bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1760: Development of bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B
Authors: Hochdörffer Katrin , Schäfer-Obodozie Cynthia , Schächtele Christoph , Kratz Felix 
Published: August 2012

Abstract
Bone metastases occur in up to 80 % of patients with advanced breast or prostate cancer and significantly affect the quality of life. Most frequently, bone metastases cause bone fractures, severe pain and hypercalcaemia. Current options for treating of bone metastases are surgery, radiotherapy, chemotherapy, hormone therapy, and the administration of bisphosphonates. These treatments are primarily palliative and can improve the quality of life in some cases, however without increasing the survival time of the patients. Bisphosphonates are presently the most active inhibitors of bone degradation, and they can reduce bone pain, bone destruction and tumor growth. Their therapeutic effects are due to the high affinity between bisphosphonates and the apatite structure of bone and bone metastases. In order to improve the outcome of treating bone metastases, new therapeutic approaches are urgently required. As bone-seeking agents, bisphosphonates show an uptake in the bone of 20-60% of the applied dose, and in general the uptake in bone metastases is 10-20-fold higher than in healthy bone tissue. In addition, bone metastases are characterized by an acidic pH and the over-expression of several proteases including cathepsins, matrix metalloproteases, plasmin and uPA. Surprisingly, no prodrug approaches have been reported to date that exploit the bone targeting effect of low-molecular weight bisphosphonates with a concomitant release of a bound drug in bone metastases. To this purpose, we developed water-soluble bisphosphonate prodrugs of doxorubicin for targeting bone metastases by conjugating a thiol-bearing aliphatic bisphosphonate with the 6-maleimidocaproyl hydrazone derivative of doxorubicin (1) that is cleaved pH dependently, or by attaching a maleimide derivative of the dipeptide Val-Ala-PABC (PABC = p-benzyloxycarbonyl) to the aliphatic bisphosphonate (2). Incubation studies with cathepsin B and 2 at 37 °C showed a cleavage of doxorubicin after two hours with a half time of ∼ 45 min and 1 released doxorubicin quantitatively at pH 5.0 after 2 h. The plasma stabilities (human and mouse) of both prodrugs were in the range of 3-6 h at 37 °C. Binding studies of 1 and 2 with a major component of bone, i.e. hydroxyapatite, demonstrated binding of 80-90 % of both prodrugs after 4 h at 37 °C. Finally, in an orientating toxicity study in nude mice the maximum tolerated dose (MTD) of 1 was three-fold higher compared to conventional doxorubicin whereas 2 showed essentially the same MTD as doxorubicin.
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 1760. doi:1538-7445.AM2012-1760
Abstract 1762: Highly potent anti-cancer ‘salan’ Titanium(IV) complexes: Structure - function relationship
Authors: Meker Sigalit , Braitbard Ori , Manna Cesar , Weiss Esther , Tshuva Edit , Hochman Jacob 
Published: August 2012

Abstract
Cisplatin is a widely used platinum-based metallo-chemotherapeutic drug that is considered an efficient treatment mainly for testicular and ovarian cancers. However, its narrow activity range and severe side effects trigger studies of other potent transition metal complexes. Two titanium(IV) anti-cancer agents that have been previously studied extensively as cisplatin alternatives are titanocene dichloride and budotitane. Despite their high activity, these complexes failed clinical trials mainly due to their poor water stability and formation of unidentified aggregates in water solutions. Our research group focuses on development of new, better-suited families of anti-tumor Ti(IV) complexes lacking Cp or diketonato ligands, and their investigation as anti-tumor agents. We recently reported the synthesis, characterization, and cytotoxicity of “salan” type Ti(IV) complexes [1]. The well defined hydrolytic behaviour, high stability, and high cytotoxicity of these compounds are strongly correlated to their particular structure. This enables fine tuning of complex properties by structural modifications. Herein we elaborate on the investigation of these salan titanium(IV) compounds. The correlation between the complex properties: structure, hydrolytic stability and cytotoxicity will be discussed, revealing insights on the biological mechanism of their cytotoxicity, suggesting an apoptotic cell death pathway.Additionally, further biological evaluation is presented, evincing that these compounds are markedly more active than cisplatin towards human and murine cancer-derived cell lines, including colon, ovarian, lung, cervix, pancreas, leukaemia, skin and breast, with activity also against cisplatin-resistant and multi-drug-resistant cells, and with minor effect on primary murine cells. In vivo experiments are now under way to determine both safety, as well as the anti-cancer activity of these complexes. [1] D. Peri, S. Meker, C. M. Manna, E. Y. Tshuva, Inorg. Chem., 2011, 50, 1030.
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 1762. doi:1538-7445.AM2012-1762
Abstract 177: MiR-10b promotes migration and invasion in pancreatic cancer cells
Authors: Ouyang Haoxu , Korc Murray 
Published: August 2012

