bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3760: A novel PKC-iota inhibitor, ICA-1 abrogates cell proliferation in breast cancer
Authors: Desai Shraddha , Patel Rekha , McCray Andrea N. , Pillai Prajit , Acevedo-Duncan Mildred 
Published: August 2012

Abstract
The objective of this research was to identify the efficacy of [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) as a novel PKC-iota inhibitor in breast cell proliferation. PKC-α is highly overexpressed in human breast cancer and is localized depending on the trend of pathologic type of the tumor [Hum Pathol. (2008) 6:824-831]; however, little is understood about its role in regulating cell proliferation in breast cancer. Results showed that PKC-α was highly activated and overexpressed in MD-MB-468 breast cancer cells. PKC-α directly associated and phosphorylated Cdk7, a master cell cycle regulator at T170 in a cell cycle dependent manner, phosphorylating its downstream target, cdk2 at T160. PKC-α co-localized with Cdk7 in nuclear and cytoplasmic region of MD-MB-468 cells. PKC-α downregulation reduced Cdk7 phosphorylation following ICA-1 (10µM) as well as PKC-α silencing (by siRNA treatment). PKC-α knockdown inhibited overall proliferation in breast cancer cells suggesting that breast cancer cells may be proliferating through a PKC-α/Cdk7/cdk2 mediated pathway. Hence, our results emphasize the potential of ICA-1 as a novel PKC-α inhibitor and chemotherapeutic agent for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3760. doi:1538-7445.AM2012-3760
Abstract 3769: Metabolic activation of batracylin and N-acetylbatracylin to reactive metabolites that bind protein and DNA: Possible role in toxicity
Authors: Buhrow Sarah A. , Kuffel Mary , Walden Chad , Reid Joel M. , Covey Joseph , Ames Matthew M. 
Published: August 2012

Abstract
Batracylin (NSC 320846, BAT) is a heterocyclic arylamine and topoisomerase II inhibitor shown to be active in murine tumor models, but with demonstrated species differences in toxicity associated with metabolism to N-acetylbatracylin (NBAT) by N-acetyltransferase (NAT). BAT is a preferential substrate of human NAT2. Accordingly, production of NBAT should be subject to population variability as a function of NAT2 polymorphisms. A phase I clinical trial of BAT in patients with advanced cancer and slow acetylator NAT2 phenotypes to reduce the risk of NBAT-related toxicity found a dose-limiting toxicity (DLT) of cystitis/hemorrhagic cystitis. In subsequent in vitro and in vivo preclinical studies to elucidate metabolic pathways that might contribute to BAT toxicity, we found oxidative metabolites and thiol conjugates of BAT and NBAT (MM Ames et al, Cancer Res 2011;71(8 Suppl):Abstract nr 1303). Since these data are consistent with metabolic activation of BAT to potentially toxic metabolites, we assessed formation of reactive intermediates as measured by covalent binding (CB) to protein and DNA or by formation of glutathione conjugates. Radiolabeled BAT and NBAT were incubated with 3-MC-induced rat (r), human (h) and dog (d) liver microsomes (LM), as well as with recombinant human cytochromes P450 (CYPs) with or without added DNA. NADPH-dependent BAT protein and DNA CB were detected in all microsomal preparations (see table below). NADPH-dependent NBAT protein CB was detected in all microsomal preparations except hCYP1B1. NADPH-dependent NBAT DNA CB was detected in all microsomal preparations except 3MC-rLM. We also detected a glutathione conjugate of mono-hydroxy BAT by lc/ms/ms analysis when BAT was incubated with hLM in the presence of glutathione and NADPH. Thus, CYP-catalyzed oxidation of BAT yields reactive metabolites that that bind protein and DNA and may contribute to drug-related DLT. Supported in part by NCI Contract N01-CM-52206.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3769. doi:1538-7445.AM2012-3769
Abstract 3793: Characterization of the mechanism of action of a novel small molecule inhibitor of HSP70
Authors: Balaburski Gregor , Leu Julia I-Ju , Andrake Mark , Hayik Seth , Beeharry Neil , Dunbrack Roland , Yen Tim , George Donna L. , Murphy Maureen E. 
Published: August 2012

