bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1895: The role of autophagy and Atg3 in erlotinib-resistant lung cancer and synergistic cell death with combination of erlotinib and cisplatin
Authors: Lee Jasmine G. , Wu Reen 
Published: August 2012

Abstract
Objective: Erlotinib is a mainstay anti-cancer agent for non-small-cell lung cancer (NSCLC) but resistance to erlotinib is a major problem, clinically. The combination of cisplatin and erlotinib has been suggested to inhibit tumor growth more effectively than a single drug alone in sensitive NSCLC. However, the mechanism underlying this finding remains unclear. The specific role of autophagy in cancer and chemotherapy resistance continues to be unclear (promotion vs. prevention of cancer). In this study, we investigate whether combination low dose erlotinib and cisplatin is effective against erlotinib resistant NSCLC and examined the role of autophagy in erlotinib resistance. Methods: PC9, a NSCLC cell line, was used to develop erlotinib resistant PC9 cells (PC9ER). Cell survival was quantified with Alamar blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA) transfection was used to block translation of protein of interest. Results: Combination low dose erlotinib and cisplatin resulted in synergistic cell death in PC9ER cells (p&lt;0.0001) and a significant decrease in autophagy (p=0.011). At baseline, there was a significantly higher level of LC3II in PC9ER cells compared to sensitive PC9 (p=0.030) suggesting autophagy may play a role in resistance. Rapamycin significantly increased ER (p=0.0004) and 3-MA significantly sensitized PC9ER cells to treatment (p=0.037). Upon examination of autophagy regulatory proteins between PC9ER and PC9 cells, there was significantly lower levels in p-mTOR (p=0.021) and higher levels of Atg3 in PC9ER at baseline (p=0.018). Among the four treatment groups (control, erlotinib-alone, cisplatin-alone, and erlotinib-cisplatin combination), there was a specific decrease in Atg3 with combination treatment (p=0.005). siRNA transfection of Atg3 resulted in the reversal of ER: 42% more cell death with erlotinib-alone (p&lt;0.0001), 18% more cell death (p=0.002) in cisplatin treatment, and 9% more cell death in erlotinib-cisplatin combination (p=0.047) compared to the counterpart treatment groups without siRNA transfection. Conclusions: Our data may suggest that autophagy may promote cancer survival and ER in NSCLC, specifically by up regulation of Atg3 and targeting of Atg3 may be the key to re-sensitizing erlotinib resistant cancers. In addition, it seems erlotinib-cisplatin combination is an effective therapy by down modulation of autophagy by targeting Atg3. Future pharmacologic therapies specifically targeting Atg3 in complement to erlotinib therapy may be effective in preventing and treating ER.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1895. doi:1538-7445.AM2012-1895
Abstract 191: Subclassification of oral cancers using a miRNA-based combinatorial approach
Authors: Jung Hyun Min , Patel Rushi S. , Cohen Donald M. , Jakymiw Andrew , Kong William W. , Cheng Jin Q. , Chan Edward KL 
Published: August 2012

