bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2111: Ciclopirox inhibits tumor cell motility by suppressing protein expression of small GTPases and phosphorylation of paxillin
Authors: Huang Shile , Shen Tao 
Published: July 2017

Abstract
Ciclopirox olamine (CPX), an off-patent antifungal drug, is used for the treatment of superficial mycoses. Recent studies have demonstrated that CPX also possesses potent anticancer activity by inhibiting cell proliferation and inducing cell death in tumor cells. However, it is unknown whether CPX inhibits cell motility. In the present study, we found that CPX potently inhibited cell motility in a concentration-dependent manner in rhabdomyosarcoma (Rh30 and RD) cells, which was independent of the reduction of cell viability. As small GTPases (RhoA, Cdc42, and Rac1) and focal adhesion proteins (paxillin) play critical roles in the regulation of cell motility, we further studied whether CPX affects these proteins. Our Western blot analysis revealed that CPX did inhibit cellular protein expression of RhoA, Cdc42 and Rac1. However, by RT-PCR analysis, CPX did not alter the mRNA levels of the small GTPases. As microRNAs (miRNAs) can regulate protein expression at transcriptional and post-transcriptional levels, we investigated the effect of CPX on the expression of miRNAs. Our miRNA PCR array revealed that treatment with 10 μM of CPX for 24 hours upregulated the expression of 27 miRNAs by 2.04-6.10 fold, and downregulated the expression of 7 miRNAs by 2.00-7.89 fold in Rh30 cells. Further research is ongoing to identify whether these up/downregulated miRNAs are linked to the reduced expression of small GTPases and potentially more proteins. In addition, we found that CPX inhibited the phosphorylation of paxillin, despite no effect on the total cellular protein expression. The results suggest that CPX inhibits tumor cell motility at least by suppressing the protein expression of small GTPases and the phosphorylation of paxillin. Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA.
Citation Format: Shile Huang, Tao Shen. Ciclopirox inhibits tumor cell motility by suppressing protein expression of small GTPases and phosphorylation of paxillin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2111. doi:10.1158/1538-7445.AM2017-2111
Abstract 2113: Mechanism of action of pixantrone in non-Hodgkin's lymphoma cells
Authors: Ng Serina , Muñoz Ruben , Hoff Daniel Von , Han Haiyong 
Published: July 2017

Abstract
Background: Pixantrone (PIX), an anthracenedione analog, has shown promising results with reduced cardiotoxicity as compared to structurally similar mitoxantrone and doxorubicin (DOX) in early phase clinical trials in patients with non-Hodgkin’s lymphoma (NHL). The exact mechanisms of action on how PIX induce cell death by targeting DNA replication through intercalating DNA and/or inhibiting Topoisomerase II has not been clearly illustrated.
Methods: A short-term cell proliferation assay (3 days treatment) and a long-term clonogenic assay (cells were treated with the drugs for 24 hours and then allowed to grow into colonies for 10-14 days) were used to assess and compare the effects of PIX and DOX on cell growth in three NHL cell lines, OCI-Ly8, Z138, and Raji. Immunofluorescent assays using γH2AX antibodies, and DAPI staining were used to examine the effect of PIX and DOX on the formation of double-strand breaks and micronuclei.
Results: In the short-term cell proliferation assay, PIX was not as potent as DOX (IC50 values ranging from 22 nM to 2737 nM for PIX and 2.8 nM to 67 nM for DOX). The two drugs were significantly more potent in the long-term clonogenic assay with IC50 values in low nanomolar range (5.1 nM to 82.8 nM) and the difference between PIX and DOX was much smaller. Cells treated with PIX displayed less increases in DNA double-strand breaks compared to those of DOX as quantified by the number of γH2AX positive foci formed in the cells. Furthermore, PIX treatment significantly increased the formation of micronuclei in a drug concentration and time dependent manner.
Conclusions: The findings from the current study indicate that PIX induces DNA damages that impair the chromosomal segregation but do not significantly trigger double-strand breakage checkpoint response. Overall, our results suggest that PIX may exert its antitumor activity via mechanisms that are different from those of DOX.
Citation Format: Serina Ng, Ruben Muñoz, Daniel Von Hoff, Haiyong Han. Mechanism of action of pixantrone in non-Hodgkin's lymphoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2113. doi:10.1158/1538-7445.AM2017-2113
Abstract 2118: The food additive agent potassium bromate prevents growth and aggressive phenotypes by targeting multiple molecular signatures in breast cancer cells
Authors: Ghosh Priyanka , Maity Gargi , Banerjee Snigdha , Banerjee Sushanta 
Published: July 2017

