bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B221: Clopidogrel augments cisplatin cytotoxicity by enhancing delivery and direct receptor mediated effects.
Authors: Pandey Ambarish , Sarangi Sasmit , Roy Bhaskar , Sengupta Poulomi , Basu Sudipta , Kopparam Jawahar , Dadwal Ushashi Chand , Sengupta Shiladitya 
Published: June 2012

Abstract
Clopidogrel, a well known P2Y12 (purinergic receptor) inhibitor is widely used for its role in preventing thrombosis by platelet aggregation inhibition. Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can promote its leakiness. This can increase the intra-tumoral delivery of chemotherapeutic nanoformulations, which depend on the Endothelial permeability and retention (EPR) effect. Also, Expression of P2Y12 receptors has been documented in some cancer cell lines like C6 glioma, kidney carcinoma and colon carcinoma. However, its direct role in altering response to chemotherapeutics has not been studied. In this project we evaluated the role of P2Y12 receptor inhibitors (Clopidogrel and 2-Methylthioadenosine 5-Monophosphate) in potentiating the tumor cytotoxicity of cisplatin based chemotherapeutics in vitro and in vivo.
Western blot studies in 4T1 breast cancer cell lines showed a low basal expression of P2Y12 receptors with significant up regulation by cisplatin treatment in a time and dose dependent fashion. Co-administration of P2Y12 inhibitor (MeSAMP) with cisplatin resulted in significantly increased upregulation of caspase dependent apoptotic pathway when compared to cisplatin alone. This was mediated by downstream inhibition of PI3K-pAKT-mTOR pathway by the P2Y12 inhibitor. In-vitro cell proliferation assay showed that co-administration of 2-MeSAMP significantly reduced the IC-50 of cisplatin from 3.9 μM to 1.8μM.
In-vivo studies in murine syngenic 4T1 breast cancer model showed significantly decreased tumour growth and increased survival in treatment groups using combination of clopidogrel and cisplatin (free and nanoformulation forms). This was more pronounced with cisplatin nano-formulation combination therapy. Further analysis of tumour tissue using Inductive Coupled Plasma-spectrophotometry confirmed that co-treatment with clopidogrel increased the delivery of free and nanoformulation form of cisplatin to tumor tissue by 1.8 and 4 folds respectively.
Taken together our study findings suggest that clopidogrel can enhance therapeutic efficiency of cytotoxic agents by increasing delivery and by direct receptor level effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B221.
Abstract B233: Identification and characterization of LY2835219: A potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity.
Authors: Gelbert Lawrence M. , Cai Shufen , Lin Xi , Sanchez-Martinez Concepcion , del Prado Miriam , Lallena Maria Jose , Torres Raquel , Ajamie Rose T. , Kreklau Emiko , Wishart Graham N. , Flack Robert Steven , Neubauer Blake , Young Jamie , Chan Edward M. , Iversen Phillip , Cronier Damien , De Dios Alfonso 
Published: June 2012

Abstract
Dysregulation of the cell cycle, which normally regulates cell proliferation in response to mitogenic signaling and other extracellular stimuli, is a hallmark of cancer. The G1 restriction point is a primary mechanism controlling cell cycle progression and is controlled by the CDK4/6 pathway (CDK4/6-cyclin D1-Rb-CDKN2). The importance of this pathway is highlighted by inactivation of restriction point control in a majority of human tumors. Transition through the restriction point requires phosphorylation of Rb by CDK4/6, and these kinases are considered highly validated cancer drug targets. We have identified and characterized a potent and selective dual CDK4/6 inhibitor, LY2835219. Preclinical characterization was performed with the monomesylate salt (LY2835219-MsOH), which inhibits these kinases with a IC50 of 2 and 10 nM for CDK4 and CDK6, respectively. In vitro, LY2835219-MsOH is a potent inhibitor of Rb phosphorylation resulting in a G1 arrest, and its activity is specific for tumors that have functional Rb protein. In a multiplexed in vivo target inhibition assay (IVTI), LY2835219-MsOH is a potent inhibitor of Rb phosphorylation and induces complete cell cycle arrest 24 hrs after a single dose. In tumor-bearing mice, oral administration of LY2835219-MsOH inhibits tumor growth in a dose-dependent manner in colon (colo-205), glioblastoma (U87MG), acute myeloid leukemia (MV4–11), mantle cell lymphoma (Jeko-1), and lung (H460) xenografts. LY2835219-MsOH may be administered up to 56 days without adverse events or tumor outgrowth. LY2835219-MsOH enhances the in vivo activity of cytotoxic drugs, suggesting that this novel CDK4/6 inhibitor can be used in combination with these anti-neoplastic agents. In summary, we have identified an oral small molecule inhibitor of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B233.