Abstract
The majority of gene expression profiling studies in cancer research is based on comparison of normal against cancerous tissues. Although these comparisons identify general mechanisms underlying certain cancer types, the heterogeneity of tumors contributes to challenges in the interpretation of results. In this study, Agilent human miRNA microarrays were used to analyze 3 normal tongue tissues and 17 oral squamous cell carcinomas (OSCC) extracted from tongue tumors to identify deregulated miRNAs. Our results showed that miRNA expression pattern provided more precise information when cancers are subcategorized based on clinicopathological parameters. Combinatorial analyses using 4 different parameters (tumor primary site, tumor stage, histological subtype, and human papillomavirus 16 status) revealed OSCC subtypes with specific expressions of selected miRNAs. Nine significantly upregulated miRNAs (miR-424, miR-15b, miR-196a, miR-21, miR-155, miR-9*, miR-9, miR-7-1*, and miR-7) and one downregulated miRNA (miR-486-5p) were applied for this analysis. Our study demonstrated the combine use of several miRNAs with multiple clinicopathological parameters could subcategorize these oral cancers. Kaplan-Meier survival analyses showed that advanced tumor stage (hazard ratio = 3.36; 95% confidence interval, 1.08-10.49; p = 0.037), and/or keratinization status (hazard ratio = 3.34; 95% confidence interval, 1.10-10.12; p = 0.033) are related to poor prognosis of oral cancer patients. Interestingly, all the tumors highly expressing miR-21 were keratinized tumors and the corresponding patients had poor survival rate &lt; 30 months after diagnosis ((hazard ratio = 12.46; 95% confidence interval, 2.57-60.32; p = 0.0017) indicating the prognostic importance of miR-21. The expression of the specific miRNAs (miR-21, miR-424, miR-7, miR-7-1*, and miR-155) overexpressed in the keratinizing tumors was significantly correlated to each other (0.438 &lt; r &lt; 0.615, p &lt; 0.041). In silico target prediction analyses using multiple bioinformatics tools identified candidate genes containing multiple binding sites for these miRNAs. The miRNA signatures are indicators for cancer diagnostics, prognostics, and therapeutics and may lead eventually to individualized clinical treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 191. doi:1538-7445.AM2012-191
Abstract 1918: Anti-metastasis effect of EW-7197, a novel ALK5 inhibitor in both breast cancer cells in vitro and mouse model in vivo
Authors: Kim Seung W. , Kim Sol J. , Park Sang A. , Kim Min J. , Kim Dae-Kee , Sheen Yhun Y. 
Published: August 2012

Abstract
We have synthesized new ALK5 inhibitor, EW-7197 and investigated their effects of on breast cancer cells as well as tumor bearing MMTV/cNeu transgenic mouse, 4T1 or 4T1-Luc cell-orthotopic implanted mouse models. The level of ß-casein or the number of metastatic nodule in the lung of the breast tumor bearing MMTV/cNeu transgenic mice or 4T1 cell-orthotopic implanted mice, respectively, were decreased by EW-7197 treatment. The treatment of the EW-7197 also inhibited the luciferase activity in the lung of 4T1-Luc cell-orthotopic implanted mouse compared to that of untreated animal. The levels of MMP2 and MMP9 were decreased in the lung and breast tumor of the EW-7197 treated mice. To determine the inhibitory effect of EW-7197 on TGF-β1-induced transcriptional activation, we performed luciferase reporter gene assay in breast cancer cells. EW-7197 effectively blocked TGF-β1-induced luciferase activity in the cells in a dose-dependent manner. TGFß signaling, the phosphorylation of smad2/3 was decreased by EW-7197. TGFß-stimulated mesenchymal markers of epithelial mesenchymal transition (EMT) were inhibited by ALK5 inhibitor concomitant treatment. Furthermore, EW-7197 rescued TGF-β-induced loss of E-cadherin in NMuMG cells. And also, EW-7197 showed higher inhibition on cell motility and cell invasion based on wound healing assay or invasion assay than SB-505124 and LY-2157299. In summary, EW-7197 have anti-metastatic effect on breast cancer cells in vitro as well as breast cancer models in vivo. This data strongly argue that the ALK5 inhibitor have anti-metastasis effects via inhibiting ALK5 activity in vivo and in vitro.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1918. doi:1538-7445.AM2012-1918
Abstract 1925: Trifluoromethylated artemisinin dimers demonstrate a potent anti-cancer activity in vitro and in vivo
Authors: Fahy Jacques , Marion Frederic , Lieby-Muller Frederic , Mordant Celine , Vispe Stephane , Brel Viviane , Gomes Bruno , Annereau Jean-Philippe , Chollet Constance , Fournial Anaïs , Crousse Benoit , Bonnet-Delpon Daniele , Kruczynski Anna , Bailly Christian , Guilbaud Nicolas 
Published: August 2012