Abstract
Pancreatic ductal carcinoma (PDAC) is the fourth leading cause of cancer-related death in Unites States. Due to its aggressive local invasion and metastatic nature, the median survival for patients with PDAC is only 6-month. There is therefore an urgent need to improve our understanding of the pathobiology of this malignancy. In this regard, microRNAs (miRs) have emerged as potentially important regulators in PDAC progression by acting on multiple signaling pathways involved in proliferation, apoptosis, invasiveness and metastasis. MiR-10b is an important RNA implicated in the facilitation of cancer cell invasion and metastasis in several cancers. We have previously shown that miR-10b is upregulated in pancreatic cancer cells, and that high levels of miR-10b are associated with decreased time to metastasis following therapy, enhanced resistance to gemcitabine, and decreased overall survival. In the present study, we have sought to characterize the mechanisms of action of miR-10b in PDAC. We found that overexpression of miR-10b promoted migration and invasion of PANC-1 cells in vitro, without enhancing their proliferation. Microarray analysis revealed that TIP30, a tumor and metastasis suppressor, was downregulated by miR-10b overexpression. Validation experiments using luciferase readout assays showed that TIP30 is a direct target of miR-10b. Taken together, these observations suggest that miR-10b plays an important role in PDAC and may be a novel therapeutic target in this deadly malignancy.
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 177. doi:1538-7445.AM2012-177
Abstract 1780: Synthesis and antitumor activity of proximicins A, B and C
Authors: Brucoli Federico , Natoli Antonino , Marimuthu Preethi , Schätzlein Andreas 
Published: August 2012

Abstract
Proximicins A, B and C are a family of three novel aminofuran antibiotics isolated from marine actinomycetes of the genus Verrucosispora. The distinctive features of these compounds are (a) the structural similarity to the DNA-binding agents distamycin (4) and netropsin (5), and (b) the presence in their molecular framework of an unusual α-aminoacid, 4-aminofuran-2-carboxylic acid. Preliminary in vitro biological evaluation of proximicins A - C against selected carcinoma cell lines has shown that all compounds have a significantly higher cytotoxicity than netropsin and distamycin. In addition, proximicins can activate cell-cycle regulatory proteins involved in the transition of cells from G1 to S phase, and proximicin C, in contrast to distamycin, can induce up-regulation of p53 and p21 in gastric adenocarcinoma cells. The total synthesis of the proximicins A, B and C was successfully carried out starting from methyl 4-Boc-aminofuran-2-carboxylate and sufficient quantities of each compound were prepared for extensive in vitro evaluation. The anticancer activity of proximicins was investigated using cellular methods. The compounds induced apoptotic cell death in L1236 (Hodgkin's Lymphoma) and Jurkat 16 (T-cell leukemia) cells as confirmed by flow cytometric DNA fragmentation analysis. Proximicin B exhibited a strong lethal effect in both L1236 and Jurkat 16 cell lines and apoptosis induction was shown to be dose-dependent after 48 h treatment. Proximicin C induced apoptosis only in Jurkat 16 cells, with L1236 showing higher resistance to the drug. In addition, the proximicins cytotoxicity was determined against selected cancer cell lines different from those previously reported. Proximicin C exhibited significantly higher cytotoxicity against U-87 MG (glioblastoma) and MDA-MD-231 (breast carcinoma) cells compared to proximicin B. Further biological experiments are currently underway to elucidate the mechanism of action of these furan-based oligopeptides. In conclusion, given their interesting molecular framework and their significant anticancer activity, proximicins represent an attractive synthetic target and could be potentially developed into anticancer drugs of broad utility.
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 1780. doi:1538-7445.AM2012-1780
Abstract 1783: Trifluorothymidine incorporation into DNA strongly enforces the potential of TAS-102 and leads to remarkably prolonged survival of cancer patients
Authors: Tanaka Nozomu , Oguchi Kei , Fujita Ryoto , Suzuki Takamasa , Yamamura Keisuke , Fujioka Akio , Okabe Hiroyuki , Noguchi Kazuharu 
Published: August 2012

