bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3378: Metformin protects head and neck cancer stem cells against DNA damage induced apoptosis
Authors: Kuo Selena Z. , Honda Thomas K. , Abhold Eric L. , Wang-Rodriguez Jessica , Altuna Xabier , Ongkeko Weg M. 
Published: August 2012

Abstract
The cancer stem cell hypothesis posits that within a tumor exists a distinct subpopulation of cells responsible for tumor initiation, progression, and maintenance. These cancer stem cells (CSCs) tend to be resistant to conventional chemotherapy and, like normal stem cells, possess the ability to self-renew and differentiate, thereby effecting tumor recurrence. Metformin, the most widely prescribed drug for the treatment of diabetes, has received attention in recent years as a potential anticancer agent capable of targeting cancer stem cells through such means as inhibiting cell proliferation and abrogating chemo-resistance. In the current study, we sought to determine the effects of Metformin on a putative head and neck squamous cell carcinoma (HNSCC) cancer stem cell culture. In contrast to the findings of previous studies, our data suggests that Metformin promotes properties of a cancer stem cell phenotype in HNSCC in vitro. Treatment with Metformin resulted in a dose-dependent induction of the stem cell genes CD44, BMI-1, Oct-4, and Nanog, as measured by qPCR. These results were supported by immunofluorescence data. Metformin treatment promoted self-renewal capacity of HNSCC stem cells, as demonstrated by the increase in size and number of tumorspheres formed in non-adherent and non-differentiating conditions. At various doses, treatment with Metformin alone had no effect on cell proliferation, as measured by MTS assay. Furthermore, when administered in combination with cisplatin, Metformin significantly protected against cisplatin-induced cell death, as demonstrated by MTS and TUNEL assays. Immunoblot experiments demonstrating a decrease in Akt phosphorylation upon treatment with Metformin suggests Metformin-mediated cytoprotection is independent of the Akt pathway. Other possible mechanisms are currently under investigation, including Metformin's ability to regulate autophagy. Although further in vivo studies are necessary, taken together, our findings suggest that Metformin may not be an effective therapeutic option for patients with HNSCC.
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 3378. doi:1538-7445.AM2012-3378
Abstract 3380: Comparison proteome analysis of scirrhous gastric carcinoma stem cell-like SP and hypoxia-resistant cell lines
Authors: Morisaki Tamami , Yashiro Masakazu , Kakehashi Anna , Okita Yoshihiro , Fukuoka Tatsunari , Aomatsu Naoki , Yoshii Mami , Hasegawa Tsuyoshi , Matsuoka Junko , Nagahara Hisashi , Kimura Kenjiro , Noda Eiji , Amano Ryosuke , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Yamada Nobuya , Maeda Kiyoshi , Nakata Bunzo , Ohira Masaichi , Wanibuchi Hideki , Hirakawa Kosei 
Published: August 2012

