bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3799: Polyamine Transport System (PTS) activity and hijacking in cancer cells: New option in Head and Neck tumors treatment with the polyamine-containing drug candidate F14512
Authors: Meignan Samuel , Mouawad Francois , Dewitte Amelie , Bertheau Charlotte , Wattez Nicole , Gros Abigaelle , Lartigau Eric , Chevalier Dominique , Bailly Christian , Lansiaux Amelie 
Published: August 2012

Abstract
The Polyamine Transport System, although not clearly identified at the molecular level in eukaryotic organisms, was found over activated in many types of cancer cells, such as leukemia, prostate, melanoma and NSCLC. Polyamines are implicated in many biological functions, and the need for polyamines in tumor cells, conveyed by the PTS, is crucial. New therapeutic strategies consist to use this transport system to deliver a cytotoxic agent specifically into cancer cells. Head and neck cancer remains the 6th common cancer with a very poor survival rate indicating the crucial need for new targeted strategies. For this study, we used 4 Head and Neck (H & N) cancer cell lines representative of various localizations: CAL 33 and CAL 27 from base of the tongue, Fadu from the pharynx and SQ20B from the larynx. Here, using a polyamine-coupled fluorescent probe, we show that the PTS is active in all head and neck cancer cell lines regardless the tumor localization. In these models, flow cytometry demonstrated that the PTS incorporates quickly, massively and specifically the probe into cancer cells. Confocal microscopy observations revealed that the spermine probe accumulates into the cell nuclei, the site of action of F14512 which is a potent topoisomerase II inhibitor. Considering this property, we evaluated the potential of the F14512 (Pierre Fabre laboratories, France) in these H & N cancer cell lines. F14512 contains a PTS-recognized spermine side chain attached to an epipodophyllotoxin moiety targeting topoisomerase II. We found that F14512 presents a much higher cytotoxicity than etoposide in the 4 cell lines. Competition assays showed that this effect is dependent of the PTS activity and confirmed the targeted action of F14512 against cells with active PTS. The high efficiency of F14512 in the head and neck cancer cell lines is reported here for the first time and may be of interest for the future development of this novel drug candidate, currently in phase 1 clinical trial in leukemia. Studies are in progress, using fresh tumor biopsies from patients with head and neck cancer, to analyze the PTS status of the tumors using the specific spermine-containing fluorescent probe and to evaluate the activity of F14512.
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 3799. doi:1538-7445.AM2012-3799
Abstract 380: Optimization of novel therapeutic paradigms for ovarian cancer using molecular imaging
Authors: Wang Hanxiao , Galban Stefanie , Wu Rong , Bowman Brittany , Fletcha Athena , Witte Amanda , Chughtai Komal , Ross Brian , Cho Kathleen , Rehemtulla Alnawaz 
Published: August 2012

Abstract
Ovarian cancer is the fifth leading cause of cancer death among American woman. Platinum-based chemotherapy, such as cisplatin, represents the standard of care for ovarian cancer. However, toxicicity and acquired resistance to cisplatin have been proven challenging in the treatment of cancer patients. Here, we evaluate the efficacy of targeted inhibition of Akt in combination with cisplatin in an ovarian endometrioid adenocarcinoma (OEA) mouse model wherein Wnt and PI3K signaling pathways are disrupted thus recapitulating the human disease. In cell culture and mouse xenograft models, inhibition of Akt activity in combination with cisplatin is more potent at inducing apoptosis compared to either agent alone. To further explore this finding in living animals, we incorporate a bioluminescence apoptosis reporter into the existing OEA mouse model, to enable monitoring of apoptosis dynamically and non-invasively in real time. Our results demonstrate that Akt inhibitors augment the efficacy of cisplatin by inducing apoptosis more efficiently in our newly developed transgenic OEA model. Magnetic resonance (MR) imaging was also accomplished to determine tumor burden and normalize changes in bioluminescence. Our results show that inhibition of Akt sensitizes OEA to apoptosis in response to cisplatin thus resulting in reducing tumor burden.
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 380. doi:1538-7445.AM2012-380
Abstract 3808: Tetrandrine blocks cell cycle progression and promotes growth arrest in prostate cancer cells by up-regulating CDK inhibitors (p21 and p27) and suppressing cyclin expression.
Authors: Koul Sweaty , Meacham Randall B. , Koul Hari K. 
Published: August 2012