Abstract
TAS-102 is a novel oral antitumor agent, consisting of trifluorothymidine (FTD) as the active component and thymidine phosphorylase inhibitor (TPI) which prevents degradation of FTD. In a double-blind randomized phase II study conducted in Japan, TAS-102 significantly improved overall survival of metastatic colorectal cancer patients, compared with placebo (TAS-102, n = 112; Placebo, n = 57; median OS, 9.0 vs. 6.6 months; HR, 0.56; p = 0.001). We investigated mechanisms of action of TAS-102 to understand how prognosis of cancer patients was improved. In vitro study, FTD was previously reported to have two mechanisms, FTD incorporation into DNA and thymidylate synthase (TS) inhibition. In this study, we show that FTD incorporation into DNA is the main mechanism of TAS-102 and the key to potentiate anti-tumor efficacy of FTD. We found that although TS inhibition of FTD reduced rapidly after drug removal, the cytotoxicity of FTD did not diminish. On the other hand, the cytotoxicity of FdUrd diminished after drug removal. As compared to FdUrd, FTD was incorporated into DNA to a greater extent by the time drug was removed. It is thought that the FTD retained in DNA contributes to sustained growth inhibition. Therefore, FTD incorporation into DNA is considered to be essential for enforcing the potential of FTD. Additionally, we investigated the in vivo potency of TAS-102 by using daily divided oral administration since this regimen was the most optimal to maximize FTD incorporation into DNA. Interestingly, TAS-102 showed marked tumor growth delay even after end of the administration and remarkable prolonged survival of mice implanted with KM20C derived from human colon cancer. Collectively, these data suggest that TAS-102 improved survival of cancer patients primarily due to FTD incorporation into DNA. FTD is previously reported to affect DNA structure, and we speculate that TAS-102 exerts its anti-tumor effects through interfering with DNA function once adequate amounts of FTD have been accumulated in the DNA.
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 1783. doi:1538-7445.AM2012-1783
Abstract 2414: The inhibitory effect of heat treatment against Epithelial-Mesenchymal Transition (EMT) in human colon adenocarcinoma cell line
Authors: Adachi Satoko , Kokura Satoshi , Ishikawa Takeshi , Sakamoto Naoyuki , Okajima Manabu , Matsuyama Tatsuzo , Matsuyama Tatsuzo , Tsuchiya Reiko , Nito Yuji , Yoshikawa Toshikazu 
Published: August 2012

Abstract
Background and Aim: In order to improve the prognosis of patients with advanced cancer, novel interventions for metastatic disease are required. While anti-tumor effects of hyperthermia have been well studied and assessed, its effects on cancer metastasis is unknown. We reported that the production of transforming growth factor-β (TGF-β) by cancer cell lines was reduced by the heat treatment, furthermore the production of the intratumoral TGF-β was also reduced by whole body hyperthermia in mouse subcutaneous tumor model. Recently, the importance of Epithelial-Mesenchymal Transition (EMT) in the progression of many cancers is recognized and many studies have shown that transforming growth factor-β (TGF-β) can induce EMT. Therefore, it is expected that heat treatment could inhibit TGF-β-induced EMT. In this study, we investigated the inhibitory effect of the heat treatment on TGF-β-induced EMT in the human colon adenocarcinoma cells. Methods: To study the effects of heat treatment on EMT, human colon adenocarcinoma cell line, HT29 cell, was used and treated with heat (43 degrees Celsius) for 1 h followed by the stimulation of TGF-β (10ng/ml). HT29 cells were examined for morphological changes using the inverted phases-contrast microscope, and the localization of E-cadherin as the epithelial adhesion factor on the cell was analyzed with fluorescent immunostaining using confocal microscope. The EMT-related factors such as vimentin, fibronectin, ZEB-1, Snail were analyzed by RT-PCR. Furthermore, the activation of nuclear factor kappa B (NF-κB) was analyzed in the nuclear extracts using an ELISA method. Results: After treatment with TGF-β, HT29 cells changed their morphology from a typical epithelium to mesenchymal spindle-shaped, and this morphological change was attenuated by the heat treatment. The expression of E-cadherin, which is the component of epithelial adhesion, was down-regulated by TGF-β, and this effect was attenuated when HT29 cells were treated with heat before the stimulation with TGF-β. The up-regulation of EMT-related factors such as fibronectin and Snail induced by TGF-β was decreased by the heat treatment. Furthermore, TGF-β treatment caused an activation of NF-κB, and heat treatment significantly attenuated TGF-β-indueced NF-κB activation in HT29 cells. Conclusions: Our results suggest that the heat treatment could suppress TGF-β-induced EMT via the inhibition of NF-κB, supporting its potential as a treatment for cancer metastasis.
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 2414. doi:1538-7445.AM2012-2414
Abstract 2415: Phenotypic stabilization of mesenchymal-like cancer cells through mesenchymal-specific DNA hypermethylation
Authors: Kozaki Ken-ichi , Kurasawa Yasuhiro , Muramatsu Tomoki , Ono Hiroaki , Ishihara Takaya , Uzawa Narikazu , Pimkhaokham Atiphan , Imoto Issei , Amagasa Teruo , Inazawa Johji 
Published: August 2012

