in treated cells. Both cell lines also exhibited cell death by positive TUNEL staining 48 hours after treatment with either inhibitor. Simultaneous treatment of T24 cells with MLN8237 and paclitaxel and subsequent MTS proliferation assay revealed an antagonistic interaction between paclitaxel and MLN8237, whereas simultaneous treatment with MLN8237 and gemcitabine resulted in an additive effect.
Conclusion: Several mitotic spindle checkpoint proteins, including the aurora kinases, are overexpressed in bladder cancer. Our data indicate that aurora kinase inhibitors have significant potential as a novel therapy for bladder cancer, as they induce abnormal mitosis, cell cycle arrest, and eventual death of bladder cancer cells in vitro.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3599. doi:10.1158/1538-7445.AM2011-3599
Abstract 360: Effect of adrenogenic androgens on androgen receptor activity in prostate cancer microenvironment
Authors: Mizokami Atsushi , Kumaki Misako , Shima Takashi , Izumi Kouji , Kadono Yoshifumi , Konaka Hiroyuki , Namiki Mikio 
Published: June 2012

Abstract
One of the mechanisms by which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. The origin of residual androgenic in PCa tissue is regarded as adrenogenic DHEA. Previously, we reported that prostate cancer-derived stromal cells (PCaSC) coordinately synthesize DHT from adrenal DHEA with LNCaP cells and that accelerated AR activity in LNCaP cells induced by DHEA. However, DHEA of high concentration was needed to accelerate androgen receptor (AR) activity. Therefore, We investigated whether adrenogenic other androgens of the physiological concentration in castrated PCa patient (androstenedione and androstenediol) could activate AR of LNCaP cells in the presence of PCaSC. Androstenedione of the physiological concentration as well as DHEA of the high concentration activated AR in the presence of PCaSC. Now we are investigating the relationship between degree of AR activity induced by adrenal androgens in the presence of PCaSC and prognosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 360. doi:10.1158/1538-7445.AM2011-360
Abstract 3606: CH5126766 is a novel allosteric inhibitor of MEK that prevents its phosphorylation by RAF
Authors: Ishii Nobuya , Harada Naoki , Sakamoto Hiroshi , Matsuda Yutaka , Tomii Yasushi , Tachibana-Kondo Yukako , Miura Takaaki , Ohara Kazuhiro , Iikura Hitoshi , Aoki Toshihiro , Shimma Nobuo , Arisawa Mikio , Joseph Eric , Poulikakos Poulikos , Sowa Yoshihiro , Rosen Neal , Aoki Yuko , Sakai Toshiyuki 
Published: June 2012

Abstract
Tumors with mutant BRAF or RAS are often dependent on the ERK signaling pathway. MEK and RAF inhibitors have significant antitumor activity in patients with BRAF mutant melanoma, but, thus far, MEK inhibitors have little activity in patients whose tumors contain mutant RAS. The effectiveness of the drugs seems to require near complete inhibition of ERK signaling. MEK inhibition has been shown to lead to relief of feedback inhibition of RAF and induction of MEK phosphorylation. It is possible that this induction attenuates inhibition of the pathway and reduces clinical activity.
We have now isolated and characterized an allosteric inhibitor of MEK, CH5126766, with novel properties that prevent its induction of MEK phosphorylation. CH5126766 causes MEK to bind to RAF tightly and in a conformation in which it cannot be phosphorylated. MEK in this complex has low kinase activity and may act as a dominant negative inhibitor when bound to RAF. Compared to the MEK inhibitor PD0325901, CH5126766 inhibits ERK signaling output in cells more potently and has greater antitumor activity in the KRAS mutant colorectal cancer HCT116 grown as a murine xenograft. MEK inhibitors such as CH5126766 will inhibit feedback induction of MEK phosphorylation and this may allow more complete pathway inhibition and result in greater antitumor activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3606. doi:10.1158/1538-7445.AM2011-3606
Abstract 3613: Down regulation of LIM kinase1 enhances taxane sensitivity of cancer cells
Authors: Ottman Richard , Chakrabarti Ratna 
Published: June 2012

Abstract
Taxane compounds, such as docetaxel and paclitaxel, are microtubule-targeted tubulin-polymerizing agents and have proven to be the first line of treatment choice for castration-resistant prostate cancer and tamoxifen-resistant breast cancer cells. However resistance to taxane compounds develops commonly due to altered beta tubulin isotypes or development of multidrug resistance (MDR) through activation of p-glycoprotein drug efflux pump. In addition there are serious side effects and systemic toxicity encountered with docetaxel treatment. There is a need to enhance the efficacy of the taxane compounds by identifying novel targets, inhibition of which would induce mitotic arrest and apoptosis. LIM kinase1 (LIMK1) is a serine/threonine kinase, which coordinates microtubule stability and reorganization of actin cytoskleton through inactivating phosphorylation of cofilin, and is involved in regulation of the mitotic process. LIMK1 is overexpressed in breast and prostate tumors and in breast and prostate cancer cells in culture. Ectopic expression of LIMK1 promotes altered cell cycle progression and mitotic defects. Furthermore, LIMK1 expression prevents normal cellular response to paclitaxel in prostate epithelial cells, such as metaphase arrest and retarded cell growth. In this study, we show that ectopic expression of LIMK1 in BPH-1 cells decreased cytotoxic effects of paclitaxel through reduction of the number of apoptotic cells. Cell viability analysis using MTT assay showed that LIMK1 expressing cells maintained a higher viable cell density compared to control cells following paclitaxel treatment. LIMK1 expression in BPH-1 cells also increased BCL2 expression and decreased translocation of BAX to mitochondria compared to control cells. siRNA-induced down regulation of LIMK1 expression increased docetaxel sensitivity of breast and prostate cancer cells. Flow cytometric analysis of LIMK1 siRNA treated cells showed increased percentage of apoptotic cells compared to control RNA treated cells. Western blot analysis showed increased cleavage of apoptotic markers PARP, caspase 3 and caspase 9 in LIMK1 shRNA transfected prostate cancer cells upon docetaxel treatment compared to cells transfected with scrambled shRNA. Our study suggests that targeted inhibition of LIMK1 expression may potentiate the effects of taxane compounds on breast and prostate cancer cells. This study will have a broad impact on management of castration-resistant prostate and tamoxifen-resistant/ER-apha negative breast cancer cells with increased sensitivity of taxane compounds at a lower dose and hence less systemic toxicity, which could be applicable to other types of cancers as well.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3613. doi:10.1158/1538-7445.AM2011-3613