Abstract
Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths in men. De-regulated cell cycle progression is one of the hallmarks of cancer cells. While many agents are available to inhibit growth and proliferation of normal cells, we do not have efficient agents that inhibit growth and proliferation of tumor cells, and no agents are able to achieve growth arrest and inhibition of cell cycle progression in castrate resistant prostate cancer. In this study we evaluated effects of Tetrandrine (Tet: a bis-benzylisoquinoline alkaloid isolated from the root of Stephania tetrandra) that has been shown to have diverse biological properties, on cell growth, proliferation and cell cycle progression in prostate cancer cells. Methods: Prostate cancer cells, LNCaP cells (androgen dependent), LNCaP C-4 and C4-B (castrate resistant lineages derived from LNCaP cells) cells were obtained from ATTCC. Cells were maintained in select media and grown in 5% CO2 in a humidified incubator maintained at 37C. Where indicated Tet (1-20 uM) was added to the growth media for various time points as indicated. Cell growth and proliferation was monitored by MTT assay and cell cycle distribution was measured by FACS assay following labeling of the cells with Propedium Iodide. Western Blotting was used to monitor changes in the levels of various cell cycle related proteins. Results: Tet treatment inhibited cell growth and proliferation in all three cell lines tested. The effects of Tet on cell growth and proliferation were dose dependent with complete growth inhibition at 20 uM. Tet treatment resulted in a significant increase in cyclin dependent kinase inhibitory (CDKi) protein p21 (WAF1, Cip1) and p27 (Kip1) and with p21 increase being most prominent. Moreover, p21 was associated with Cyclin D kinases as monitored by IP assays. Gene expression analysis revealed that Tet decreased mRNA levels of cyclins. FACS analysis revealed that Tet treatment resulted in cell cycle arrest in G1/G0 phase of cell cycle. Finally TET inhibited growth of LNCaP-derived tumors in nude mice. These in vivo effects of TET were also associated with a dramatic increase in p21. Conclusions: Tet inhibits growth and proliferation of prostate cancer cells by effectively blocking cell cycle progression, in part by mediating increase in p21 (WAF1, Cip1) and p27 (Kip1) proteins and suppressing cyclin expression.
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 3808. doi:1538-7445.AM2012-3808
Abstract 381: Non-invasive histology for early detection of cutaneous melanoma and pigmented lesions in vivo
Authors: Degan Simone , Wilson Jesse W. , Mitropoulos Tanya E. , Zhang Jennifer Y. , Selim Maria A. , Warren Warren S. 
Published: August 2012

Abstract
Rationale The diagnosis of melanoma is based on clinical identification followed by histopathologic confirmation. Surgical excision remains the mainstay for a suspicious lesion that will be evaluated for the morphological and cytological signatures of melanomas. However, in some patients such as those with atypical mole syndrome, multiple biopsies of each lesion can be burdensome. We have previously reported that imaging the distribution of eumelanin and pheomelanin can be used to detect melanomas from benign lesions (Matthews TE et al. Sci Transl Med Feb 23;3(71)). In this pre-clinical study we extend our investigation in vivo using nonlinear pump-probe microscopy. We assess cellular morphology and detect the expression of eumelanin and pheomelanin, the two forms of melanin found in skin as markers of melanoma progression. Methods Two melanoma cells lines (A2058; SK-MEL-28) were incubated in human skin dermis. Grafts were xenotransplanted onto SCID mice (n=13, A2058; n=6, SK-MEL-28; n=2 control) and imaged every 8-10-days for cancer progression and morphological changes. Pump-probe microscopy was performed concurrently with two other established laser scanning microscopy methods, multiphoton autofluorescence (MPAF) and reflectance confocal scanning laser microscopy (RCSLM). After 4-8 weeks the subjects were euthanized and the tumor excised for histological examination. Hematoxylin and eosin staining was performed to confirm the presence of the tumor and to correlate with the morphological findings after laser image acquisition. Results The in vivo pump-probe images of the cancer subjects showed an irregular distribution of the pigment, lacking the organized structure typical of skin. Pump-probe images of both melanoma cell lines indicated pigmentation that was either primarily eumelanin or a mixture of eumelanin and pheomelanin with marked spatial heterogeneity. Pigmentation was observed in the two control mice but localized on the basal cells with a well-organized cellular architecture. At the end of the cancer subjects’ life the histological examination showed atypical melanocytes mainly present as single cells in the dermal area. Hyperplasia was also present in the dermal compartment and in the dermal-epidermal junction of the skin. Conclusions The present work may open new avenues for the non-invasive detection of cellular and pigment lesions to prevent melanoma development and invasiveness. Such method can play a role in the diagnosis of melanoma in those patients with multiple lesions or in the areas of the body where the lesion is very exposed such as the face or neck and in ocular region.
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 381. doi:1538-7445.AM2012-381
Abstract 3810: Ciclopirox olamine downregulates Cdc25A expression in tumor cells
Authors: Shen Tao , Zhou Hongyu , Huang Shile 
Published: August 2012