Abstract
The epithelial-mesenchymal transition (EMT) plays a crucial role in normal and disease processes including tumor progression. In this study, we first classified epithelial-like and mesenchymal-like oral squamous cell carcinoma (OSCC) cell lines based on expression profiles of typical EMT-related genes using a panel of 18 OSCC cell lines. Then, we performed methylation-based and expression-based analyses of components of the Wnt signaling pathway, and identified WNT7A and WNT10A as genes silenced by mesenchymal-specific DNA hypermethylation in OSCCs. A significant association was revealed between some clinicopathologic findings and the DNA methylation status of WNT7A (Normal vs Tumor, P = 0.007; T1-2 vs T3-4, P = 0.040; I-III vs IV, P = 0.016) and WNT10A (N0-N1 vs N2-N3, P = 0.046) in the advanced stages of OSCC. Moreover, we found that E-cadherin expression in cancer cells may be positively regulated by WNT7A, whose expression is negatively regulated by mesenchymal-specific DNA hypermethylation or ZEB1 in mesenchymal-like OSCC cells. Our findings indicate that epithelial-specific gene silencing through mesenchymal-specific DNA hypermethylation may stabilize the phenotypic plasticity of cancer cells during EMT/MET.
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 2415. doi:1538-7445.AM2012-2415
Abstract 242: Anti-obesity drugorlistat enhances sensitivity toTRAIL by two different pathways inhormone-refractory prostate cancer cells
Authors: Fujiwara Jun , Sowa Yoshihiro , Horinaka Mano , Koyama Makoto , Wakada Miki , Miki Tsuneharu , Sakai Toshiyuki 
Published: August 2012

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as one of the expected cancer therapeutics. However, since hormone-refractory prostate cancer (HRPC) cells are sometimes resistant to TRAIL, we need to develop a novel strategy to overcome. We demonstrated that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in HRPC cells. The combination of orlistat and TRAIL remarkably induced apoptosis in DU145 and PC3 cells. Orlistat induced the expression of DR5, which is one of the TRAIL receptors. The suppression of DR5 with siRNA reduced the enhanced apoptosis, suggesting that the enhanced apoptosis was at least partially due to the up-regulation of DR5. Although the up-regulation of DR5 at both mRNA and protein levels by orlistat was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of the CHOP and DR5 expressions in both cell lines. These results suggest that there are two different pathways of up-regulation of DR5 by orlistat, which are ROS-CHOP pathway and ROS-direct pathway. In conclusion, orlistat enhances the sensitivity to TRAIL in the ROS mediated pathways in prostate cancer cells. We believe that the administration of TRAIL and orlistat is considered a promising strategy for cancer therapy in HRPC.
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 242. doi:1538-7445.AM2012-242
Abstract 2424: Conditioned media enhances proliferation and mobility in triple negative breast cancer cells
Authors: Parker-Johnson KiTani A. , Yearby Letitia , Beverly Gabriel , Ochieng Josiah 
Published: August 2012

Abstract
Background. Triple negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and disproportionally affects African American women. This subtype of breast cancer is characterized by the absence of the estrogen, progesterone, and HER2/neu receptors. Our research has provided insight on understanding that the microenvironment, specifically noncancerous cells, play in enhancing cancer progression and metastasis. However, the role of adjacent noncancerous cells in the metastatic phenomenon is poorly understood. Therefore, the aims of this project were: 1) to determine if conditioned media from MCF-10A cells would enhance proliferation of MDA-MB-231 and MDA-MB-468 cells and 2) to evaluate the ability of the effects of migration of the conditioned media on the MDA-MB-231 and MDA-MB-468 cells. Methods. Crystal violet and alamar blue dye exclusion assays were performed to measure proliferation in the different medias. The trans well migration assay was used to evaluate motility enhancement based on the media used, either conditioned media and the Cellometer was used to evaluate whether the MDA-MB-468 and MCF-10A cells shared the same microenvironment. Results. Conditioned media is made from base medium with a concentration of 1.0 g/L glucose with .5% FBS exposed to non-cancerous MCF-10A cells that have been driven into crisis. This conditioned media encouraged robust and continuous proliferation of the tumorigenic MDA-MB-231 and MDA-MB-468 cell lines. HGCM was extracted in our lab using sterile technique and reused to analyze the proliferative effects on cancerous and non-cancerous cells. MDA-MB-231 cells demonstrated significant proliferation when compared to the control. MDA-MB-468 cells demonstrated a similar response. The trans well migration assay demonstrated that the GFP labeled MDA-MB-468 cells had a higher percentage of motility than with MCF-10A cells in standard media. Conclusions: Taken together, these data indicate that factors secreted into the microenvironment from noncancerous cells may contribute to the mobility of TNBC cells and the conditioned media contains unknown factors that promote the cell mobility of the MDA-MB-231 and MDA-MB-468 cells.
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 2424. doi:1538-7445.AM2012-2424