bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3194: Platycodin D induces growth arrest and cell cycle arrest by activating MDM2 and interacting with FOXO3a in prostate cancer
Authors: Xu Hongxia , Zhou Rui , Lu Zongliang , Liu Kai 
Published: May 2015

Abstract
Purpose: The present study was designed to evaluate the anti-tumor activity and possible mechanism of action of Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, in human prostate cancer.
Experimental Design: Human prostate cancer cells with different p53 status (p53 wildtype LNCaP cells, p53 null PC3 cells and p53 mutant DU145 cells), and the normal human prostate cell line, RWPE-1, were exposed to various concentrations of PD to compare its cytotoxicity in vitro (via the MTT assay). Detailed invitro and invivo studies on the anti-tumor effects of PD were then performed.
Results: PD exerted cytotoxicity against all three prostate cancer cell lines, with half-maximal inhibitory concentrations in the range of 11.16 to 26.13μmol/L. The PC3 cells were the most sensitive to PD, whereas RWPE-1 cells were not sensitive to PD.A further study in these cell lines showed that PD could potently affect the cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (by Annexin V-FITC flow cytometry) and cause cell cycle arrest (PI staining). After being treated with PD for 48 hours,the DU145 and LNCaP cells were arrested in the G0 /G1 phase, and the PC3 cells were arrested in the G2/M phase. A Western blot analysis indicated that PD decreased the expression of MDM2 and increased the expression levels of FOXO3a, p21 and p27 in the three cell lines. In PC3 cells, PD exposure decreased the levels of cell cycle-related proteins, including E2F1, cdk2, cdk4, cdk6, cyclin D1 and cdc2. PD exposure increased apoptosis-related proteins, Bax, caspase9 and caspase3, and downregulated Bcl-2, PARP, and caspase8. Real-time PCR indicated that the same changes had occurred at the transcriptional level for all of these targets. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blot analysis of the xenograft tumors indicated that similar changes in protein expression also occurred in vivo.
Conclusion: PD exhibits significant activity against prostate cancer cells in a p53-independent manner. MDM2 and the FOXO3a transcription factor appear to be involved in the mechanism of action of PD, which provides a basis for future development of this agent for human prostate cancer therapy.
Citation Format: Hongxia Xu, Rui Zhou, Zongliang Lu, Kai Liu. Platycodin D induces growth arrest and cell cycle arrest by activating MDM2 and interacting with FOXO3a in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3194. doi:10.1158/1538-7445.AM2014-3194
Abstract 3196: Antitumor effect of a Compound A, a derivative of a naturally occurring rotenoid deguelin, by inhibition of ATP binding to heat shock protein 90
Authors: Lee Su-Chan , Lee Ju-Sung , Hyun Seung-Yeob , Choi Hoon , An Hongchan , Kim Kyu-Won , Suh Young-Ger , Lee Ho-Young 
Published: May 2015

Abstract
Despite several decades of intensive efforts to develop anti-cancer drugs and therapeutic strategies, lung cancer is still one of the main causes of cancer-related deaths worldwide. Deguelin, a natural plant product, has shown anti-cancer activities in skin, colon, breast and non-small cell lung (NSCLC) cancers. However, the potential side effects of deguelin could be an obstacle to its use in clinic. In the current study, we aimed to develop a derivative of deguelin with reduced potential side effects. We have synthesized a novel deguelin analog, compound A, and evaluated its effects on cancer and normal bronchial epithelial cell proliferation, survival, and colony formation by the MTT, FACS, and/or anchorage-dependent and -independent colony forming assays. Mechanisms underlying anti-tumor effects of compound A were investigated by Western blot, and RT-PCR. Treatment with compound A inhibited cancer cell proliferation and colony formation, promoted cell cycle arrest and induced apoptosis. Compound A also suppressed the expression of HIF-1α protein and its target gene, VEGF, in NSCLC cells. Administration of compound A to NSCLC xenograft-bearing mice significantly decreased tumor growth by inhibiting tumor angiogenesis and by inducing apoptosis. In its action mechanism, compound A was involved in binding to the ATP-binding pocket of HSP90, leading to the suppression of HSP90 function. These collective results suggest that a novel deguelin derivative, compound A, has a strong potential as an anti-cancer drug.
Citation Format: Su-Chan Lee, Ju-Sung Lee, Seung-Yeob Hyun, Hoon Choi, Hongchan An, Kyu-Won Kim, Young-Ger Suh, Ho-Young Lee. Antitumor effect of a Compound A, a derivative of a naturally occurring rotenoid deguelin, by inhibition of ATP binding to heat shock protein 90. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2014-3196
Abstract 3197: Gedunin inactivates the co-chaperone p23 causing cancer cell death by apoptosis
Authors: Patwardhan Chaitanya A. , Peterson Laura B. , Blagg Brian , Chadli Ahmed 
Published: May 2015