Abstract
Potassium bromate (KBrO3) is by-product of ozone that has found multifunctional purpose in modern society. It is used as disinfectant in drinking water, a bleaching agent to improve flour, a component of cold-wave hair lotion and an ingredient in the production of fish paste and fermented beverages. Potassium bromide has also been used in America for bread-baking as a safe food additive since 1914. Despite the commercial value of this chemical, some studies suggest that KBrO3 could be a carcinogen. During the bread-baking process, Potassium bromate is normally converted into a stable and inert compound, potassium bromide (KBr). However, due to incomplete reduction, the residual KBrO3 remains in the bread, which eventually acts as a potential carcinogen to humans. Interestingly, our studies, in breast cancer cells, found contrasting results. We found that KBrO3 delays growth of ER-α positive luminal type breast cancer cells and triple-negative breast cancer cells (TNBC) via inducing apoptosis in a dose-dependent manner. KBrO3-induced apoptosis is mediated via targeting BCL-2/Bax and Caspase-3 signaling pathway. Moreover, aggressive phenotypes such as migration, invasion and sphere-forming ability of breast cancer cells are significantly impaired by KBrO3-treatment via targeting multiple molecular signatures in breast cancer cells. The growth inhibition effect of KBrO3 is also documented in a tumor xenograft model. Collectively, our findings provide a rationale for the basic and pre-clinical evaluation of the role of KBrO3 in breast cancer progression and therapy.
Citation Format: Priyanka Ghosh, Gargi Maity, Snigdha Banerjee, Sushanta Banerjee. The food additive agent potassium bromate prevents growth and aggressive phenotypes by targeting multiple molecular signatures in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2118. doi:10.1158/1538-7445.AM2017-2118
Abstract 2124: Differentiation of myeloid and multiple myeloma cell lines by inecalcitol involves a marked decrease in CD44 and CD49d cell surface labeling
Authors: Benjamin Susan , Planquette Cecile , Delansorne Remi 
Published: July 2017

Abstract
Inecalcitol is a vitamin D receptor (VDR) agonist characterized by a high antiproliferative activity on various cancer cell lines (Okamoto et al., 2012; Ma et al., 2013) and a low calcemic potential as demonstrated by the high maximal tolerated oral daily dose of 4 mg in human patients (Medioni et al., 2014). On myeloid cells, inhibition of proliferation by vitamin D derivatives is paralleled by induction of differentiation into a monocyte/macrophage phenotype, mostly described as gain of functions (increase in lysozyme activity, phagocytosis and cell motility; Abe et al., 1981) and of the cell surface CD11b and CD14 biomarkers. The stimulation of the secretion of cathelicidin, a natural human antimicrobial peptide, is another specific activity of vitamin D and its derivatives (Wang et al., 2004).
During a screening of 48 CD biomarkers on 4 human myeloid cell lines (HL-60, U-937, MOLM-13 and THP1) and 4 human multiple myeloma cell lines (MM.1R, MM.1S, L-363 and RPMI-8226) treated for 72 hours at 10 nM, we recently discovered that inecalcitol reproducibly induces CD38 expression (Benjamin et al., 2016), another gain of function. We now report the decrease in CD44 and CD49d cell surface labeling in all 8 cell lines (except CD44 in L-363 cells). This loss of functions reached -60% to -70% in MOLM-13 and HL-60 cells. We have then determined the EC50 (mean ± SEM; n = 3 or 4) of inecalcitol for several differentiation parameters on HL-60 cells. The most sensitive gains or loss of functions were the secretion of cathelicidin (0.2 ± 0.1 nM), the induction of CD38 (0.3 ± 0.1 nM) and the decrease in CD44 (0.8 ± 0.4 nM). Inhibition of proliferation (1.9 ± 0.8 nM) was exactly parallel to induction of CD11b (1.8 ± 0.8 nM). Decrease in CD49d (6.6 ± 1.1 nM) and increase in CD14 (8.0 ± 0.5 nM) occurred as final markers of differentiation by inecalcitol.
CD44 is the receptor for hyaluronic acid; it is found on the surface of acute myeloid leukemia stem cells and suspected to favor the spread and relapse of the disease. CD49d is the integrin α4-subunit involved in the interactions of tumor cells with their microenvironment resulting in their “hiding” and survival. Therefore, decreasing both CD44 and CD49d represents newly identified potential beneficial pro-differentiation effects of inecalcitol.
Citation Format: Susan Benjamin, Cecile Planquette, Remi Delansorne. Differentiation of myeloid and multiple myeloma cell lines by inecalcitol involves a marked decrease in CD44 and CD49d cell surface labeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2017-2124
Abstract 2126: CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo
Authors: Tchaparian Eskouhie H. , Lin Louis 
Published: July 2017