Abstract C117: Preclinical pharmacokinetics of an antibody-drug conjugate targeting 5T4.
Authors: Leal Mauricio , Wentland Joann , Clark Tracey , Zhang Jenny , Marcek John , Khandke Kiran , DiJoseph John , Lucas Judy , Groeber Elizabeth , Han Xiaognag , Hu George , Gerber Hans-Peter , Sapra Puja 
Published: June 2012

Abstract
The pharmacokinetics of a novel antibody (huA1)-drug (auristatin tubulin inhibitor MMAF) conjugate, targeting 5T4-expressing cells, were obtained in female nu/nu mice after a single IV dose of 1, 3 or 10 mg/kg and in male cynomolgus monkeys from a 2-cycle exploratory toxicity study at doses of 1, 3 or 10 mg/kg/cycle. Plasma/serum samples, collected over a 336 hr period after dosing, were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the Auristatin payload using an LC/MS/MS method. A comparison across doses (1 − 10 mg/kg) suggests lower CL values at the higher doses (3 and 10 mg/kg) in mice. Exposure in the mouse at anti-tumor doses was within the exposure observed at nontoxic doses with the monkeys. The huA1 and conjugate toxicokinetic data in monkeys dosed with A1mcMMAF indicates that exposure (AUC) increases with increasing dose although it appears to increase in a greater than proportional manner at the higher doses. In both mice and monkeys, the elimination half-life was longer as the dose increased from 1 to 10 mg/kg (from 4.2 to 8.7 days in monkeys, respectively). Systemic exposure (as assessed by Cmax and AUC) of the released payload increased with increasing dose although exposure was very low and its pharmacokinetics appeared to be formation rate limited. The analytical data from these studies are being used to inform PKPD models, to both quantitatively characterize the system and ultimately provide dose projections for this ADC construct
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C117.
Abstract C166: Preclinical studies of Ureidomustin, a potent water-soluble anticancer agent.
Authors: Su Tsann-Long , Chen Yi-Ren , Kakadiya Rajesh , Hsiao Pei-Wen , Lee Te-Chang , Chou Ting-Chao 
Published: June 2012

Abstract
Most anticancer agents have poor water-solubility and thus, have a higher risk of failure during the period of new drug discovery and development. Our previous exploration of water-soluble N-mustard-benzene conjugates has led to an anticancer drug candidate, Ureidomustin (1-[3-((2-(dimethylamino)ethyl) carbamoyl)phenyl]-3-[4- (bis(2-chloroethyl)amino)phenyl]urea hydrochloride. This agent exhibits a broad spectrum of antitumor activity. Ureidomustin shows potent therapeutic efficacy against various human solid tumor xenografts. Complete tumor remission was observed in nude mice bearing human breast carcinoma MX-1 xenograft treated with Ureidomustin. This was observed continuously for 75 days; no tumor relapse was detected and the average body-weight was recovered after ceasing of drug treatment. In addition, this water-soluble derivative exhibits potent antitumor activity against other tumor xenografts. This agent induced &gt;95% suppression of human colon cancer HCT-116 and &gt;99% suppression of prostate adenocarcinoma PC3 xenografts (subcutaneous implantation) in nude mice. We also found that this agent is as potent as Docetaxel (&gt;93% suppression), but more potent than carboplatin (65% suppression) in nude mice bearing colon tumor 22Rv/HL2 (orthotropic implantation). Examination of the pathology changes of different organs removed from Ureidomustin treated mice showed that there are no apparently pathological changes between the control group and the drug treated groups. Moreover, the average body-weight of the drug treated mice recovered after stopping of drug treatment. These results indicate that Ureidomustin has very little toxicity to the host. Studies on the mechanism of action of this agent revealed that this compound is able to induce DNA interstrand cross-linking. Furthermore, the pharmacokinetic (PK) study revealed that Ureidomustin has an acceptable PK profile in rats with a half-life of 0.77 h. Rapid distribution and slow elimination were found after administrating this agent in rats. In summary, Ureidomustin is a promising candidate for clinical application and is currently undergoing further preclinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C166.