Abstract
Pharmacological inhibition of Hsp90 is an exciting option for cancer therapy. The clinical efficacy of Hsp90 inhibitors is, however, less than expected. Binding of the co-chaperone p23 to Hsp90, and induced overexpression of anti-apoptotic proteins, Hsp70 and Hsp27, are thought to contribute to this outcome. Herein, we report that the natural product, gedunin, may provide a new alternative to inactivate the Hsp90 machine. We show that gedunin directly binds to p23 and inactivates it, without overexpression of Hsp27 and relatively modest induction of Hsp70. Using molecular docking and mutational analysis, we mapped the gedunin-binding site on p23. Functional analysis shows that gedunin inhibits p23 chaperoning activity, blocks its cellular interaction with Hsp90 and interferes with p23-mediated gene regulation. Cell treatment with gedunin leads to cancer cell death by apoptosis through inactivation of p23 and activation of caspase 7, which cleaves p23 at the C-terminus. These results provide important insight into the molecular mechanism of action of this promising lead compound.
Citation Format: Chaitanya A. Patwardhan, Laura B. Peterson, Brian Blagg, Ahmed Chadli. Gedunin inactivates the co-chaperone p23 causing cancer cell death by apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3197. doi:10.1158/1538-7445.AM2014-3197
Abstract 3199: Pterostilbene supresses prostate cancer progression in transgenic mice model
Authors: Zhang Liangfen , Dhar Swati , Rimando Agnes M. , Kumar Avinash , Lage Janice , Lewin Jack R. , Zhang Xu , Levenson Anait S. 
Published: May 2015

Abstract
Metastasis-associated protein 1 (MTA1) is a cancer progression-related epigenetic modifier whose overexpression is associated with aggressive prostate cancer (PCa), disease recurrence and metastasis in men. We previously found that MTA1 expression is significantly increased in Pten-null murine cells, and that resveratrol and its analogues inhibit MTA1 expression. In the current study, we used the murine Pten knockout PCa model to evaluate the effect of pterostilbene (PTER) on MTA1-mediated events in PCa progression. Pterostilbene is a potent natural analogue of resveratrol with improved pharmacokinetic properties and superior pharmacological potency. The Pten conditional knockout mice that mimic human disease and provide fast stage-defined development of PCa were fed, starting at 3 weeks of age, with phytoestrogen-free diet AIN 76A and injected daily (i.p.) either with 10% DMSO (control, untreated) or with 10 mg/kg bw PTER until 6, 10, 15 and 25 weeks of age. At necropsy, mouse prostates were formalin-fixed and paraffin-embedded for histological and immunohistochemical analysis. For protein analysis, mouse prostate dissection was performed to distinguish anterior prostate (AP) and dorso-latero-ventral (DLV) lobes. Our results showed that the PTER-treated group had a lower tumor grade and higher incidence of prostate intraepithelial neoplasia (PIN) at the expense of a substantial decrease in adenocarcinoma incidence. Prostate tissues from the PTER-treated group presented a decrese in Ki67 proliferation marker-positive cells and an increase in apoptosis. As potential mechanisms of PTER efficacy, 50-75% decrease in MTA1 and pAkt levels were observed at different time points. In addition, PTER inhibited androgen receptor (AR) expression, especially in the AP. Taken together, our findings suggest that PTER blocks PCa growth and progression at PIN stage in Pten conditional knockout mice model through inhibition of MTA1-Akt axis.
Citation Format: Liangfen Zhang, Swati Dhar, Agnes M. Rimando, Avinash Kumar, Janice Lage, Jack R. Lewin, Xu Zhang, Anait S. Levenson. Pterostilbene supresses prostate cancer progression in transgenic mice model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3199. doi:10.1158/1538-7445.AM2014-3199
Abstract 320: Frequent inactivation of the Mieap-regulated mitochondrial quality control in pancreatic and breast cancer
Authors: Kamino Hiroki , Nakamura Yasuyuki , Sano Hitoya , Murai Ryuya , Saito Yuri , Futamura Manabu , Yoshida Kazuhiro , Hiraoka Nobuyoshi , Kanai Yae , Kushima Ryoji , Katagiri Toyomasa , Arakawa Hirofumi 
Published: May 2015