Abstract
Intro Cancer stem cells (CSCs) are considered to be responsible for cancer metastasis, and hypoxia is supposed to be an important regulator of CSCs differentiation. Furthermore, tumor hypoxia was reported to be associated with more aggressive tumor phenotypes such as high metastatic ability and resistance to various anti-cancer therapies which may lead to a poorer prognosis. This raises the question of whether there might be proteins representing similar alterations which are responsible for the correlation between hypoxic and CSCs phenotypes. We have established a diffuse-type of gastric carcinoma cell line (OCUM-12), and a hypoxia-resistant cancer cell line (OCUM-12/Hypo) cloned from parent OCUM-12 cells by continuous exposure to 1% oxygen. The side population (SP), as evaluated by a flow cytometric analysis using Hoechst 33342, has been known as CSC-rich population. To investigate and compare the proteomes of the hypoxic (OCUM-12/Hypo), stem cell (OCUM-12SP) and parent OCUM-12 diffuse-type gastric carcinoma cell lines, protein lysates from those cell lines were analyzed using QSTAR Elite LC MS/MS. Method Triplicate pooled samples (10 ug protein each) from stomach cancer cell lines were prepared and labeled with iTRAQ reagents. MS/MS data were searched against the Swiss Protein database (HUMAN) using ProteinPilot™ 2.0 software (AB Sciex). The Ingenuity Pathway analysis program was utilized, to assign biological significance, and to identify networks of interacting differentially expressed proteins, functional groups and pathways. Result In both OCUM-12SP and OCUM-12/Hypo cells, significant overexpression of Wnt signaling pathway was obvious. Furthermore, elevation of MTHFD1, a protein controlling histidine and purine nucleotide metabolism, cytokeratins 18 (CK18), and 19 (CK19) regulating cell cycle, apoptosis and angiogenesis, transcriptional regulator ANP32A, and cellular chaperones heat shock proteins A9 and STIP was observed as compared to the parent OCUM-12 cell line. Furthermore, anterior gradient homolog 2 (AGR2)was down-regulated in both cell lines. Conclusion Wnt signal, MTHFD1, CK18, CK19, ANP32A, HSPA9 and STIP, AGR2 might be responsible for the stem-like phenotype, hypoxia resistance and higher invasiveness of gastric 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 3380. doi:1538-7445.AM2012-3380
Abstract 3841: HIF-143, a novel inhibitor of complex III, inhibits pancreatic cancer growth by suppressing reactive oxygen species production and epidermal growth factor signal
Authors: Kim Se Nyun , Han Youn Ho , Kang Dae Pill , Park Sung Ho , Kim Jung-Ho , Kim Se Won , Kim Jung Keun 
Published: August 2012

Abstract
Reactive oxygen species have been considered as a therapeutic target for cancer treatment. In this study, we characterized the anticancer activity of novel small molecule inhibitor of cytochrome bc1, HIF-143, in pancreatic cancer. HIF-143 shares common structural moiety with known cytochrome bc1 Qo inhibitors including azoxystrobin and E-α-methoxyacrylate-stilbene. HIF-143 inhibits reduction of cytochrome c by purified mitochondria in the presence of rotenone and induction of reactive oxygen species by hypoxia or epidermal growth factor in cellular context. HIF-143 also suppresses activation of EGFR and downstream ERK and AKT induced by EGF treatment. EGF-induced transcription was also inhibited by HIF-143. Interestingly, these effects were synergistic when combined with EGFR inhibitor such as Erlotinib and Gefitinib. Cell proliferation, survival, and anchorage-independent growth were also synergistically inhibited by HIF-143 and Erlotinib. HIF-143 also inhibited pancreatic tumor growth in BxPC-3 human pancreatic cancer xenograft model. The inhibition of tumor growth was much higher when animals were treated with both HIF-143 and Erlotinib than individual treatment, suggesting synergistic anticancer activity in vivo. In addition, when HIF-143 was combined with Erlotinib and Gemcitabine, anticancer efficacy was increased without the increase of sign of toxicity, showing addition of HIF-143 can give clinical benefit to pancreatic cancer patients. Toxicological study showed that combination of HIF-143 and Erlotinib is safe enough with safety margin higher than 6-fold. These findings suggest that pharmacological targeting of complex III might be a promising approach to treat pancreatic cancer. These results provide scientific rational for testing of HIF-143 in the clinical trial to develop as a novel anticancer drug.
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 3841. doi:1538-7445.AM2012-3841
Abstract 3843: Targeting FACT complex suppresses mammary tumorigenesis in Her2/neu transgenic mice
Authors: Gurova Katerina V. , Garcia Henry , Commane Mairead , Safina Alfiya 
Published: August 2012