Abstract C200: Second-generation PIM inhibitors exhibit improved activity in solid tumor models in vitro.
Authors: Foulks Jason M. , Xu Yong , Saunders Michael , Liu Xiao-hui , Brenning Benjamin , Clifford Adrianne , Wilkes Marcus , Luo Bai , Lai Shuping , Merx Shannon , Chan Ashley , Huang Liwen , Vollmer David , Senina Anna , Liu Jihua , Ho Kan , McCullar Michael V. , Kanner Steven B. 
Published: June 2012

Abstract
The proto-oncogene PIM kinase family (PIM-1, -2 and -3) comprises constitutively active serine/threonine kinases upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, prostate, bladder, gastric and head & neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The PIM kinases function by inhibiting apoptosis in MYC-driven tumors, promoting tumor cell survival and proliferation. PIM-1 and PIM-2 overexpression models were obtained in the human prostate cancer cell lines PC-3M and 22RV-1 and the non-tumorigenic mouse NIH-3T3 background. Overexpression of PIM kinases led to enhanced cell growth and tumorigenicity in both NIH-3T3 and 22RV-1 cell lines. In the PC-3M cell line, enhanced phosphorylation of the PIM kinase substrate BAD (pBAD) was observed following PIM overexpression. Enhancement of pBAD was inhibited by SGI-1776, a well-described PIM inhibitor, as well as next generation PIM inhibitors exhibiting 4–10 fold improved potency against the PIM kinase family. The current PIM inhibitors display sub-μM activity in pharmacodynamic marker, proliferation and 2D colony formation assays using the PC-3M prostate cancer cell line, the UM-UC-3 bladder cancer cell line, and the HSC3 head & neck cancer cell line. The second generation PIM inhibitors possess favorable hERG and CYP inhibition profiles compared with SGI-1776, and demonstrate excellent oral bioavailability. In vivo xenograft studies using both PIM overexpression models and clinically relevant solid tumor models will facilitate identification of a clinical candidate.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C200.
Abstract 1008: Prevalence of FoxM1 expression in Middle Eastern epithelial ovarian carcinoma patients and its potential role as a therapeutic target
Authors: Ahmed Maqbool , Jehan Zeenath , Bavi Prashant , Hussain Azhar R. , Olayan Aisha Saad , Saravanan Thangavel , Dayel Fouad Al , Ghourab Samir , Uddin Shahab , Al Kuraya Khawla S. 