Abstract
Aberrant PI3K/Akt/mTOR signaling pathway is common in several human cancers, including CRC. The pathway regulates many major cellular processes and promotes tumorigenesis and inhibition of apoptosis. Targeting the PI3K/Akt/mTOR network could be important in resistance mechanisms in cancer. CA102N, is a conjugate of Hyaluronic Acid (HA) and H-Nim, a nimuselide (COX-2 inhibitor) derivative, currently under investigation for preclinical development in CRC. Studies have suggested that the anti-proliferative effects of COX-2 inhibitors could be attributed to modulation of the PI3K/AKT signaling pathway; therefore, in this study we aimed to examine the overall molecular mechanism of the antitumor activity of CA102N and evaluate its impact on the PI3K pathway proteins. Cell based studies indicated that in addition to cell cycle arrest; the antitumor activity of CA102N is also related to apoptosis. Administration of CA102N to nude mice bearing established HT29 subcutaneous tumor xenografts caused significant tumor growth inhibition with no signs of systemic toxicity. Immunohistochemical analyses of xenograft tumors demonstrated inhibition of VEGF and CD31, suggesting a role for CA102N in angiogenesis. Disruption of angiogenesis and apoptosis was correlated with a decrease in VEGF and the antiapoptotic protein BCL-2. Suppression of PI3K downstream signaling was a key observation in HT29 cells in vitro and in xenograft tumors treated with CA102N. As compared to untreated vehicle control, a significant decrease in phosphorylation of AKT, mTOR, p70S6K, PRAS40, 4EBP1 and FOXO1 was detected by Western blot analyses. The reduction observed may be caused by both specific protein dephosphorylation/deactivation and by ubiquitin-mediated proteasomal degradation of pathway proteins. These results suggest that the antitumor activity of CA102N may be at least partly related to the modulation of the PI3K/Akt pathway proteins. CA102N represents a promising anticancer agent with minimal toxicity, the insights provided into the mechanisms of its anticancer activity may be the basis for advancing this candidate into clinic.
Citation Format: Eskouhie H. Tchaparian, Louis Lin. CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2017-2126
Abstract 2128: PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival
Authors: Jung Jinkyu , Gilbert Mark R. , Park Deric M. 
Published: July 2017