Abstract
We have recently found that expression of Facilitates Chromatin Transcription (FACT) complex consisting of SSRP1 and SPT16 protein subunits is elevated in many types of cancer comparing with normal tissues. Moreover, survival of tumor cell, but not normal cells is significantly compromised upon genetic knockdown of any of the FACT subunits. In our recent studies we have shown that FACT is essential for the transcriptional activity of NF-κB and Heat Shock Factor 1 and identified small molecules that inhibit activity of both transcription factors by causing functional inactivation of FACT. Since both NF-kB and HSF1 are activated in the process of transformation, we proposed that FACT may be involved in tumor transformation and that inhibition of FACT activity may prevent or reduce tumorigenesis. Objectives of our study were: (i) to check if FACT level is changed in the process of oncogene-induced transformation in vitro and in vivo; and (ii) to test safety and efficacy of anti-FACT therapy with Curaxin-137 in prevention of tumor formation in mice prone to cancer due to oncogene overexpression. We used in vitro (Ha-ras12V) and in vivo (MMTV-neu transgenic mouse model) models of transformation to monitor changes in FACT subunits. We treated the MMTV-neu transgenic mice, in which mammary carcinomas are spontaneously developed due to estrogen receptor-regulated expression of the Her2 proto-oncogene, with Curaxin-137 to determine whether the drug has any toxic effect on normal tissues and/or impact on mammary carcinogenesis. Expression of FACT was elevated in the process of transformation in all models tested. Chronic administration of Curaxin-137 to MMTV-neu mice at doses not having any toxic effect, inhibited tumor onset, delayed tumor progression, and prolonged survival of mice in a dose-dependent manner. Curaxin-137 induced much stronger changes in FACT in tumors than in normal organs, expressing FACT (spleen). Thus, Curaxin-137 may be considered as a potential preventive and/or early stage therapeutic 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 3843. doi:1538-7445.AM2012-3843
Abstract 3846: Vitamin D3 potentiates the antitumor effects of arsenic trioxide in human leukemia (HL-60) cells
Authors: Rogers Christian , Yedjou Clement , Tchounwou Paul 
Published: August 2012

Abstract
Arsenic trioxide (ATO) is an innovative form of therapy that has recently been found to benefit acute promyelocytic leukemia (APL) patients. Our laboratory has demonstrated that ATO stimulates oxidative stress therefore causing ATO-induced cytotoxicity in human leukemia (HL-60) cells. Pro-oxidants have been known to play a role in free radical-mediated oxidative stress. Vitamin D3, an active metabolite of vitamin D, inhibits the growth of a number of cancer types such as prostate, breast, colorectal, leukemia, and skin cancers. The specific aim of this research was to determine whether co-exposure to vitamin D3 increases the efficacy of ATO through cytotoxicity, oxidative stress and apoptosis associated with increased ATO toxicity in human leukemia (HL-60) cells. In our current investigation, we performed the MTT assay and trypan blue exclusion test to measure cell viability. We also performed the lipid peroxidation assay to determine the levels of malondialdehyde (MDA) production in HL-60 cells co-exposed to ATO and vitamin D3 in combination. The results of trypan blue exclusion and MTT assay indicated that vitamin D3 exposure potentiates the toxic activity of ATO in HL-60 cells in a dose dependent manner. Co-administration of vitamin D3 and ATO resulted in a significant (P&lt;0.05) increase in MDA level compared to ATO alone. A statistically significant and dose-dependent increase (p &lt;0.05) was recorded in annexin V positive cells (apoptotic cells) with increasing doses of vitamin D3 in ATO-treated cells. This finding was confirmed by the result of DNA laddering assay showing clear evidence of DNA fragmentation in ATO and vitamin D3 treated HL-60 cells. Overall, the present study indicates that vitamin D3 potentiates the antitumor effects of ATO at least part, via cytotoxicity, oxidative stress, nucleosomal fragmentation and phosphatidylserine externalization.
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 3846. doi:1538-7445.AM2012-3846
Abstract 3852: Improved coiled-coil design enhances interaction with Bcr-Abl and induces apoptosis
Authors: Miller Geoffrey D. 
Published: August 2012