Abstract
The stress-induced heat shock protein HSP70 is an ATP dependent molecular chaperone that plays a role in the folding of nascent peptides, assembly of multi-protein complexes, and transport of proteins across membranes and overall. Additionally, HSP70 has significant cytoprotective and anti-apoptotic functions. High levels of HSP70 can be found in many cancers, and are associated with poor therapeutic response and poor patient prognosis. These findings suggest that HSP70 may be a desirable molecular therapeutic target, in addition to being a useful tumor prognostic marker. Previously we demonstrated that the compound 2-phenylethynesulfonamide (PES) interacts with HSP70 and antagonizes HSP70 function by disrupting the interaction between HSP70 and its co-chaperones and client proteins. We showed that PES is toxic to cancer cells but not non-transformed cells. Moreover, PES was able to significantly extend the lifespan of mice in a Myc-driven model of lymphoma (p&lt;0.02; Leu et al., Mol Cell 36:15-27, 2009; Leu et al, Mol Can Res 9:936-47, 2011). Here we utilized binding assays, molecular modeling and in silico docking in order to predict the binding site for PES with HSP70. We were able to verify this binding site by identifying point mutants of HSP70 that fail to bind to PES. We used this information in order to predict potentially superior analogues, and we report that a novel analogue, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl) shows superior toxicity to tumor cells, and greater efficacy as an anti-cancer agent in Myc-driven lymphoma, compared to the parent compound (p&lt;0.0006). Moreover, we report that treatment with PES-Cl causes cell cycle arrest in G2/M, and that a significant fraction of tumor cells escape this checkpoint and die by apoptosis. These data implicate HSP70 in G2/M progression, and identify PES-Cl as a promising anti-cancer therapeutic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3793. doi:1538-7445.AM2012-3793
Abstract 3801: Prostate cancer cells are selectively targeted by zinc-sequestration chemotherapy
Authors: Dambal Shweta K. , Mihelich Brittany , Hergenrother Paul , Nonn Larisa 
Published: August 2012

Abstract
Introduction: Zinc accumulates at levels 10-fold higher in the prostate than other soft tissues and this metal is implicated in prostate cancer (PCa) pathogenesis. Prostatic lesions have 6-fold lower concentrations of zinc than normal adjacent prostate tissue. Zinc levels are even lower in normal and malignant prostate tissue from African American (AA) men, who are 1.5 times more likely to develop prostate cancer than their Caucasian (Cauc) counterparts, thus highlighting the associative that that zinc could have in prostate cancer carcinogenesis. PAC-1 is a chemotherapeutic agent that induces cell death via zinc sequestration by activation of pro-caspase 3, which is a major player in cell death. We hypothesized that the low zinc levels in prostate cancer cells will cause the cells to be uniquely sensitive to cell death by PAC-1. Secondarily we hypothesized that AA patients, who have lower zinc in the prostate, may have enhanced response to PAC-1. Methods: PAC-1 cytotoxicity was investigated in LNCaP, PC-3, 957e/hTERT (immortalized normal primary cell line) and patient-derived normal and cancer primary epithelial cells (PrE) by treatment with 100, 50, 25,10,1, 0 micromolar concentrations of PAC-1 and PAC-1 analogs. Cell death was analyzed via the MTS colorimetric assay. Results and conclusion: Normal and cancer prostate cells are sensitive to PAC-1 and even more sensitive to PAC-1 analogs. PAC-1 was growth inhibitory and induced cell death at higher concentrations. Ongoing studies will examine zinc-dependency of PAC-1-induced death. PAC-1 and its analogs-induced cell death and caspase-3 activation will be measured in zinc-depleted, zinc sufficient and zinc-excess media. Studies will also determine PAC-1 cytotoxicity in normal and cancer prostatic epithelial cells. PAC-1 cytotoxicity levels in patient-matched prostate cancer cells (PrCa) from AA and Cauc men will also be studied to interrogate the disparate role of zinc in regards to sensitivity to PAC-1. These results may be translated to the clinic since a derivative of PAC-1 (S-PAC-1) has been shown to have positive effects in a Phase I clinical trial in pet dogs with lymphoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3801. doi:1538-7445.AM2012-3801
Abstract 3803: Anti-cancer activity of Capridine, a novel nitroacridine chemotherapeutic, in glioblastoma
Authors: Shanmugam Arulkumaran , Rajoria Shilpi , George Andrea L. , Jussim Casey , Suriano Robert , Konopa Jerzy , Mittelman Abraham , Tiwari Raj K. 
Published: August 2012