Published: June 2012

Abstract
FoxM1 is a member of Forkhead transcription factors and its expression has been found to be altered in a variety of cancers. Several studies have indicated the importance of FoxM1 in cell proliferation, as it is a key cell-cycle regulator of both the transition from G1 to S phase and the progression to mitosis. In this study, we investigated the functional consequences of FoxM1 signaling pathway in a large cohort of epithelial ovarian cancer (EOC) tumor (patient) samples, panel of cell lines, and in nude mouse model. Using immunohistochemistry, FoxM1 was detected in 47.4% (64/135) of the ovarian tumor samples. EOC with FOX-M1 expression showed a significantly better disease free survival(p=0.0148) of 21.9 months as compared to the EOC with low FOX-M1 expression(14.4 months). Overexpression of FoxM1 was also significantly associated with activated p-AKT(p=0.0072), SKP2(p=0.0121), p-Rb(p=0.0357), UBE2C(p=0.0106), FAS-N(p=0.0179), PIK3CA p110αIHC(p=0.0362), XIAP(p=0.0033) and tumor proliferative marker Ki167 (p&lt;0.0001). Treatment of a panel of EOC cell lines with thiostrepton, an inhibitor of FoxM1, inhibited cell proliferation and induced apoptosis. Thiostrepton treatment caused apoptosis by involving the mitochondrial pathway, through activation of caspases and down regulation of XIAP and survivin. FoxM1 inhibition in EOC cells by thiostrepton resulted in the down regulation of Skp2 and accumulation of p21, possibly causing G2/M arrest. Furthermore, FoxM1 inhibition also down regulated cell migration and cell invasion in EOC cells by inducing decreased secretion of VEGF and MMP2. In addition, pharmacological inhibition of FoxM1 or its gene silencing with siRNA causes downregulation of FoxM1, AKT and its associated downstream signaling molecules. Altogether, these results suggest that FoxM1 and its role in the deregulated survival pathway make this a potential target for therapeutic intervention of EOC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2011-1008
Abstract 1020: Investigating LKB1 regulation in osteosarcoma
Authors: Eskandarpour Malihe , Duhamel Laure , Tirabosco Roberto , Flanagan Adrienne 
Published: June 2012

Abstract
Osteosarcoma (OS) accounts for approximately 60% of primary malignant bone tumours diagnosed in the first two decades of life. The incidence of osteosarcoma is 200/year in the UK, but is higher in children and young adults. On introduction of multimodal chemotherapy for the treatment of osteosarcoma, patients’ average 5 year survival rate increased from 20% to 70% but there has been little improvement since. Also, despite this improvement in survival it is not possible to predict which patients are likely to respond to therapy. Knowledge of the molecular biological characteristics of osteosarcoma may resolve this problem and help in selecting patients for targeted therapy.
LKB1 is a serine/threonine kinase and a tumour suppressor gene that is frequently lost in some cancer types. However, its role in the pathogenesis of human OS pathogenesis is unknown although it has been reported that mice deficient in one LKB1 allele (LKB1+/-) develop osteoblastic tumours. We therefore investigated the role of this gene in the pathogenesis of osteosarcoma.
We showed that 85% (17/20) of osteosarcomas have a low or undetectable protein expression level as assessed by western blotting (WB), and 59% (153/259) by immunohistochemistry. However, no cases showed LKB1 copy number loss when analyzed by fluoresence in situ hybridisation, and none of the previously reported somatic mutations in this gene was detected in 21 tumours. Since no significant differences were detected in the mRNA level by q-RT-PCR in these cases it is postulated that the low level of LKB1 protein is regulated by a post-transcriptional mechanism.
Recently has been shown that SIRT1 protein antagonizes LKB1-dependent AMPK activation through promoting the acetylation, ubiquitination and proteasome-mediated degradation of LKB1. SIRT1 is a class III deacetylase and is implicated in a wide range of cellular functions. We hypothesised that SIRT1 regulates LKB1 degradation. We first demonstrated an inverse correlation between LKB1 and SIRT1 in OS cell lines by WB, and in OS tumours by double immunofluoresence. Using the proteosome inhibitor (PS-341), we showed protection of LKB1 from degradation. We also showed prevention of LKB1 degradation by applying the SIRT1 inhibitor (sirtinol) or SIRT1 suppressor (morpholinos) in OS cell lines, SaOS2, U2OS and MNNG/ HOS.
