bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4491: Discovery of potent small molecular tubulin inhibitors for the treatment of cancer.
Authors: Cai Sui Xiong , Yu Zenghui , Chen Lei , Xu Qingbing , Wu Lizhen , Liu Lijun , Yin Feng , Wang Guoxiang , Jiang Yangzhen , Zhang Xiuyan , Kong Lingsheng , Bao Qingli , Tian Ye Edward 
Published: August 2014

Abstract
Microtubule is a well-established drug target for the treatment of cancer. Drugs acting at this target include paclitaxel and docetaxel that stabilize the microtubules and prevent cancer cells from going through mitosis. These drugs are very successful chemotherapy agents and widely used for the treatment of cancer. In this presentation, we report the discovery of several series of novel and potent small molecular tubulin inhibitors and the identification of IMP03138 as a preclinical candidate. IMP03138 has advantages over the most commonly used anti-cancer drug paclitaxel in several in vitro assays and in vivo efficacy studies. Importantly, IMP03138 is highly effective against multi-drug resistant cancer cells. IMP3138 is currently undergoing IND enabling studies.
Citation Format: Sui Xiong Cai, Zenghui Yu, Lei Chen, Qingbing Xu, Lizhen Wu, Lijun Liu, Feng Yin, Guoxiang Wang, Yangzhen Jiang, Xiuyan Zhang, Lingsheng Kong, Qingli Bao, Ye Edward Tian. Discovery of potent small molecular tubulin inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4491. doi:10.1158/1538-7445.AM2013-4491
Abstract 4494: MPT0G066, a novel microtubule-destabilizing agent, induces cell apoptosis and potentiates antineoplastic effects of cisplatin in human ovarian cancer cells in vitro and in vivo.
Authors: Chen Chun-Han , Li Ya-Chi , Chang Li-Hsun , Liou Jing-Ping , Pan Shiow-Lin , Teng Che-Ming 
Published: August 2014

Abstract
Ovarian cancer is one of the leading causes of death in women with gynecological malignancy in the United States. About 70% of ovarian cancer cases are diagnosed at an advanced stage resulting in poor survival rate. In the present study, we provide the data showing that MPT0G066, a novel synthetic arylsulfonamide compound, inhibited cell growth and viability in human ovarian cancer cell lines as evidenced by sulphorodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell cycle distribution was also determined by flow cytometry, the data revealed that MPT0G066 induced cell cycle arrest at multipolyploidy (MP) phase (SKOV3 cells) or at G2/M phase (A2780 cells) in 24 hours and ultimately increased the cell population in sub-G1 phase in 48 hours. Moreover, in vitro tubulin polymerization assay, in situ labeling of β-tubulin and western blot analysis showed that MPT0G066, similar to colchicine and vincristine, promoted tubulin depolymerization and altered the expression of G2/M cell cycle regulatory proteins. Mechanistically, MPT0G066 induced JNK activation and altered Bcl-2 family proteins by increasing the expression of p-Bcl-2, Bax, Bim, Puma and decreasing the level of Bcl-2 and Mcl-1. Disruption of mitochondrial proteins triggered intrinsic apoptotic pathways through the cleavage of caspase-3, -7, -9, and poly (ADP-ribose) polymerase (PARP). Moreover, treatment with SP600125, a JNK inhibitor, abolished the effects of MPT0G066 on cell viability, Bcl-2 family proteins and apoptotic cell death. Finally, we used xenograft mouse model to demonstrate that MPT0G066 is able to suppress the growth of ovarian carcinoma A2780 cells and potentiated the antineoplastic effects of cisplatin in vivo. Immunohistochemistry data also confirmed MPT0G066-induced JNK activation in tumor sections. In summary, these results suggested that MPT0G066 could disrupt microtubule dynamics, and lead to cell cycle arrest at MP phase or G2/M phase. MPT0G066 induced JNK activation and altered Bcl-2 family proteins, which ultimately caused apoptosis through the intrinsic apoptotic pathways. These finding indicated that MPT0G066 is a potential anticancer agent worthy for further development and may foster novel treatment for patients with ovarian cancer.
Citation Format: Chun-Han Chen, Ya-Chi Li, Li-Hsun Chang, Jing-Ping Liou, Shiow-Lin Pan, Che-Ming Teng. MPT0G066, a novel microtubule-destabilizing agent, induces cell apoptosis and potentiates antineoplastic effects of cisplatin in human ovarian cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4494. doi:10.1158/1538-7445.AM2013-4494
Abstract 4497: TW01001, a novel piperazinedione compound, induces mitotic arrest and autophagy in non-small cell lung cancer A549 cells.
Authors: Chen Mei-Chuan , Wang Hui-Po , Chen Chun-Han , Liu Yi-Nan , Pan Shiow-Ling , Teng Che-Ming 
Published: August 2014