Abstract
BACKGROUND: Platelet-derived growth factor (PDGF) signaling plays a key role in gliomagenesis. Glioblastomas express all PDGF ligands and both cell membrane receptors, PDGFRα and PDGFRβ, that are involved in pro-survival autocrine and paracrine loops. Our previous work demonstrated that expression of PDGFRβ is enriched in hypoxic glioblastoma tumor tissues. Also, induction of mitophagy is a well-known critical coping response to tissue hypoxia. We therefore investigated the role of PDGFRβ signaling cascade in regulating hypoxia-induced mitophagy of glioblastoma.
METHODS: Protein detection was performed by immunoblotting and immunofluorescence to determine changes in levels of target proteins upon RNA interference, treatment with PDGFRβ inhibitor, and ectopic gene transfection. MitoSox assay was used to measure mitochondrial reactive oxygen species (ROS). Tumor growth assays were performed in vitro and in vivo using subcutaneous tumor implantation model.
RESULTS: PDGFRβ signaling was essential for induction of hypoxia-mediated mitophagy in glioblastoma cells. Nix, a hypoxic responsive protein and regulator of mitophagy, was necessary for PDGFRβ-mediated glioblastoma survival. Inhibition of PDGFRβ signaling pathway killed glioblastoma cells by suppressing mitophagy and leading to subsequent elevation of mitochondrial ROS. Furthermore, interference of mitophagic response by blocking PDGFRβ signaling enhanced cell death even in chemotherapy-resistant tumor cells.
CONCLUSION: This work suggests a potential mechanism by which PDGFRβ inhibition could kill glioblastoma cells through suppression of NIX-mediated mitophagy. Manipulation of NIX and PDGFRβ pathway may provide novel therapeutic opportunities in chemoresistant tumor models.
Citation Format: Jinkyu Jung, Mark R. Gilbert, Deric M. Park. PDGFR beta signaling is required for hypoxia induced mitophagy in glioblastoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2128. doi:10.1158/1538-7445.AM2017-2128
Abstract 2130: Antitumor activity of marin natural product derived Psammaplin A analogs in human lung cancer cells
Authors: Byun Woong sub , Shin Yoonho , Lee Sang Kook , Park Hyeung-geun , Hong Suckchang 
Published: July 2017

Abstract
Natural products are important sources for bioactive molecules, which have been developed to treat various human health-related symptoms. In our continuos efforts to search for anticancer agents from natural sources, Psammaplin A (PsA), isolated from marine natural products, was found to be a potential candidate in the growth inhibition of cancer cells. PsA, a unique symmetrical bromotyrosine contained in a number of marine sponges of the order Verongida, has exhibited a variety of bioactivities including antimicrobial activity, cytotoxicity against the leukemia cell line, and inhibitory activity of DNA gyrase and DNA topoisomerase. PsA is also known to be a potent inhibitor of DNA methyltransferase and histone deacetylase with growth-inhibitory activity of cancer cells. However, its underlying mechanism of action and the structure-activity relationship (SAR) with PsA analogs have not been elucidated yet. In the present study, twenty-eight synthetic analogs of PsA were newly synthesized and examined the potential of cytotoxicities against cancer cells. A SAR study revealed that the presence of free oxime and disulfide functional groups was responsible for high cytotoxicity. Furthermore, the bromotyrosine component in PsA was relatively tolerable and hydrophobic aromatic groups preserved the cytotoxicity. The aromatic groups were dependent on their size and spatial geometry. Among them, a β-naphthyl derivative of PsA showed a potential cytotoxicity and was comparable to that of PsA. The compound also exhibited a potential antitumor activity in a nude mouse xenograft model. These findings indicated that free oxime and disulfide linker in the chemical structure play an important role for cytotoxicity and PsA analogs might be provided as potential antitumor agents. This work was supported by the National Reseach Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (NRF-2016M3A9B6903499) and also supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (No.2009-0083533).
Citation Format: Woong sub Byun, Yoonho Shin, Sang Kook Lee, Hyeung-geun Park, Suckchang Hong. Antitumor activity of marin natural product derived Psammaplin A analogs in human lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2130. doi:10.1158/1538-7445.AM2017-2130
Abstract 2148: Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effects
Authors: Zhang Wen , Tam Kin Yip 
Published: July 2017