Abstract
Glioblastoma is characterized by highly proliferative tumor cells, increased cellularity, necrosis, and proliferation of capillary endothelial cells. The incidence rate of glioma in adults is 50% greater in men than in women suggesting that there may be a male hormonal component that modulates glioblastoma progression. Our preclinical developmental program identified Capridine as a chemotherapeutic agent that had specificity towards prostate cancer with minimal bone marrow toxicity. Since the DNA intercalating activity of Capridine does not completely correlate with its cytotoxic activity, we examined other alternative cellular targets. Our investigation identified the androgen receptor (AR) and its dependent signal transduction mechanism as a possible cellular mediator of its cytotoxic activity. In this study, our analysis revealed that glioblastoma cell lines T98G and MO59K expressed AR and their growth was responsive to the AR-mediated signal transduction. Capridine inhibited the growth of glioblastoma cells by down regulating the AR and inhibiting the phosphorylation of Focal adhesion kinase (FAK). Since FAK is associated with integrin and neuropeptide mediated signaling, critical for cell migration and invasion, we examined the activity of Capridine on cell invasion and migration using a Boyden Chamber assay. Capridine inhibited the migration and invasion of the glioblastoma cell lines T98G and MO59K. Our data not only validate AR as a target of Capridine as with prostate cancer but also implicate a novel target, FAK in glioblastoma. Combination approaches using Capridine and anti-hormonal therapy may prove to be viable chemotherapeutic regimen for primary glioblastoma as well as an inhibitor of metastatic propensity. These preclinical studies are being extended in an in vivo animal model with combination treatment approaches with a view to develop novel chemotherapy based treatment for glioblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3803. doi:1538-7445.AM2012-3803
Abstract 3805: Identification of a distinctive pattern of lipid composition in Irvalec® resistant tumor cells
Authors: Molina-Guijarro José M. , Moneo Victoria , Martínez-Leal Juan F. , Fernández-Rodríguez Rogelio , Cuevas Carmen , Garcia-Fernandez Luis F. , Galmarini Carlos M. 
Published: August 2012

