bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3823: 2-Methyl-6-substituted pyrrolo[2,3-d]pyrimidine classical antifolates as selective folate receptor substrates, glycinamide ribonucleotide formyltransferase inhibitors and antitumor agents
Authors: Gangjee Aleem , Zhao Sai , Wang Lei , Orr Steven , Etnyre Erika , Raghavan Sudhir , Matherly Larry H. , Kisliuk Roy L. 
Published: August 2012

Abstract
The important role of reduced folates in one-carbon transfer reactions has rendered folate metabolism an attractive target in cancer chemotherapy for decades. Clinically used antifolates enter cells via folate uptake systems, such as the reduced folate carrier (RFC), folate receptors (FRs), and the proton-coupled folate transporter (PCFT). Toxicity of clinically used antifolates is due to their lack of selectivity for tumor cells, since these antifolates are transported by RFC which occurs in normal as well as tumor cells. FRs are not usually expressed in normal cells. However, the ≤ isoform of FR is abundantly expressed in certain tumor cells, such as ovarian, endometrial, etc. Thus, selective FR-targeted antifolates that also possess cytotoxic activity without transport by RFC would likely circumvent the major toxicities of currently used antifolates. 2-Methyl-6-substituted pyrrolo[2,3-d]pyrimidine antifolates were designed to evaluate the importance of the 2-amino group for transport by RFC, FR, and /or PCFT, as well as for inhibition of α-glycinamide ribonucleotide formyltransferase (GARFTase) in de novo purine biosynthesis, compared with the 2-amino analogs. The most active compound in our series, AG179, showed an IC50 of 1.6 nM in inhibiting proliferation of KB human tumor cells, and was ∼3-fold less potent than the corresponding 2-amino compound AG71 (0.55 nM). In Chinese hamster ovary (CHO) cells engineered to individually express the major folate transporters, AG179 also inhibited growth of FRα-expressing RT16 cells but was inactive toward RFC-expressing PC43-10 and PCFT-expressing R2/PCFT4 CHO cells. The 2-amino analog, AG71, is inert toward RFC but is avidly transported by PCFT and is cytotoxic toward PCFT-expressing cells. In KB cells, growth inhibition by AG179 like AG71 is protected by excess adenosine and 5-amino-4-imidazole carboxamide, establishing GARFTase and de novo purine biosynthesis as the likely intracellular targets. These results establish that replacement of the 2-amino group of AG71 with a methyl group has a limited impact on FRα uptake and anti-proliferative activity, however, this replacement has a profound impact on cellular uptake by PCFT. This report will present the details of the design, synthesis, biological evaluation and molecular modeling of the title compounds.
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 3823. doi:1538-7445.AM2012-3823
Abstract 3828: Potent curcumin analogues inhibit pancreatic cancer cell growth and angiogenesis
Authors: Nagaraju Ganji Purnachandra , Zhu Shijun , Diaz Roberto , Shoji Mamoru , El-Rayes Bassel F. 
Published: August 2012