Abstract
Ciclopirox olamine (CPX), a synthetic fungicide clinically used to treat mycoses of the skin and nails, has been demonstrated as a novel anticancer agent. Recently we have identified that CPX inhibits tumor growth by inhibiting proliferation and inducing apoptosis of tumor cells. This study was set to investigate the underlying mechanisms. We found that CPX slowed down cell cycle progression and accumulated cells at G1 phase in a concentration-dependent manner in human rhabdomyosarcoma (Rh30) and breast carcinoma (MDA-MB-231) cells. Concurrently, CPX downregulated Cdc25A protein, a key cell cycle regulator that is frequently overexpressed in tumor cells. Further studies revealed that CPX did not alter the mRNA and protein synthesis level, but promoted the protein degradation of Cdc25A. In addition, we found that CPX caused DNA damage, activated ATR/ATM-Chk1 cascade, elevated phosphorylation of Cdc25A (S76) and inhibitory phosphorylation on both CDK2 (T14/Y15) and CDK6 (Y24), and reduced phosphorylation of retinoblastoma protein (Rb). Furthermore, CPX activated JNK pathway, which links to apoptosis, and is negatively regulated by Cdc25A. Moreover, CPX disrupted the interaction between ASK1 and Cdc25A. These results suggest that CPX may inhibit cell proliferation and induce cell apoptosis by targeting Cdc25A.
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 3810. doi:1538-7445.AM2012-3810
Abstract 3811: The receptors-independent anti-cancer effect of anandamide in head and neck squamous cell carcinoma cells
Authors: Park Seok-Woo , Sung Myung-Whun 
Published: August 2012

Abstract
It has been suggested that endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), might be the promising anti-cancer agents in clinical fields of cancer treatment. In this study, we tried to check the anti-cancer effects of AEA and 2-AG in head and neck squamous cell carcinoma (HNSCC) cell lines. AEA inhibited effectively cell proliferation of three HNSCC cells (SNU-1041, 1066 and 1076) but 2-AG did not. Cannabinoid receptor-1 (CB1) was expressed only in SNU-1066 and expression of VR1 was observed in all tested cells (no CB2 was detected). Anti-cancer effect of AEA seemed to be mediated by their receptors-independent action since the antagonist of CB1 and VR1 (AM251, cay10448 and capsazepine) did not reverse AEA-inhibited cell proliferation. From references on cancer-cell killing effect of COX-2 metabolites of AEA in some types of cancer such as colon cancer, we checked the possibility of COX-2-mediated anti-cancer effect of AEA in HNSCC cells but COX-2 inhibition (by its inhibitors and siRNA) had no effect on it. Instead, we observed the increase of reactive oxygen species (ROS) and 8-isoprostane production by AEA and antioxidants (NAC and ebselen) reversed AEA-inhibited cell proliferation partially. In addition, AM404 and cay10412 (inhibitors of AEA transporter) reversed perfectly AEA-inhibited cell proliferation. These findings suggest that AEA might have anti-cancer effect by their receptors-independent action in intracellular localization of HNSCC cells (such as increase of ROS). The investigation on detailed mechanism of anti-cancer action of AEA in HNSCC cells is ongoing.
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 3811. doi:1538-7445.AM2012-3811
Abstract 3816: Comparative cellular effects of 4-phenyl-3-butenoic acid and suberoylanilide acid in tumorigenic and non-tumorigenic cells
Authors: Burns Timothy , Matesic Diane 
Published: August 2012