Abstract
Targeting cellular mitosis in tumor cells is an attractive treatment strategy. Here, we report TW01001, a novel compound from the sodium 3-((6-((Z)-((Z)-5-benzylidene-3,6-dioxopiperazin-2-ylidene)methyl)pyridin-3-yloxy)methyl)benzoate, as a new mitotic inhibitor which inhibit tubulin polymerization for non-small cell lung cancer treatment. We focus the detailed mechanism of action of TW01001 in a non-small cell lung carcinoma cell line A549 cells. Treatment of A549 cells with TW01001 caused the cells to accumulate at the G2/M phase of the cell cycle, with a concomitant induction of mitotic phase marker such as MPM2, cyclin B, and phospho-Histone H3. An increase levels of cyclin-dependent kinase 1 (CDK1) Thr161 phosphorylation and bcl-2 Ser70 phosphorylation was found in TW01001-treated cells, suggesting the drug induced CDK1 activity. We showed that the p53 accumulation was detected and was required for the TW01001-induced mitotic arrest. Moreover, TW01001 induced autophagy concentration- and time-dependently by the conversion of microtubule associated protein 1 light chain 3 (LC3-I) to LC3-II and p62/SQSTM1 degradation. After 48 h of TW01001 exposure, apoptotic cell death occurred by revealing caspase-3 activation and PARP cleavage. Notably, blockade of autophagy by either pharmacological inhibitor or siRNAs targeting Atg5 resulted in reduced cytotoxicity in response to TW01001, suggesting that TW01001-induced autophagy led to cell death. Taken together, these results indicated that the combination of autophagy inducers might be attractive for the management of cancer therapy and provides the framework for further development of TW01001 as a new therapeutic agent for lung cancer treatment.
Citation Format: Mei-Chuan Chen, Hui-Po Wang, Chun-Han Chen, Yi-Nan Liu, Shiow-Ling Pan, Che-Ming Teng. TW01001, a novel piperazinedione compound, induces mitotic arrest and autophagy in non-small cell lung cancer A549 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4497. doi:10.1158/1538-7445.AM2013-4497
Abstract 4498: CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model.
Authors: Min Young Joo , Moon Chang Hoon , Lee Seung Ju , Ryu Sang Ryun , Cho Wha Ja , Yoon Nal Ae , Park Sungchan , Cha HeeJeong 
Published: August 2014