Abstract
Irvalec® is a marine derived synthetic depsipeptide showing cytotoxic activity against a wide diversity of tumor cells both in vitro and in vivo. The compound is currently undergoing Phase II clinical studies in patients with solid tumors. The existing data on the mechanism of action of Irvalec® indicate that the compound inserts and self-organize in the plasma membrane of tumor cells, rapidly inducing loss of membrane integrity and cell permeabilization, giving rise to a fast and dramatic necrotic death. By continuous exposure of human colon carcinoma HCT-116 cells to stepwise increasing concentratrions of Irvalec®, a resistant subclone of the cell line was established, named HCT-116-Irv. In dose-response cytotoxicity assays, HCT-116-Irv cells showed a GI50 value &gt;50 μM, representing a specific resistance index to the compound greater than 10.8 as compared to their wt counterpart. The resistant cells did not show any of the morphological and physiological responses to Irvalec® observed in parental cells and no overexpression of Pgp efflux pump or significant cross-resistance to other antitumoral drugs was detected. Due to the presumably direct effect of Irvalec® on the cell membrane, we searched for possible changes in the lipid composition of the resistant cells, acquired during the process of resistance development. After fractionation of the lipid extracts using thin layer cromatography (TLC), two differential fractions, that were completely absent in the resistant cells as compared to wt cells, were identified and purified. Interestingly, one of these fractions, named F4, was found to be able to interact with a biotinilated derivative of Irvalec®, using a standard overlay assay. These results suggested that the lipid composition could be directly related to the sensitivity of tumor cells to Irvalec®. Efforts are now focused on the chemical characterization of the selected lipid fraction and its putative biological role mediating the cytotoxic response to Irvalec®.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3805. doi:1538-7445.AM2012-3805
Abstract 3812: Deguelin as a novel therapeutic agent for Herceptin resistant breast cancers
Authors: Mehta Rajeshwari , Alimirah Fatouma , Gupta Akash , Kalra Amit , Mehta Rajendra 
Published: August 2012

Abstract
Human breast cancers overexpressing HER-2 are generally highly aggressive. Current therapeutic strategies to target HER-2 signaling pathway with antibodies or small molecule tyrosine kinase inhibitors have shown impressive success in the management of these tumor types, although most women exhibit short term response to these therapies. Acquired resistance to HER-2 target drugs, especially Herceptin is a major challenge to clinicians. Patients receiving Herceptin therapy invariably recur and most often with highly aggressive tumors. Thus identifying new drugs which target multiple molecular pathways is desired to treat Herceptin resistant breast cancer. Using paired HER-2 overexpressing parental Herceptin responsive (BT-474) and its Herceptin resistant variant cells (BT-474HR) we showed that acquired resistance to Herceptin is associated with enhanced expression of HER-2, EGFR, CyclinD1, P-AKT (Ser-473), PI-3K, JAB1 proteins and decreased expression of nuclear pten and p27 proteins. These results are similar to those observed in recurrent breast tumors in patients following Herceptin treatment. Deguelin, a natural product derivative of rotenoids and has been shown to inhibit growth of diverse cancer types. Deguelin is a known AKT inhibitor, however its efficacy is never tested in breast cancers resistant to Herceptin which express high levels of p-AKT. We examined effect of Deguelin on HER-2 overexpressing BT-474 BT-474-HRcells. Deguelin inhibited growth of both, BT-474 and BT-474HR cells in concentration (0-250nM) and time dependent (24-72h) manner. There was a 40-50%- inhibition of both BT474and BT-474HR cells at 25nM Deguelin treatment at 72h. Deguelin decreased cell surface expression of HER-2 in both these cell lines. In parental BT-474 cells both Herceptin 5-10ug/ml and Deguelin down regulated HER-2 expression, but only Deguelin reduced HER-2 (125-250nM) over expression in both BT-474 and BT-474HR cells. Down regulation of HER-2 following Deguelin treatment was associated with simultaneous down regulation of nuclear accumulation of cyclin D1, and JAB1, and p-AKT (Ser-473) proteins and up regulation of nuclear p27 and p53in both BT-474 and BT474 HR cells. These results suggest that Deguelin inhibits growth of both HER-2 overexpressing and those resistant to Herceptin therapy breast cancer cells. Effect of Deguelin appears to be mediated through down regulation of HER-2, PI3K AKT, JAB1, Cyclin D1, and p27 pathway. Our preliminary results warrant further investigation into Deguelin as a potential therapeutic agent for Herceptin resistant breast cancers. (This work was supported by NCI CA140321.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3812. doi:1538-7445.AM2012-3812
Abstract 3814: Combination of selective modular of the glucocorticoid receptor (SEGRA) with proteasome inhibitors as a novel strategy for chemotherapy of hematologic malignancies
Authors: Yakubovskaya Marianna G. , Lesovaya Ekaterina A. , Yemelyanov Alexander , Kirsanov Kirill I. , Budunova Irina 
Published: August 2012