Abstract
4-phenyl-3-butenoic acid (PBA) is a small molecule anti-inflammatory agent which was previously shown to inhibit growth, increase gap junction intercellular communication, increase phosphorylation of p38 mitogen activated protein kinase (p38 MAPK), and decrease phosphorylation of c-Jun N-terminal Kinase (JNK) in tumorigenic cells at concentrations that do not similarly affect non-tumorigenic cells. Suberoylanilide acid (SAHA), which is also known as vorinostat, is a relatively new anticancer agent structurally similar to PBA. The purpose of this study was to compare the effects of these two agents on JNK and p38 activation in vitro, as well as on cell growth. p38 MAPK and JNK are stress-activated members of the MAPK family that play important roles in the control of cell proliferation in a wide variety of cell types. Altered expression or activation of these MAPKs has been observed in numerous tumorigenic cells and human cancers. Our studies utilized human lung carcinoma cells (H2009), transformed rat liver epithelial cells (WB-ras) as well as non-tumorigenic cells from the same line (WB-neo). Cells were grown to 60-70% confluence and were subjected to treatment with PBA (0.1 mg/ml), SAHA (500 nM) or vehicle for 48 hours. Whole cell lysates were extracted and individual proteins were separated by SDS-PAGE, followed by western blotting using phosphorylation site-specific antibodies to p38 and JNK proteins. For cell counting, cells were trypsinized and suspended followed by counting utilizing a Biorad TC-10TM cell counter. PBA and SAHA were shown to have similar effects on JNK and p38 MAPK phosphorylation in tumorigenic WB-ras and H2009 cell lines. These effects included an increase in p38 MAPK phosphorylation and a decrease in JNK phosphorylation. Both compounds were shown to significantly decrease cell growth under these conditions. In untransformed WB-neo cells significant differences in p38 MAPK phosphorylation were not seen with either treatment. However it was shown that a decrease in phosphorylation of JNK occurred following SAHA treatment, but not PBA treatment in the WB-neo cells. Overall these studies demonstrate that PBA has similar effects on JNK and p38 MAPK compared to SAHA in tumorigenic cells, while being less potent in the non-tumorigenic WB-neo cells. This earmarks PBA for further studies as a targeted anti-tumor therapy.
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 3816. doi:1538-7445.AM2012-3816
Abstract 384: CD14+S100A9 high monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer
Authors: Feng Po-Hao , Lee Kang-Yun , Chang Ya-Ling , Kuo Han-Pin 
Published: August 2012