Abstract
Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1, 2). Two mitochondrial outer membrane proteins, BNIP3 and NIX are essential mediators of MALM (3). Previously, we reported that the Mieap-regulated mitochondrial quality control (MQC) pathway was inactivated in almost 80% of colorectal cancer patients. To evaluate the role of the Mieap-regulated MQC in pancreatic and breast cancer, we analyzed the status of p53, Mieap, BNIP3 and NIX in 50 cases of primary pancreatic cancer and 63 cases of primary breast cancer by examining p53 mutation and Mieap/BNIP3/NIX promoter methylation. As the result, the Mieap-regulated MQC pathway was inactivated in 71% of pancreatic and 27% of breast cancer patients. Interestingly, the BNIP3 promoter methylation was frequently detected in colorectal and pancreatic cancer patients (49% and 58%, respectively) whereas it was not detected in breast cancer patients at all (0%). Instead, the Mieap promoter methylation was highly detected in breast cancer patients (12.7%) compared to colorectal and pancreatic cancer patients (8.8% and 2.0%, respectively). These results suggest that the Mieap-regulated MQC pathway plays a critical role in tumorigenesis of pancreatic and breast cancer, and that there may be some different mechanisms between colorectal/pancreatic and breast cancers for inactivation of the Mieap-regulated MQC pathway. Inactivation of Mieap-regulated MQC pathway leads to the accumulation of unhealthy mitochondria generating high level of mitochondrial reactive oxygen species. We are now investigating whether the p53/Mieap/BNIP3 MQC pathway affects cell growth, cell motility or tumorigenicity using several pancreatic and breast cancer cell lines that are subcutaneously implanted into nude mice. In this paper, we discuss the potential role of the Mieap-regulated MQC in pancreatic and breast tumor suppression.
1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011
2. Kitamura N et al. PLoS ONE 6: e16060, 2011
3. Nakamura Y et al. PLoS ONE 7: e30767, 2012
Citation Format: Hiroki Kamino, Yasuyuki Nakamura, Hitoya Sano, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Nobuyoshi Hiraoka, Yae Kanai, Ryoji Kushima, Toyomasa Katagiri, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in pancreatic and breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2014-320
Abstract 3201: Parthenolide ameliorates experimental colitis associated colon cancer by inhibition of NF-kB signaling
Authors: Kim Se Lim , Kim Sang-Wook , Kim Seong Hun , Kim In Hee , Lee Seung Ok , Lee Soo Teik , Kim Dae Ghon 
Published: May 2015

Abstract
Parthenolide (PT), a NF-kB inhibitor, has recently been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. We previously showed that PT suppresses tumor growth in a xenograft model of colorectal cancer cells by regulation of Bcl-2 family. Unfortunately, little is known about its role in the process of tumor development in colitis associated colon cancer (CAC). Therefore, this study was designed to investigate the effects of PT on an experimental murine CAC model. Experimental CAC was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Mice were divided into 3 groups: AOM+DSS, AOM+DSS+2mg/kg PT and AOM+DSS+4mg/kg PT. We demonstrated that administration of PT significantly reduced the severity of AOM/DSS-induced CAC as assessed by histological analysis, and resulted in downregulation of phospho-NF-κB p65 expression by the blockade of phosphorylation and subsequent degradation of IκB-a. Administration of PT ameliorated the carcinogenesis through the downregulation of antiapoptotic protein Bcl-2 and Bcl-xL mediated by inhibition of NF-kB activation. Moreover, apoptosis and caspase-3 expression also increased markedly in PT administration group. These findings demonstrate that PT downregulates NF-kB resulting in initiation of apoptosis and eventual suppression of CAC development, suggesting that PT exerts beneficial effects in experimental CAC and could therefore be a potential chemopreventive and therapeutic agent of CAC.
Citation Format: Se Lim Kim, Sang-Wook Kim, Seong Hun Kim, In Hee Kim, Seung Ok Lee, Soo Teik Lee, Dae Ghon Kim. Parthenolide ameliorates experimental colitis associated colon cancer by inhibition of NF-kB signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2014-3201
Abstract 3202: Deciphering the targets and mechanism of action of the natural product Tonantzitlolone in clear cell renal cell carcinomas
Authors: Sourbier Carole , Scroggins Brad , Mannes Philip Z. , Beutler John A. , Linehan W. Marston , Neckers Len 
Published: May 2015