Abstract
Beside their widely recognised efficacy as antimalaric drugs, artemisinin derivatives are also known for their cytotoxic properties since the early nineties. More recently, artemisinin dimers (ADs) were shown to possess an increased potential as anti-cancer agents due to their ability to inhibit cancer cells proliferation in the low nanomolar range. Taking advantage of an original chemistry, we synthesized a new series of trifluoromethylated artemisnin dimers which proved to be particularly potent depending on the size and nature of the linker. Different mode of linkage were performed by either carbon 16 or carbon 10 and were tested in vitro and in vivo. Best combination was found in a hybrid linking position delivering non-symmetrical C10-C16 ADs. One of the lead compound of this series, F98458 demonstrated a moderate (but statiscally significative) anti-tumor activity in mice against a human melanoma xenograft that is, to our knowledge, the first demonstration of in vivo antitumor properties of ADs in preclinical models. Many efforts to understand the molecular origin of the cytotoxic effect of monomeric artemisinin derivatives have been undertaken. One of the aims of this study was to investigate the mechanism of action of ADs in comparison with artemisinin: the antimalaric drug artesunate, a representative monomeric derivative of artemisinin, is known to induce DNA damage and ROS generation while our ADs did not under the same experimental conditions. Moreover ADs did not induce apoptosis (caspase 3/7, annexin V), leading us to investigate cell death related to senescence and autophagy. We have also synthesized partially reduced ADs possessing only one endoperoxide functionality. These compounds did show the same potency than non reduced ADs, underlaying that a tight molecular recognition is involved in its biological response. All these observations suggest that monomeric artemisinin derivatives such as artesunate and ADs possess distinct modes of action. The high in vitro potency associated with the in vivo response led us to synthesize affinity probes in order to identify the molecular target of ADs which could provide fundamental informations for further developpement of these compounds as anti-cancer agents. This work currently underway will also be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1925. doi:1538-7445.AM2012-1925
Abstract 1943: On-demand reversible boronate-catechol crosslinked nanocarriers for cancer therapy
Authors: Lam Kit S. , Li Yuanpei , Xiao Kai , Xiao Wenwu , Luo Juntao 
Published: August 2012

Abstract
We have previously reported the development of a versatile nanocarrier platform comprised of PEG-cholic acid cluster telodendrimers that can self-assemble together with hydrophobic cytotoxic anti-cancer agents to form stable nanoparticle drugs. We have successfully loaded these nanoparticles with a number of different cancer drugs. These include paclitaxel, doxorubicin, vincristine, vinblastine, actinomycin D, bortezomib, temsirolimus, sarofinib, and lapatinib. Using electron paramagnetic resonance spectroscopy, we have demonstrated that the micelles can be disrupted by LDL and VLDL causing premature drug release. Such undesirable properties can be eliminated by cross-linking the telodendrimers with disulfide bonds. The disulfide crosslinked micelles can be triggered to release drugs by endogenous glutathione inside the cancer cells or via exogenous addition of N-acetyl cysteine, a FDA approved-drug that has been used for years in the treatment of Tylenol overdose. Very recently, we created a novel crosslinking strategy by incorporating boronic acids or catechols into the telodendrimers. The final nanocarriers were crosslinked by boronate-catechol bonds resulting in stable micelles, thus avoiding premature drug release. Inside the endosomal compartment, the boronate-catechol bonds were cleaved by the acidic environment resulting in drug release. An additional very important feature of this nanocarrier is that exogenous mannitol (another FDA-approved drug for diuresis) can be administered in vivo to trigger drug release. Therapeutic studies in ovarian cancer xenograft model indicated that paclitaxel-loaded boronate-catechol crosslinked nanoparticles were much more efficacious when mannitol was given 24 hours after each dose of nanoparticle drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1943. doi:1538-7445.AM2012-1943
Abstract 1948: Tissue accumulation and release of platinum from a novel chitosan-hybrid gel after intraperitoneal drug delivery
Authors: Cho Sungpil , Sun Yongen , Soisson Andrew P. , Dodson Mark K. , Gaffney David K. , Peterson C. Matthew , Janat-Amsbury Margit-M 
Published: August 2012