Abstract
PURPOSE: CKD-516 is a benzophenone analog with a modification of the B ring, which is replaced by a carbonyl group. The aim of this study is to assess the antivascular effects and the inhibition of cell proliferation of CKD-516.
MATERIALS AND METHODS: To assess the effect of CKD-516 on vascularization, we analyzed the effect on endothelial cells (HUVECs). To determine the inhibition of cell proliferation of CKD-516, we used a lung carcinoma cell line (H460). The alteration of microtubule analyzed using immunoblot, RT-PCR and confocal image. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) or gemcitabine (40 mg/kg) or CKD-516 + gemcitabine, and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues were taken at 12 and 24 hours after CKD-516 injection from H460 xenograft mice.
RESULTS: We determined that cytoskeletal changes of HUVECs treated with 10 nM CKD-516 were assessed by immunoblot and confocal imaging. CKD-516 disrupts tubulin assembly and results in microtubule dysfunction inducing cell cycle arrest (G2/M). CKD-516 markedly enhanced the depolymerization of microtubules which may be related to vascular disrupting properties of CKD-516. Interestingly, CKD-516 decreased amount of total tubulin protein in HUVECs. Especially, CKD-516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460) at early time point (4 h). Immunocytochemical analysis showed that CKD-516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. We also showed extensive central necrosis of tumor by 24 h after treated with CKD-516 (2.5 mg/kg, i.p.). In H460 xenograft, CKD-516 combined with gemcitabine significantly delayed tumor growth as compared to control and gemcitabine alone.
CONCLUSION: These results suggest that CKD-516 is a novel agent with vascular disrupting properties, and enhances anti-tumor activity in combination with chemotherapy.
Citation Format: Young Joo Min, Chang Hoon Moon, Seung Ju Lee, Sang Ryun Ryu, Wha Ja Cho, Nal Ae Yoon, Sungchan Park, HeeJeong Cha. CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2013-4498
Abstract 4499: Total synthesis of tubulysins: A new chemical reaction leads to analogues with enhanced cytotoxicity.
Authors: Vlahov Iontcho , Qi Longwu , You Fei , Hahn Spencer , Santhapuram Hari K. , Wang Kevin , Kleindl Paul , Vaughn Jeremy , Vetzel Marilynn , Reddy Joseph , Leamon Christopher 
Published: August 2014

Abstract
Tubulysins are natural products isolated from myxobacterial species and are mitotic poisons which exceed the cell growth inhibition of any clinically relevant traditional chemotherapeutic. Structurally, tubulysins are linear tetrapeptides comprised of N-methyl pipecolic acid (Mep), isoleucine (Ile), the novel amino acid tubuvaline (Tuv), and the novel tyrosine analogue tubutyrosine (Tut). All isolated tubulysins possess an acid- and base-sensitive N-acyloxymethyl substituent not previously found in nature. This N,O-acetal of formaldehyde is attached as a side chain to the amide N-atom of the Tuv fragment. The isolation of natural tubulysins from culture extracts provides only limited quantities. Recently, we reported a large scale total synthesis of natural tubulysin B. Among the multiple synthetic and stereochemical challenges, the most striking were: a) the incorporation of the labile N,O-diacyl N,O-acetal and b) the regioselective hydrolysis of the C-terminal methyl ester (OMe) in the tripeptide Mep-Ile-Tuv-OMe.
Herein, we present a convergent total synthesis of tubulysin analogues incorporating an alkoxymethyl side chain. Such molecular architecture allows for compounds that are more base and esterase inert, thus providing additional metabolic/catabolic stabilization. The key step in our synthetic strategy relies on use of a novel reagent for the efficient conversion of the N-acyloxymethyl substituent to novel side chain groups with concomitant facilitated hydrolysis of the C-terminal methyl ester. Following LiOH-based hydrolysis of the C-terminal ester, the Tut fragment is added resulting in novel tubulysin analogues.
This novel process opens the door to tubulysin analogs with improved potency for treating cancer.
Citation Format: Iontcho Vlahov, Longwu Qi, Fei You, Spencer Hahn, Hari K. Santhapuram, Kevin Wang, Paul Kleindl, Jeremy Vaughn, Marilynn Vetzel, Joseph Reddy, Christopher Leamon. Total synthesis of tubulysins: A new chemical reaction leads to analogues with enhanced cytotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4499. doi:10.1158/1538-7445.AM2013-4499
Abstract 450: Host-tumor immune response for breast cancer patients.
Authors: Imoto Shigeru , Nakatsugawa Noriko , Isaka Hirotsugu , Ito Hiroki , Imi Kentaro , Miyamoto Kaisuke , Nakatsura Tetsuya 
Published: August 2014