Abstract
Glucocorticoids are widely used for the treatment of hematological malignancies; however chronic treatment with steroids results in numerous adverse effects. Glucocorticoid receptor (GR) regulates gene expression via transactivation that requires GR homodimer binding to gene promoters; and transrepression mediated via negative interaction between GR and other transcription factors. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. One of the novel GR modulators is 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium-chloride also called CpdA. CpdA is a synthetic analogue of a aziridine precursor isolated from the Namibian shrub Salsola tuberculatiformis Botschantzev. Using representative human T cell (CEM) and B cell (NCEB) lymphoma cell lines expressing functional GR, and their counterparts with blocked GR expression, we showed that CpdA indeed acted as dissociated GR ligand, and inhibited growth and survival of these cells via GR. Sensitivity to therapeutic effects of GCs directly depends on the amount of functional GR. The 26S protesome controls GR protein stability, and is responsible for desensitization to GCs via hormone-induced GR degradation and following development of glucocorticoid resistance in patients. Thus, the use of proteasome inhibitors represents a pharmacological approach to prevent GR down-regulation and to elevate the level of GR in cells. Proteasome inhibitor Bortezomib (BZ) was approved by FDA for the treatment of patients with multiple myeloma and mantle cell lymphoma. Since proteasome inhibitors stabilize GR, we hypothesized that BZ will augment CpdA effects as a selective GR modulator and enhance its chemotherapeutic activity. We showed that pretreatment of CEM and NCEB cells with proteasome inhibitor Bortezomib resulted in GR accumulation, and enhanced CpdA ligand properties further shifting GR activity towards transrepression evaluated by inhibiton of NF-kB and AP-1 factors. We also revealed remarkable GR-dependent synergy between CpdA and BZ in suppressing growth and survival of T and B lymphoma cells. Overall, our data provide the rationale for novel GR-based therapy for lymphoma and leukemia based on the combination of non-steroidal GR modulators with proteasome inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3814. doi:1538-7445.AM2012-3814
Abstract 3818: Arsenic hexaoxide (As4O6) shows anticancer effects on human colon cancer cells in vitro and in vivo
Authors: Yun Jeong Won , Lee Won Sup , jeong Kim Min , Lu Jing Nan , Kim Dong Chul , Choi Yung Hyun , Jeong Jae-Hoon , Kim GonSup 
Published: August 2012

Abstract
Arsenic hexaoxide (As4O6) has been used as a folk remedy for the treatment of cancer since the late 1980's in Korea, and evidence suggests that As4O6-induced cell death pathway was different from that of As2O3. Here, we investigated the anticancer activities of As4O6 on SW620 human colon cancer cells. As4O6 induced cell death in a dose-dependent manner. The cell death was caspase-independent. In addition, the apoptosis was associated with suppression of p-Akt and activation of p-P38. As4O6 suppressed TNF-induced NF-κB activation through suppression of phosphorylation of IαB. As4O6 also suppressed NF-κB-regulated genes (Bcl-2, XIAP, and Bcl-xL) which are involved in anti-apoptosis. In animal experiments, As4O6 inhibited tumorigenicity of SW620 cells in a xenograft mouse model without showing any harmful effects on mice. As4O6 significantly inhibited intratumoral microvessel density. However, the inhibitory effects of As4O6 on NF-κB was minimal. In summary, in vitro study indicates that the As4O6 have anti-cancer effects on SW620 human colon cancer cells through inducing apoptosis by inhibiting anti-apoptotic molecules and in vivo study suggested that As4O6 should have additional anti-angiogenic activity. This study provides the evidence that As4O6 might be useful in the treatment of human colon cancer. [This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare & Family Affairs, Republic of Korea (0820050), and National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0007389)]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3818. doi:1538-7445.AM2012-3818