Abstract
In cancer cells, the metabolic features are significantly different from those of normal ones, which are hallmarks of several malignancies. Recent studies brought atypical cellular metabolism, such as aerobic glycolysis or the Warburg effect, into the scientific limelight. Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme in the pathway of glucose metabolism, could inactivate the pyruvate dehydrogenase (PDH) by phosphorylating it and preserving the substrates pyruvate, lactate and alanine for gluconeogenesis. Overexpression of PDK1 could block the oxidative decarboxylation of pyruvate to satisfy high oxygen demand in cancer cells, while inhibition of PDK1 could upregulate the activity of PDH and rectify the balance between the demand and supply of oxygen, which could lead to cancer cell death. Thus, inhibitors targeting PDK1 might be a promising strategy for cancer treatment by acting on glycolytic tumors while showing minimal side effects on the oxidative healthy organs.
Phenyl butyrate (PB) has been proved to decrease PDH phosphorylation level and increase PDH activity by inhibiting PDK1 in fibroblast cells, PDH deficiency zebrafish and wild type mice. PB has also shown efficacy in many cancers and so far, all of its anti-tumor activity has been attributed to the histone deacetylase (HDAC) inhibitor mode of action. As PDK1/PDH controls the critical switch between oxidative phosphorylation and glycolysis in cancer cells, PDK1 is a key target in tumor metabolism for anti-cancer treatment. We hypothesize that the therapeutic effects of PB in cancers might depend on suppressing PDKs and promoting PDH activity, in addition to its proposed role as HDAC inhibitor. We showed that PB directly inhibited the kinase activity of PDK1 in a purified system. In several different cancer cell lines, PB reduced the phosphorylation level of PDH, increased the mitochondrial respiration, decreased glycolysis in cytoplasm, reversed mitochondrial hyperpolarization, activated some proteins in apoptotic signalling pathway and then induced the apoptosis of cells. In summary, this is the first study indicated that PB could exert its anti-cancer effects through inhibiting PDK1, altering the mitochondrial bioenergetics and inducing apoptosis.
Note: This abstract was not presented at the meeting.
Citation Format: Wen Zhang, Kin Yip Tam. Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2148. doi:10.1158/1538-7445.AM2017-2148
Abstract 2150: Oncogenic role of GAEC1 and its potential modulation with p53 in pathogenesis of colon cancer
Authors: Wahab Riajul , Islam Farhadul , Gopalan Vinod , Lam Alfred King-Yin 
Published: July 2017

Abstract
Introduction: GAEC1 (Gene amplified in esophageal cancer 1), is frequently amplified and overexpressed in colon cancer tissues. In the present study, we aimed to unveil the oncogenic potential of GAEC1 in carcinogenesis of colon cancer by studying the underlying cellular functions and molecular interactions by in vitro and in vivo experiments.
Method: Transient overexpression of GAEC1 with pcDNA3.1-GAEC1 and silencing with GAEC1-siRNA was performed and several downstream assays were done such as migration, clonogenic and apoptotic assay. Analysis of cell kinetics was done using flow cytometry and cell counting kit-8 was used for cell proliferation assay. Immunofluorescence and Western blot assay were used to determine the expression of different target proteins. Co-immunoprecipitation was used to confirm the protein-protein interaction. For xenotransplantation the severely combined immunodeficient (SCID) mice (4 groups, 6 in each group) were injected subcutaneously with GAEC1 shRNA and control shRNA transfected (stable) SW480 and SW48 colon cancer cells.
Result: The overexpression of GAEC1 increased cell proliferation, migration, reduced apoptosis in colon cancer cells. Also, these cells showed cell cycle arrest at the synthetic phase, activation of Bcl-2, K-ras, pAKT proteins as well as inhibition of p53, PUMA, p21 and BAX proteins. Conversely, knockdown of GAEC1 reduced cell proliferation, migration, decreased the phosphorylation of AKT, and induced apoptosis, G2/M phase arrest and cleavage of poly (ADP-ribose) polymerase (PARP). Co-immunoprecipitation revealed GAEC1’s interaction with p53. In addition ectopic over expression and silencing of GAEC1 lead to reciprocal effects of p53 protein expression. Moreover, knockdown of GAEC1 reduced the nuclear translocation of murine double minute 2 protein (mdm2) indicating that GAEC1 is responsible for the degradation of p53 through the direct interaction between mdm2-p53 in nucleus. Furthermore, our in vivo data demonstrate that the loss of GAEC1 inhibits the tumor formation in xenograft model.
Conclusion: Collectively our study demonstrates that GAEC1 exhibits the oncogenic role in colon cancer by reducing expression of p53 through protein-protein interaction which leads to the inhibition of PUMA, p21, BAX, and activation of Bcl-2, K-ras and pAKT protein expression.
Note: This abstract was not presented at the meeting.
Citation Format: Riajul Wahab, Farhadul Islam, Vinod Gopalan, Alfred King-Yin Lam. Oncogenic role of GAEC1 and its potential modulation with p53 in pathogenesis of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2150. doi:10.1158/1538-7445.AM2017-2150