Abstract
Tonantzitlolone is a diterpene ester first extracted in 1990 from the native Mexican plant Stillingia sanguinolutea (Euphorbiaceae), which displays anti-tumor activity. Although its structure and total synthesis have been elucidated, its cellular target(s) and potential mechanism of action remain unknown. We identified Tonantzitlolone as a dual PKCα and PKCθ activator in vitro. However in clear cell renal cell carcinoma (CCRCC), its activity was mostly PKCθ-dependent. Through activation of PKCθ, Tonantzitlolone induced an insulin-resistant phenotype by inhibiting IRS1 and the PI3K/Akt pathway. Simultaneously, Tonantzitlolone activated the transcription factor heat shock factor 1 (HSF1), driving glucose dependency. Thus, similar to the selective PKCθ activator Englerin A, Tonantzitlolone induces a metabolic catastrophe in CCRCC, starving the cells of glucose while increasing their glycolytic dependency, ultimately leading to cell death.
Citation Format: Carole Sourbier, Brad Scroggins, Philip Z. Mannes, John A. Beutler, W. Marston Linehan, Len Neckers. Deciphering the targets and mechanism of action of the natural product Tonantzitlolone in clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3202. doi:10.1158/1538-7445.AM2014-3202
Abstract 3203: Honokiol inhibits growth and migration of renal cell carcinoma
Authors: Cheng Shujie , Welty Matt , Eliaz Isaac , Castillo Victor , Sliva Daniel 
Published: May 2015

Abstract
Renal cell carcinoma (RCC) is a common urological cancer worldwide and is known to the high risk of recurrence and metastasis. Approximately 70% of patients with RCC will develop recurrence after surgical resection, and 25%-30% of patients will eventually develop progression to distant metastasis. Honokiol is a small-molecule polyphenol isolated from the genus Magnolia, which has been shown to be a potential anticancer agent in multiple facets of signal transduction. Here we demonstrate that honokiol inhibits proliferation of RCC cells 786-0 and A498 without affecting cell viability. Moreover, honokiol also significantly inhibited migration of 786-0 cells in a dose-dependent manner. DNA microarray analysis showed that honokiol regulated expression of many genes related to human tumor metastasis in 786-0 cells. Real time PCR analysis confirmed that the expression of metastasis suppressor KISS1 and its receptor, KISS1R, were upregulated in 786-0 cells after treatment with honokiol. In addition, the shape changes and excessive formation of actin stress fibers were identified in 786-0 cells treated with honokiol. This phenomenon disappeared when treated cells with the pharmacological Rho-kinase inhibitor Y-27632 and honokiol. This inhibition can also be identified in 786-0 cells treated with Y-27632 only. Our present results demonstrated that honokiol could inhibit the growth and migration of RCC, which is likely to be regulated by the Rho and Rho-Associated Kinase (ROCK) pathway. In conclusion, honokiol is a biologically active natural compound which can be considered for the alternative treatment of RCC. The investigation of detailed mechanisms and molecular targets are in progress.
Citation Format: Shujie Cheng, Matt Welty, Isaac Eliaz, Victor Castillo, Daniel Sliva. Honokiol inhibits growth and migration of renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3203. doi:10.1158/1538-7445.AM2014-3203
Abstract 3207: Curcumin induces pancreatic cancer cell death by targeting IAPs
Authors: Osterman Carlos J. Diaz , Valenzuela Malyn May Asuncion , Bennit Heather R. Ferguson , Khan Salma , Wall Nathan R. 
Published: May 2015