In conclusion, absence of LKB1 protein expression is a common event in human osteosarcomas; the mechanism appears to be a post-transcriptional event and our findings implicate a role for SIRT1 in LKB1 regulation through degradation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1020. doi:10.1158/1538-7445.AM2011-1020
Abstract 1029: Identification of novel MEK1 inhibitors by computer docking and virtual screening
Authors: Kim Dong Joon , Reddy Srinivasa , Li Yan , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
The mitogen-activated protein kinase kinase 1 (MEK1) signaling pathway is a major component of the RAS/RAF/MEK/ERK signaling axis that regulates tumorigenesis and cancer cell proliferation. MEK1 is frequently activated in various cancers, especially in tumors that have mutations in the KRAS and BRAF oncogenes. Therefore MEK1 is an important cancer therapy target and the discovery of novel MEK1 inhibitors is of great interest. We used the MEK1 protein crystal structure and supercomputer screening of chemical libraries combined with simulation modeling and in vitro, ex vivo and in vivo assays to identify novel inhibitors of MEK1. Herein, we report the discovery of threee novel MEK1 inhibitors, herein referred to as Compound #7, #9 and #12. All three were highly effective to suppress MEK1 activity in HCT116 and HCT15 colorectal cancer cells. Based on in vitro and ex vivo data, these compounds inhibited MEK1 activity and phosphorylation of ERK1/2 in a dose-dependent manner and were twice as effective than the known MEK1 inhibitor, U0126. The compounds completely inhibited anchorage-independent cell growth and proliferation of colon cancer cells. Overall these results suggest that these novel MEK1 inhibitors might be used for chemotherapy; and computer modeling and simulation could be very useful for finding additional MEK1 or other inhibitors for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1029. doi:10.1158/1538-7445.AM2011-1029
Abstract 1045: Src-mediated Tyr20 phosphorylation of transferrin receptor 1 (TfR1) promotes its anti-apoptotic effect: A novel function of TfR1 in cancer cells
Authors: Huang Xi , Jian Jinlong , Yang Qing 
Published: June 2012

Abstract
Transferrin receptor 1 (TfR1) is highly expressed in cancer cells and its overexpression is widely thought to be a result of the increased requirement of iron uptake for cell growth. In the present study, we have found that two ligands of TfR1, gambogic acid (GA) but not holo-transferrin (Tf) induced apoptosis in breast cancer MDA-MB-231 cells and activated the JNK and p38 signal pathways. Furthermore, PP2, an inhibitor of steroid receptor coactivator (Src), a tyrosine kinase, greatly promoted GA-mediated apoptosis. These results indicate that Src is involved in GA-mediated TfR1-dependent apoptotic pathway. Following immunoprecipitation of TfR1 and immunoblotting of Src or verse versa, TfR1 was found to be associated with Src. This association was further illustrated by their co-localization with confocal fluorescence microscope and shown resulting in constitutive tyrosine phosphorylations of the TfR1. A type II membrane receptor, TfR1 contains a short intracellular N-terminal domain with 61 amino acids. 20YTRF23, the only Tyr(Y) site within the cytoplasmic domain, has been shown as the motif essential for TfR1-Tf complex internalization. To elucidate which Tyr is phosphorylated, we used a Chinese hamster ovary (CHO)-TRVb cell line that does not express TfR1. Point mutation Y20L showed that Tyr20 of TfR1 was the phosphorylation site by Src. Further treatments of wild type and point mutant revealed that it is the Tyr20 phosphorylation that enhanced the anti-apoptotic effects of TfR1 against GA. Our results indicate that in addition to the known function of iron transport, TfR1 has a novel function of regulating cell survival and antiapoptosis through its Tyr20 phosphorylation by Src. This new function is particularly significant and relevant to cancer cells since high expression of TfR1 not only fulfills the requirement of more iron as a co-factor in DNA synthesis but also enhances their survival. This work is supported by R21 CA132684.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1045. doi:10.1158/1538-7445.AM2011-1045