Abstract
Background: Curcumin, a component of turmeric, has demonstrated anti-cancer properties mediated through inhibition of NF-κB in preclinical models. In clinical trials, curcumin failed to demonstrate activity against pancreatic cancer. The pharmacologic properties, low absorption, and low potency of curcumin may account for this discrepancy between preclinical and clinical results. Using the curcumin molecular model, our group synthesized over 100 analogs. Of these analogs, EF31 and UBS109 demonstrated higher potency in squamous cell cancer xenograft models as well as inhibition of NF-κB signaling pathways. Based on this preclinical data, we hypothesized that these analogs EF-31 and UBS-109 would be more effective in inhibiting growth of pancreatic cell lines than curcumin. Methods: MiaPaCa-2 and PANC-1 cell lines were used in the experiments. Cells were cultured and then treated with nothing (control), curcumin, UBS-109, EF-31, 5FU, or combination. Cell proliferation was evaluated using XTT assay. Western blot was used to evaluate effects on HSP90, HIF-1α, and VEGF levels. Angiogenic effects were measured by tube formation and chicken egg chorioallantoic membrane (Egg CAM) assays. Results: UBS-109 and EF-31 demonstrated significantly improved inhibition of cell proliferation as compared to curcumin. UBS-109 and EF-31 potentiated the growth inhibitory effects of 5FU. UBS-109 and EF-31 resulted in significant inhibition of expression of protein and mRNA for HSP90 and HIF-1α as compared to curcumin. In turn, UBS-109 and EF-31 significantly inhibited VEGF protein and mRNA expression resulting in inhibition of HUVEC tube formation in vitro and also inhibited angiogenesis in vivo using the Egg CAM assay. Conclusion: UBS-109 and EF-31 are more potent analogs of curcumin. Preliminary data demonstrate potentiation of chemotherapy effects as well as antiangiogenic effects. Evaluating UBS-109 and EF-31 in patients with pancreatic cancer is a rational approach to target HSP90 and HIF-1α in this disease.
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 3828. doi:1538-7445.AM2012-3828
Abstract 3833: Ceramide/tamoxifen nanoliposomal combination - A promising strategy for treatment of chemoresistant breast cancer
Authors: Morad Samy A.F. , Levin Jonathan C. , Kester Mark , Shanmugavelandy Sriram S. , Cabot Myles C. 
Published: August 2012

Abstract
Drug resistance in breast and other cancers results from multiple gene interactions. Ceramide, a key intermediate in the sphingolipid pathway, can act as a powerful tumor suppressor. The employ of ceramide-based agents as opposed to the administration of ceramide generators such as daunorubicin, could be a smart strategy for cancer therapy. Polychemotherapy remains the best option for treatment of breast cancer at the aggressive, metastatic stage. The aim of our study was to investigate the cytotoxic and antiproliferative effects of ceramide (short-chain C6-ceramide) administered in combination with tamoxifen, used here as an inhibitor of ceramide glycosylation. We previously demonstrated the cytotoxicity of this combination in MDA-MB-231 cells; however, little regarding mechanism was established. The present study employs nanoliposomal formulations of both agents, a strategy to enhance efficacy. Four triple-negative chemoresistant breast cancer cell lines, MDA-MB-231, MDA-MB-468, BT-20 and Hs578T were used. Cytotoxicity assays revealed that C6-ceramide/tamoxifen synergistically reduced viability, compared to single agents in all four cell lines. For example, in MDA-MB-468 cells, nanoliposomal C6-ceramide (2.5 µM), tamoxifen (5 µM), and the combination reduced cell viability to 70, 85, and 10% of control, respectively (96 hr). A hallmark of cancer, implicated in tumor growth as well as metastasis, is resistance to induction of apoptosis. Assessment of cellular apoptosis showed that C6-ceramide/tamoxifen treatment promoted DNA fragmentation in a dose-dependant manner, attaining a value that was 36% over control at 24 hr. Introduction of the pan-caspase inhibitor, z-VAD-fmk, completely reversed DNA fragmentation, showing that apoptosis was mediated by caspase activation. The aggressive and metastatic behavior of any tumor is dependent on the ability of the cells to proliferate. Interestingly, the lower concentrations of our drug combination (2.5 µM) induced cell cycle arrest at G1, the first growth phase. In summary, this approach has potential to circumvent limitations of ceramide-based therapies, such as rapid ceramide clearance due to metabolism, the inability to attain therapeutic levels when ceramide-generating agents are employed, and inherent insolubility that is encountered. These findings demonstrate the in vitro efficacy of combination C6-ceramide/tamoxifen nanoliposomal formulations for suppressing growth of breast cancer cells, and suggest that tamoxifen may be an effective adjuvant for enhancing ceramide-driven cell death cascades. Supported by NIGMS 77391 and ABC's, Los Angeles.
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 3833. doi:1538-7445.AM2012-3833
Abstract 3835: Identification and characterization of inhibitors of 5′-nucleotidase cN-II issued from virtual screening
Authors: Jordheim Lars P. , Marton Zsuzsanna , Rhimi Moez , Chaloin Laurent , Cros-Perrial Emeline , Lionne Corinne , Peyrottes Suzanne , Aghajari Nushin , Dumontet Charles 
Published: August 2012