Abstract
Introduction: Myeloid-derived suppressor cells (MDSCs) are heterogeneous family of myeloid cells suppressing T cell immunity in tumor bearing hosts. We recently described an increased population of granulocyte-like CD11b+/CD14-/CD15+ MDSC in non-small cell lung cancer (NSCLC) patients. The role of CD11b+/CD14+ MDSC, being characterized as an inflammatory-type monocyte in mice, has not been well studied in human cancer. Methods: CD11b+/CD14- and CD11b+/CD14+ cells, determined and phenotyped by FACS analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naïve advanced NSCLC patients were correlated to clinical data. T cells activation in response to CD3/CD28 co-stimulation was determined by CFSE staining and ELISA analysis of IFN-γ. Cytokines and growth factors in the cultured supernatants were analyzed by ELISA. Results: NSCLC patients had significant higher ratio of CD11b+/CD14+ and CD11b+/CD14- cells than normal subjects. CD11b+/CD14+, but not CD11b+/CD11b- cells, correlated with poor performance and poor response to chemotherapy. Suppression of CD8+ and CD4+ T cells in NSCLC PBMCs was reversed by depleting either CD11b+ cells or CD14+ cells, an effect not seen in normal PBMCs. Both isolated CD11b+/CD14- and CD11b+/CD14+ cells suppressed CD8+ T cells proliferation and IFN-γ production in CD11b-depleted PBMC with equal ability. Enrichment of HLA-DR-/low cells decreased the suppressive ability of the CD14+ cells. CD11b+/CD14+ cells were monocyte-like expressing CD33+, CD15-/low, IL-4Rα+ and S100A9high and produced iNOS/arginase. The ratio of S100A9high cells positively correlated with the suppressive ability of the CD14+ cells and was associated with poor response to chemotherapy. CD11b+/CD14+ cell suppression of T cell proliferation was revered by the iNOS inhibitor aminoguanidine hydrochloride, the arginase inhibitor nor-NOHA, the STAT3 inhibitor AG490 and the blocking antibodies for IL-13, IL-4Rα+ and IL-10. CD11b+/CD14+ MDSCs secreted significant higher amounts of TNF-α, IL-8, IL-10, IL-13 and HGF than normal CD11b+/CD14+ cells. Conclusion: The CD11b+/CD14+ inflammatory monocyte in NSCLC patients is a distinct subset of MDSC with important clinical relevance, probably through secreting inflammatory cytokines and growth factors. These cells expressed IL-4Rα and high levels of S100A9. Among CD11b+/CD14+ monocytic MDSC, the expression of S100A9 protein seemd to be related to the immunosuppression activity and clinical response to chemotherapy. The role of S100A9 protein deserves further investigation.
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 384. doi:1538-7445.AM2012-384
Abstract 3978: Mechanism of orlistat hydrolysis by fatty acid synthase thioesterase
Authors: Fako Valerie E. , Liu Jingyuan , Zhang Jian-Ting 
Published: August 2012

Abstract
Fatty acid synthase (FASN), a seven domain enzyme, is the sole protein capable of de novo synthesis of free fatty acids, most commonly 16-carbon palmitate. The fatty acid synthesis cycle begins with the condensation of acetyl-CoA and malonyl-CoA, and continues with the elongation of the fatty acid chain, which is tethered to an acyl carrier protein domain (ACP), via a repeating cycle. At the end of elongation, the thioesterase (TE) domain of FASN, a member of the serine hydrolase family with an Asp-His-Ser catalytic triad, cleaves the bond between palmitate and ACP, and releases free palmitate. FASN has been found to be over-expressed in a wide variety of human cancers, and this over-expression is correlated to a higher metastatic potential and poorer prognosis in cancer patients. FASN over-expression is also associated with increased resistance toward cancer chemotherapeutics. Orlistat, an FDA approved drug for obesity treatment that prevents uptake of dietary fats by inhibiting pancreatic lipases in the gastrointestinal tract, is a compound found to act as a reversible inhibitor of FASN TE. A previous study using the co-crystal structure of the TE domain with orlistat found that orlistat was covalently bound to the active site Ser within the TE domain, indicating that inhibition of FASN by orlistat halts the fatty acid synthesis cycle by blocking the release of free palmitate from the ACP. A hydrolyzed form of orlistat was also observed in the active site of TE, demonstrating that orlistat is not a stable inhibitor of FASN. In this study, we examined the mechanism of orlistat hydrolysis within the TE domain of FASN using molecular dynamics simulations. We found that the hexanoyl tail of orlistat is capable of shifting while covalently bound to the active site Ser, and that this shift is accompanied by the destabilization of a hydrogen bond that exists between a hydroxyl moiety of orlistat and the active site His. Once this hydrogen bond is destabilized, a catalytic water molecule can enter the active site of TE with the proper orientation for catalysis of the covalent bond between orlistat and Ser. These findings suggest that the hexanoyl tail of orlistat plays an important role in its hydrolysis and may guide the future design of new inhibitors that target the TE domain of FASN with greater endurance for potential use in the treatment of 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 3978. doi:1538-7445.AM2012-3978