Abstract
Background
Pancreatic cancer has among the highest mortality rates compared to other cancer types, with 94% of patients dying within five years of diagnosis. Contributing to the high mortality rate, patients with pancreatic cancer do not present significant symptoms until the disease is advanced. Moreover, treatment strategies have not improved substantially over the last decade. For this reason, a recent trend has led toward focusing on the use of herb-derived compounds, such as curcumin (turmeric derivative), to explore alternative treatments that will improve current pancreatic cancer therapy.
Objective
The objectives of this study were (1) to determine the effects of curcumin on pancreatic cancer cell metabolism, viability, cell cycle and morphology, and (2) to determine the mechanism by which curcumin induces cell death in pancreatic cancer cells by analyzing intracellular expression levels of inhibitor of apoptosis proteins (IAPs).
Design/method
Pancreatic adenocarcinoma cell lines (Panc-1 and MiaPaCa-2) were used to assess the effects of curcumin in pancreatic cancer. Effects on metabolism, viability and cell cycle were assayed by Alamar Blue, Trypan Blue and Propidium Iodide (PI) staining/flow cytometry (FACSCalibur). Morphological imaging was performed using Hoffman Modulation microscopy. Apoptosis was detected by Annexin V/PI flow cytometry (MACSQuant) and the expression of IAPs was assessed by Western blot.
Results
These data show that curcumin decreases pancreatic cancer cell metabolism and viability. Cell cycle stages were arrested in pancreatic cancer cells treated with curcumin compared to the non-treated controls. Apoptotic cells were detected by microscopy and confirmed by Annexin V/PI staining with subsequent flow cytometry analysis. IAPs levels are reduced in pancreatic cancer cell lines treated with curcumin compared to non-treated controls.
Conclusion
These results demonstrate that pancreatic adenocarcinoma cell lines are sensitive to curcumin treatment. Moreover, curcumin's possible mechanism of action is inducing apoptosis by targeting IAPs. Collectively, these data suggest a potential role for curcumin in pancreatic cancer therapy.
Citation Format: Carlos J. Diaz Osterman, Malyn May Asuncion Valenzuela, Heather R. Ferguson Bennit, Salma Khan, Nathan R. Wall. Curcumin induces pancreatic cancer cell death by targeting IAPs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3207. doi:10.1158/1538-7445.AM2014-3207
Abstract 3208: Identification and characterization of a small molecule involved in the downregulation of RET transcription in MTC
Authors: Kumarasamy Vishnu Muthuraj , Shin Yoon-Joo , Sun Daekyu 
Published: May 2015

Abstract
The gain of function mutations in the RET proto-oncogene, which results in the constitutive activation of the mitogenic pathways, were found mainly in Medullary Thyroid Carcinoma (MTC). In our study, a new therapeutic strategy has been explored to repress the expression of the RET gene by targeting the transcriptional activation of this gene with small molecules. The transcriptional inhibitor of the RET gene was initially screened from the NCI chemical libraries using the cell-based luciferase reporter gene assay, which has a promoter sequence identical to the RET promoter. As a result of our screening effort, a small molecule, nonactin, has been identified as a potential lead compound, downregulating the transcriptional activity of the RET gene promoter. The effect of this molecule in the downregulation of the RET mRNA levels and the protein levels was confirmed by RT-PCR and western blotting respectively. We also observed that Egr1 expression is downergulated in a dose dependent manner by this small molecule, which is in correlation with the RET downregulation. The RET promoter has a highly conserved GC rich region, which acts as a binding site for Egr-1, which is involved in the transcription of many growth factor genes. Thus, we conclude that Egr1 would be one of important transcriptional factors involved in the activation of the RET and nonactin inhibits the expression of Egr1, which in turn downregulates the transcription of RET oncogene.
Citation Format: Vishnu Muthuraj Kumarasamy, Yoon-Joo Shin, Daekyu Sun. Identification and characterization of a small molecule involved in the downregulation of RET transcription in MTC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3208. doi:10.1158/1538-7445.AM2014-3208