Abstract
We demonstrated immune suppression of regulatory T cells (Treg) and M2 macrophage in breast cancer (BC) patients at AACR 2011. In summary, to compare between 38 early and 12 advanced BC cases, CD163-positive tumor cells and CCR4-positive tumor cells were detected more frequently in advanced cases than in early cases. Treg cells in PBMC significantly increased in percentage of the population in 37 BC patients than in 21 healthy volunteers. To explore host-tumor immune response, several cytokines were examined in the same cases. Plasma from 32 early and 9 advanced BC cases was preoperatively obtained. Human IL-2, IL-4, IL-6, IL-10, TNF, INFγ, and IL-17A were measured using cytometric beads array system. Statistical significance was analyzed using Mann-Whitney U-test. Plasma IL-17A had significantly higher levels in early BC than in advanced BC (103 pg/ml v.s. 51 pg/ml at mean level). Th17 cells may have some potential to control tumor progression in BC. In conclusions, induction of host-tumor immune response due to chemotherapy and anti-HER2 therapy and release from immune suppression such as CCR4 monoclonal antibody are important issues to explore a new strategy for BC patients.
Citation Format: Shigeru Imoto, Noriko Nakatsugawa, Hirotsugu Isaka, Hiroki Ito, Kentaro Imi, Kaisuke Miyamoto, Tetsuya Nakatsura. Host-tumor immune response for breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2013-450
Abstract 4500: Tubulin binding agent BPR0L075 induces iitotic catastrophe in paclitaxel-resistant ovarian cancer cells that is independent of caspase-3 activation.
Authors: Liu Xinli , Sun Weimin , Wang Xiaolei , Wu Erxi 
Published: August 2014

Abstract
Paclitaxel resistance is a significant clinical problem. In the current study, we evaluated antiproliferative effects of a tubulin binding agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50 = 2-7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III β-tubulin or mutation of β-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage and DNA fragmentation. Immunoblot analysis shows that survivin protein expression was depleted in resistant cells. BPR0L075 induced cell death in the paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms, supported by the absence of caspase-3 cleavage and ineffectiveness of caspase-3 inhibitor in protecting the resistant cells from BPR0L075 induced cell death. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a promising antimitotic agent in controlling taxane-resistant ovarian cancer cells.
Citation Format: Xinli Liu, Weimin Sun, Xiaolei Wang, Erxi Wu. Tubulin binding agent BPR0L075 induces iitotic catastrophe in paclitaxel-resistant ovarian cancer cells that is independent of caspase-3 activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2013-4500
Abstract 4504: Potential use of polyethyleneimine as a gene delivery vehicle for breast cancer.
Authors: Thomas T. J. , Venkiteswaran Sripriya , Thomas Thresia 
Published: August 2014