Abstract
Clinical and preclinical observations have lead to the hypothesis that 5′-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se, either to increase the activity of cytotoxic nucleoside analogues. We performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant full length cN-II, soaking experiments with crystals of truncated cN-II and biological evaluation of inhibitors alone or in combination with cytotoxic nucleoside analogues on cancer cells both in vitro and in vivo. The top ranked compounds from virtual screening contained an anthraquinone-derivative (A) and a trisubstituted triazine (B) that were selected for further studies. In vitro enzymatic assay experiments with recombinant protein showed that compound A is a competitive inhibitor with Ki of approximately 3 mM, whereas derivative B is a non-competitive inhibitor with Ki of 1.1 mM. We also obtained crystallographic data at a resolution of 2.0 Å after soaking experiments with crystals of truncated cN-II. These showed interaction between A and F354/N154 situated in the effector site 1 of cN-II, whereas B was not found in crystallographic data even though crystals were degraded in presence of B over a longer time. Derivative A showed different levels of cytotoxicity in vitro on several cancer cell lines such as Raji (IC50=782 µM), RL (IC50=210 µM), CCRF-CEM (IC50=824 µM), MCF-7 (IC50=654 µM), A549 (IC50=569 µM) and HCT-116 (IC50=793 µM), whereas B was much less cytotoxic. When used at 1 mM, A and B did not modify IC50 of the nucleoside analogues cladribine, clofarabine or fludarabine in CCRF-CEM cells. When used at 100 µM, compound A increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5 µM cladribine, 0.05 µM clofarabine or 30 µM fludarabine. The administration of A (200 mg/kg, 5d/w, 4w) to mice xenografted with RL cells, induced a delay of tumor development that was higher than in mice treated with fludarabine (50 mg/kg, 1d/w, 4w). We showed that virtual screening can be used for the identification of potent cN-II inhibitors, and we produced clear evidences for the interaction of one inhibitor with the enzyme. Our biological evaluation indicated interesting activity for one lead compound that will be developed further in order to identify candidates with higher biological activity.
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 3835. doi:1538-7445.AM2012-3835
Abstract 3985: Senescent cells in growing tumors: population dynamics and cancer stem cells
Authors: LaPorta Caterina Anna Maria , Zapperi Stefano , Sethna James 
Published: August 2012

Abstract
Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutatations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted.
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 3985. doi:1538-7445.AM2012-3985
Abstract 3995: C-terminal fragment of prostate apoptosis response-4 (Par-4) generated by caspase-3 cleavage induces apoptosis in cancer cells
Authors: Chaudhry Parvesh , Singh Mohan , Parent Sophie , Asselin Eric 
Published: August 2012