Abstract
The fusion protein Bcr-Abl responsible for the oncogenic activity in chronic myelogenous leukemia (CML) depends heavily on oligomerization for function. Formation of Bcr-Abl oligomers occurs through a coiled-coil domain existing at the N-terminal portion of the Bcr segment. Previously, we have shown that disruption of this oligomerization utilizing a modified coiled-coil domain (CCmut2) both decreases the proliferation of CML cells and results in the induction of apoptosis. An important contributing factor to these results stems from the increased destabilization of CCmut2 homo-dimers. This phenomenon occurs due to the rationally mutated residues in the modified coiled-coil which allow for favorable interactions with the wild-type Bcr-Abl, but destabilizing interactions with other CCmut2 molecules, thus discouraging the formation of CCmut2 homo-dimers. In turn, this increases the availability and affinity for the modified coiled-coil to interact with and inhibit endogenous Bcr-Abl in CML cells. An additional mutation (K39E) was included that could potentially further destabilize the mutant homo-dimer. Added to the other mutations found in CCmut2 (C38A, S41R, L45N, E48R, Q60E), the new construct was termed CCmut3. To show that CCmut3 results in enhanced binding to a wild-type coiled-coil domain (representative of endogenous Bcr-Abl), 2 separate assays were performed. Colocalization studies were used to show the degree to which CCmut3 localizes intracellularly with Bcr-Abl. Additionally, a mammalian two-hybrid assay was conducted to show the relative selective dimerization between CCmut3 and the Bcr-Abl coiled-coil. Next, caspase 3/7 assays were performed and showed the ability of CCmut3 to induce apoptosis. The CCmut 3 also showed nuclear segmentation (a measurement of late-stage apoptosis) and decrease in oncogenic proliferation (via the colony forming assay). Taken together, these results provide strong evidence for using CCmut3 as a therapeutic for CML. Lastly, attempts to truncate the CCmut3 to find the smallest possible sequence needed (e.g., helix 2) to bind and kill cells effectively is currently underway.
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 3852. doi:1538-7445.AM2012-3852
Abstract 3854: Gamma-linolenic Acid (GLA) sensitizes pancreatic cancer cells to gemcitabine
Authors: Lupu Ruth , Busby Robert , Cheol Park-Hong , Espinoza Ingrid 
Published: August 2012

Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and continues to be a disease with few options for treatment. Current therapeutic regimens for pancreatic cancer often include the nucleoside analog gemcitabine (GEM), but while it has been in use for many years, the overall five year survival rate continues to be about 5%. New therapies are urgently needed to treat this disease. The nutritional supplement gamma-linolenic acid (GLA) is a poly-unsaturated fatty acid (PUFA) of the n-6 PUFA family, and has garnered attention for its cytotoxic effects against tumor cell lines while not affecting normal cells. In this study we look at the effect GLA has on Panc-1 cells and its ability to increase the sensitivity of these cells to treatment with GEM. Through the use of cell viability assays, immunofluorescence, 3-D growth assays, and western blotting, our results show that GLA alone will inhibit growth and induce apoptosis in Panc-1 cells. When GLA is combined with GEM, the results are synergistically enhanced. In addition, our results show that GLA may act through disruption of lipid rafts in the cellular membrane and may activate the extrinsic apoptotic pathway causing cell death. These results suggest that the nutritional supplement GLA could be used in combination with GEM to increase the therapeutic effectiveness of GEM while treating pancreatic 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 3854. doi:1538-7445.AM2012-3854
Abstract 3859: Multivalency of non-peptide integrin αVβ
3 antagonist slows tumor growth
Authors: Kim Yoo-Shin , Li Feng , O'neill Brian E. , Li King CP , Li Zheng 
Published: August 2012