Abstract
Breast cancer is the second leading cause of cancer death in US women, after lung cancer. A major impediment in advancing gene therapy approaches to breast cancer is the resistance of cancer cell membrane to transport DNA/RNA. Viral vectors are efficient to deliver target genes; however, they are associated with the risk of immune response, random integration into the host genome or recombination with other wild type viruses. In contrast, non-viral vectors, that include lipoplex and polyplex forming carriers, are more advantageous as they are less expensive, easier to manufacture, and can carry large molecules of DNA. Polyethyleneimine (PEI) has emerged as a very effective gene transfection agent. PEI is water soluble, positively charged, and can envelope negatively charged DNA and protect it from lysosomal degradation. However, gene transfection efficacy of PEI for breast cancer cells remains poorly understood. In addition, information on the relationship between the polymer structure and its biological function, such as DNA condensation, toxicity and transfection efficacy is still limited. In this study, we evaluated the transfection efficiency of PEIs differing in molecular weight and branching. pGL3 control plasmid (5256 bp) containing a coding for the firefly luciferase gene driven by the SV40 promoter was used for this study. pGL3 complexed with different PEIs was tested for gene transfection study in breast cancer cells, using luciferase activity measurements with a luminometer. Cytotoxicity was measured by trypan blue exclusion assay. Static and dynamic laser light scattering was used to determine the ability of PEIs to condense plasmid DNA to nanoparticles and determine the size of the nanoparticles. Our results showed maximum transfection efficiency with 22 kDa linear PEI at N/P (nitrogen/phosphorus) ratio of 4.8 to 6. Linear and branched 25 kDa PEIs were less efficient than 22 kDa PEI. Low molecular weight (0.6 and 1.2 kDa) PEIs had negligible effect in transporting plasmid DNA, whereas 10 kDa PEI showed some activity. Cytotoxic effects of the PEIs were suppressed by DNA complexation. Both branched and linear PEIs condensed plasmid DNA to nanoparticles (hydrodynamic radius: ∼155 nm). Taken together, these results demonstrate structure-function relationships of PEIs in condensing and transporting plasmid DNA. Our results might be useful in selecting and improving the properties of PEI as a gene delivery vehicle for breast cancer.
Citation Format: T. J. Thomas, Sripriya Venkiteswaran, Thresia Thomas. Potential use of polyethyleneimine as a gene delivery vehicle for breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4504. doi:10.1158/1538-7445.AM2013-4504
Abstract 4511: An evaluation of the role of Mucin in nano drug delivery.
Authors: Allkholief Musaed , Campbell Robert 
Published: August 2014

Abstract
Introduction: Solid tumors comprise more than 85% of cancers that affect humans. The presence of the extracellular matrix, namely mucin, on the tumor cell is considered one of the barriers against effective treatment of solid tumors. In tumor cells, mucin is aberrantly overexpressed producing a mucin mesh which may impede the rate of entry of chemotherapy medications. The type O-glycosylation inhibitor, benzyl-α-GalNAc, significantly reduces mucin type O-glycosylation in mucin-producing tumor cells resulting in enhanced cytotoxic drug action. We next seek to determine the role of mucin in the delivery of nano-sized drug delivery systems.
Methods: The cell lines used in our studies were derived from tumor or normal tissues representing multiple different tissue environments. A fluorescence microplate reader was used to evaluate the MUC1 expression in the cell lines by using CD227 (anti-MUC1 antibody). We investigated the cellular uptake of the fluorescently labeled polystyrene microsphere beads in Capan-1 (a human pancreatic cancer cell line). The size of these beads was determined by particle size analysis. FACS analysis was used to determine cellular uptake following inhibition of mucin type O-glycosylation and compared to control. Finally, fluorescence microscopy was used to show the effect of inhibitor on the uptake of the beads into ZR-75-1 (a human breast cancer cell line) and Capan-1 cells.
Results: Different levels of mucin expression were observed among the various cell lines. By investigating the antibody association with the MUC1, Capan-1and ZR-75-1have shown the greatest cellular uptake following inhibition of glycosylation. The microspheres used in this study were 920 ±70 nm, 100 ±36 nm, and 52 ±8 nm in size. Cellular uptake studies of the microsphere beads into Capan-1 showed a significant increase in the uptake of the 920 nm beads in cells when compared to control cells. However, in case of the smaller beads, we did not observe a significant increase of the cellular uptake following inhibition of the mucin glycosylation. FACS analysis of the beads with Capan-1 cell line showed a red shift in the fluorescence peak of the 920 nm beads in cells treated with inhibitor compared to control. The smaller beads (52 nm and 100 nm), however, did not show any shift indicating that the uptake of the beads was hindered by the mucin mesh.
Conclusion: Our results suggest that inhibiting the mucin type O-glycosylation alters the uptake of relatively large microsphere beads. This might be helpful in developing a better therapeutic approach to treat cancer.
Citation Format: Musaed Allkholief, Robert Campbell. An evaluation of the role of Mucin in nano drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4511. doi:10.1158/1538-7445.AM2013-4511