Abstract
Prostate apoptosis response-4 (Par-4) is a ubiquitously expressed pro-apoptotic tumor suppressor protein. Previously, we have shown that Par-4 undergoes caspase-3 mediated cleavage in normal and cancer cells. In the present study, we demonstrated that caspase-3 generated cleaved fragment of Par-4 displays apoptotic activity. Hela cells were transiently transfected with empty or Myc tagged C-terminal fragment of Par-4. The results from immunofluorescence studies revealed that the cleaved fragment of Par-4 is predominantly localized in the nuclear compartment of the cells. Further, cells expressing C-terminal Par-4 fragment underwent significant apoptosis as compared to empty vector transfected cells as measured by flow cytometry using annexin V/PI staining. Next, we tested whether C-terminal fragment of Par-4 follows similar mechanism of apoptosis induction as the full length Par-4 by the inhibition of protein kinase C (PKC)/NF-κB pathway. Western blot analysis revealed that the overexpression of C-terminal Par-4 fragment reduced the protein levels of Bcl-2 and FLIP as compared to empty vector transfected cells. Overexpression of the C-terminal Par-4 fragment also reduced the levels of phosphorylated IαBβ, however, there was no change in the levels of total IαBβ. Interestingly, C-terminal fragment of Par-4 prevented the nuclear mobilization of NF-κB (p65) compared to empty vector transfected cells. On the other hand, NF-κB (p50) protein levels were found to be decreased in cells expressing the C-terminal Par-4 fragment suggesting that C-terminal fragment of Par-4 possesses pro-apoptotic activity and regulates apoptotic induction by inhibiting the nuclear localization and activity of NF-κB in a manner similar to wild type full length Par-4. To conclude, our data suggest that caspase-3 mediated cleavage of Par-4 results in nuclear localization of C-terminal Par-4 fragment which possesses pro-apoptotic activity.
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 3995. doi:1538-7445.AM2012-3995
Abstract 3998: The role of serum amyloid A1 (SAA1) in nasopharyngeal carcinoma (NPC)
Authors: Lung Hong Lok , Cheung Arthur Kwok Leung , Chung Yeung Man , Liu Edison Tak-Bun , Chua Daniel , Lung Maria Li 
Published: August 2012

Abstract
Background and aims: Nasopharyngeal carcinoma (NPC) is a cancer which occurs in high frequency in Southern China. The identification of diagnostic and prognostic markers will be highly beneficial for early stage NPC detection. Previous microcell-mediated chromosome transfer (MMCT) studies showed that the transfer of an intact human chromosome 11 suppresses the in vivo tumor growth of a NPC cell line (HONE1) in nude mouse tumorigenicity assays. We aim to identify candidate genes which are associated with tumor suppression in NPC. Methods: Differential expression analysis of 19K genes was performed in oligonucleotide microarray hybridization for the chromosome 11 microcell hybrids (MCHs)/ tumor segregants (TSs) pairs to hunt for some other unknown NPC genes. The gene expression of the candidate gene was examined in the NPC cell lines and tumor tissues. Functional analysis of restoration of the candidate gene expression was studied. Results: Using oligonucleotide microarray analysis, Serum Amyloid A 1 (SAA1), mapping close to 11p15.1, was identified as showing consistent down-regulated expression in the TSs, as compared to their parental tumor-suppressing MCHs. Gene expression and protein analyses show that SAA1 was not expressed in the NPC HONE1 recipient cells, tumor segregants, and other NPC cell lines; SAA1 was exclusively expressed in the non-tumorigenic MCHs. The mechanism of SAA1 gene inactivation in these NPC cell lines was attributed to hypermethylation. The clinical relevance of SAA1 in NPC was examined by RT-PCR; 54.8% (23/42) of NPC specimens showed either down-regulation or loss of SAA1 gene expression. After transfection of SAA1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. Conclusions: These findings suggest that SAA1 is a candidate tumor suppressor gene in NPC. Acknowledgments Grant support: Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China grant HKU772309 (H.L. Lung)
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 3998. doi:1538-7445.AM2012-3998
Abstract 4014: The gp130/Stat3 pathway enables Wnt induced regeneration and tumorigenesis in the mouse intestine
Authors: Phesse Toby J. 
Published: August 2012