Abstract
To date, more than 200 angiogenesis inhibitors have been reported. These include only a few antiangiogenic peptide drugs. In addition, many molecules upregulated on angiogenic endothelial cells have been explored in the past decades. One of these is integrin αvβ3, which recognizes RGD (Arg-Gly-Asp) motifs in extracellular protein components. Targeting the αvβ3 integrin with drugs may provide an opportunity to destroy tumor vessels without harmful effects on microvessels of normal tissues. Multivalency is a strategy for increasing the binding affinity of compounds ostensibly to increase their potency or imaging potential. Surprisingly, multivalent versions of successful drugs showing enhanced binding have not always demonstrated enhanced therapeutic efficacy. For example, multivalent RGDs have not generally shown better therapeutic efficacy. In our study, we prepared a multivalent nonpeptide integrin αvβ3 antagonist (multivalent IA, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-halanine monomer, dimer and trimer) for anti-tumor therapy. The anti-tumor efficacies of the IA multivalent compounds were evaluated in B16F10 melanoma tumor-bearing mice. Tumors were inoculated subcutaneously and allowed to progress before treating. IA compounds were given by intraperitoneal injection every 12 hours for 14 days. It was observed that 30 mg/kg of IA-trimer showed higher antitumor efficacy and lower toxicity compared to IA-Monomer and IA-Dimer, as shown by changes in tumor volume against control group (IA-Trimer, 32.05 % &gt; IA-Dimer, 45.33 % &gt; IA-Monomer 59.29 %). Based on these results, we conclude that the success of a multivalent strategy depends on the details of the individual components and how they are put together. This may be the first αvβ3 multivalent ligand showing clear enhancement in anti-tumor effectiveness.
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 3859. doi:1538-7445.AM2012-3859
Abstract 386: Differential roles of uPAR in peritoneal ovarian carcinomatosis: the inflammatory link
Authors: Said Neveen A. , Al-Hassan Nada , Ivanova Vessela S. , Syed Viqar , Motamed Kouros 
Published: August 2012

Abstract
Epithelial Ovarian cancer is the 4th leading cause of death from gynecologic malignancies in the United States. More than 75% of patients are diagnosed at late stages, with the solid tumor masses growing either as peritoneal implants, or floating within the ascitic fluid, a condition known as “peritoneal ovarian carcinomatosis (POC)”. Despite aggressive surgical treatment “debulking” recurrence, with acquired chemo- and radio-resistance are frequent with poor 5-year survival rate. Efforts to improve survival rates are hindered by suboptimal compliance with strategies that can detect, and effectively treat ovarian cancer in its early stages. A number of factors have been implicated as mediators POC, including integrins, growth factors, and proteases. The urokinase plasminogen activator receptor (uPAR) which is multifunctional receptor involved in a myriad of tumor cell processes, including invasion, ECM remodeling, adhesion, migration, angiogenesis, and metastasis. However the role of uPAR in modulating the inflammatory ovarian cancer microenvironment is still elusive. To define the potential pro-inflammatory role of uPAR in ovarian cancer, first, we characterized its expression in human ovarian cancer tissue microarray and found the expression of tumor as well as stromal uPAR is significantly upregulated as a function of tumor grade and stage. Second, using a syngeneic murine model of POC injecting ID8 cells intraperitoneally in uPAR knockout mice, we found that genetic ablation of uPAR restrained tumor take, peritoneal implants and prolonged the survival of uPAR knockout mice compared to their wild type counterparts. Ascitic fluid accumulation was significantly decreased in uPAR knockout mice with significantly lower levels of soluble pro-inflammatory cytokines/chemokines and bioactive lipids (8-isoprostane and PGE2) compared to the wildtypes. In addition, absence of uPAR was associated with decreased tumor infiltrating and associated macrophages. Third, in vitro mechanistic studies revealed that both OvCa cell- and macrophage-uPAR contributed to OvCa cell invasiveness and secretion of inflammatory mediators. In summary, our studies indicated that uPAR plays a significant role in ovarian cancer cell-macrophage crosstalk and contributes to the inflammatory ovarian cancer microenvironment. This provides a rationale for targeting the uPAR with either specific neutralizing antibodies or targeting its downstream inflammatory effectors in patients with ovarian 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 386. doi:1538-7445.AM2012-386