Abstract
The transcription factor Stat3 is frequently activated in human intestinal tumors. Using a hyperactive gp130 mutant mouse, gp130Y757F (in which the Socs3 site of the gp130 receptor is mutated leading to constitutive activation of Stat3), we have recently demonstrated a key role for Stat3 during inflammation associated colonic cancer (1). However, although gp130Y757F mice are predisposed to gastric adenomas due to hyper Stat3 activation, they do not develop intestinal tumors. Deregulated Wnt signaling is also a key event in intestinal tumorigenesis. Mice which are heterozygous for the negative Wnt regulator Apc (ApcMin/+) develop multiple intestinal neoplasia, and in humans, constitutive heterozygosity for Apc underlies familial adenomatous polyposis (FAP) syndrome. To investigate a possible interaction between Stat3 and Wnt signaling in intestinal cancer we generated compound ApcMin/+ mutant mice to modulate expression and/or activation of Stat3. Compared to ApcMin/+ or gp130Y757F mice, corresponding gp130Y757F ApcMin/+ mice have a significantly reduced lifespan associated with an increase in the number of intestinal tumors. Conversely, when Stat3 is reduced in ApcMin/+Stat3+/− mice the number of polyps in both the small and large intestine is significantly reduced. Tumor initiation, but not tumor growth, is promoted in gp130Y757F ApcMin/+ mice compared to ApcMin/+ littermates. These results suggest that Stat3 is rate limiting for Wnt induced intestinal tumourigenesis. In support of this data we found that the in vitro colony forming potential of human colonic cancer cells (SW480 cells) was reduced when gp130/Stat3 signaling was inhibited. Importantly, inhibition of gp130/Stat3 did not reduce the colony forming potential of SW480 colon cancer cells expressing full-length APC (by stable transfection of APC), suggesting that Stat3 is only rate limiting during cellular conditions of high Wnt signaling. We have recently demonstrated that intestinal regeneration is characterized by high Wnt signaling and requires an intact Wnt signaling pathway (2). Stat3 is also rate limiting for intestinal regeneration in vivo and for intestinal organoid assays in vitro. Together these data provide a novel role for gp130/Stat3 signaling, which becomes rate limiting in situations of high Wnt signaling in the intestinal epithelium including regeneration and tumourigenesis. Mechanistically we find that Stat3 up-regulates Bcl2 (an apoptosis inhibitor protein) expression and allows cells to evade apoptosis, providing a survival advantage. Thus, compound gp130Y757F Bcl2+/− mice have reduced regenerative capacity in vitro and in vivo. (1) Bollrath and Phesse et al. 2009. Cancer Cell (2) Ashton and Phesse et al. 2010. Dev Cell
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 4014. doi:1538-7445.AM2012-4014
Abstract 4020: The Sox17 gene hypermethylation is useful as a molecular diagnostic application in early stage of gastric cancer
Authors: Hama Ryota , Watanabe Yoshiyuki , Shinada Kanako , Yamada Yosuke , Oishi Yoshichika , Yoshida Yoshihito , Hiraishi Tetsuya , Oikawa Ritsuko , Maehata Tadateru , Suzuki Hiromu , Itoh Fumio 
Published: August 2012

Abstract
Although minimal invasive treatment is widely accepted for early stage of gastric cancer (GCa), we still do not have any appropriate risk markers to detect residual neoplasia and some potential of recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. Our goal is to find and identify some candidate genes as a treatment marker using genome wide DNA methylation analysis for early stage of gastric cancer (EGC). We studied Methylated CpG Island Amplification Microarray (MCAM) analysis using 12 gastric washes (each 6 before (Pre) and after (Post) endoscopic treatment in same patients). One of them are Sox17. We examined the DNA methylation status of Sox17 in a validation set consisting of 128 washes samples (Pre, 64: Post, 64) at EGC. We next identified functional studies about Sox17 as a putative tumor suppressor gene. Sox17 showed significantly differential methylation between before and after treatment in EGC patient (Sox17, p&lt;0.0001). Moreover, treating GCa cells that lacked Sox17 expression with a methyltransferase inhibitor, 5-aza-2′-deoxycytidine, restored the gene's expression. Moreover, introduction of exogenous Sox17 into silenced cells suppressed colony formation. Gastric washes based DNA methylation analysis is easy and useful for early detection of recurrence after ER in EGC patients. Our data suggest that silencing of Sox17 occurs frequently in EGC and may play a key role in development and progression of the disease.
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 4020. doi:1538-7445.AM2012-4020