Abstract
Gynecological malignancies such as cervical, endometrial and ovarian cancer still are the leading causes of death for women worldwide. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have shown limited-efficacy by accessibility as well as nonspecific toxicity. To overcome those limitations, we previously reported about the development of a muco-adhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with alginate beads containing cisplatin (CDDP) for a local, intraperitoneal application (# 3232, AACR 2011). Here we report the results of CDDP release from the (CS(BCDDP)), its cellular activity in vitro and CDDP accumulation to genomic DNA (gDNA) of tissues in vivo. To determine the amount of CDDP released from (CS(BCDDP)) in vitro, we used a colorimetric SnCl2 assay following the incubation in 0.9% NaCl solution for 24 hrs. (CS(BCDDP)) demonstrated successful release of 90% CDDP within 2 hrs and consistent CDDP-release could be maintained for up to 24 hrs. To test activity of CDDP released from (CS(BCDDP)), clonogenic assay was performed with Hela (human cervical adenocarcinoma) cells. Cells treated with (CS(BCDDP)) demonstrated a significantly low number of colonies, generating 9 (± 6) colonies per 500 cells seeded compared with 233 (± 10) colonies per 500 cells treated with an empty, no drug containing control gel (CS). To further assess CDDP accumulation to gDNA of tissues in vivo, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nude mice following treatment with a control gel mixed with CDDP (CSCDDP), (CS(BCDDP)), and intravenously (i.v.) CDDP(CDDPIV). The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from (CS(BCDDP)) when compared to CDDPIV. Moreover, (CS(BCDDP)) also demonstrated higher accumulation of CDDP to gDNA when compared with CSCDDP. Relative values were 3.2 (±0.9) for (CS(BCDDP)) and 1.3 (± 0.4) for CSCDDP compared to values obtained from CDDPIV. Our in vitro and in vivo results, strongly suggest the feasibility of applying this hybrid gel locally to mucosal surfaces of the female reproductive tract and its advantage for intraperitoneal drug accumulation. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in orthotopic endometrial, ovarian and cervical cancer animal models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1948. doi:1538-7445.AM2012-1948
Abstract 1950: LHRH Peptide decorated cross-linked micelles for the targeted drug delivery to breast cancer
Authors: XIAO KAI , Lam Kit 
Published: August 2012

Abstract
We have recently developed a series of micellar nanoparticles (NPs) based on linear polyethylene glycol (PEG) and dendritic cholic acids (CA) block copolymer (telodendrimer), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers. The tumor targeting specificity and efficiency of drug-loaded NPs might be further improved by the decoration of cancer cell surface targeting ligands. LHRH (Luteinizing hormone releasing hormone), a natural hormone peptide, is able to bind specifically to the LHRH receptor, which has been reported to be over-expressed in more than 50% breast cancer patients. In the present study, we incorporated the passive targeting of our micellar NPs and the active targeting of LHRH peptide into a single platform with an attempt to further improve the therapeutic index of NPs delivered drugs in the treatment of breast cancer. We synthesized the LHRH peptide on the tentagel resin bead via the solid-phase peptide synthesis method, and demonstrated that human breast cancer cell lines MDA-MB-231 and MDA-MB-435 were able to bind strongly with LHRH peptide beads. Besides breast cancer cell lines, immunohistochemistry staining further demonstrated LHRH peptide was able to specifically bind to human breast tumor tissue as well as transgenic murine mammary carcinoma tissue, but not to normal breast tissue. Alkyne-containing LHRH peptides were successfully conjugated to the azide group at the distal PEG terminus of PEG5k-Cys4-L8-CA8 telodendrimer (cross-linked micelle forming unit) via the “click chemistry”. LHRH peptide ligand significantly enhanced the intracellular delivery of cross-linked micelles in both MDA-MB-231 and MDA-MB-435 breast cancer cells. In addition, the enhanced uptake of LHRH-targeted micelles in those cells can be inhibited by the addition of access of LHRH antibody, indicating the LHRH receptor-medicated internalization. The co-localization of internalized FITC-labeled LHRH-micelles with lysosomal compartment in human breast cancer cells were also observed, suggesting that the endocytosis pathway is likely to be involved in the internalization process. Furthermore, when loaded with paclitaxel (PTX), LHRH-micelles had significantly higher in vitro cellular toxicities against breast cancer cells as compared with the non-targeted micelles. The in vivo biodistribution, tumor targeting specificity and therapeutic efficacies of LHRH targeted micelles in MDA-MB-231 xenograft mouse model are currently under investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1950. doi:1538-7445.AM2012-1950
Abstract 1954: Synthesis and self-assembly of highly PEGylated dendron-coils: A potential nanocarrier platform
Authors: Pearson Ryan M. , Bae Jin Woo , Patra Niladri , Sunoqrot Suhair , Uddin Sayam , Vukovic Lela , Kral Petr , Hong Seungpyo 
Published: August 2012

Abstract
Dendron-based amphiphilic copolymers possess unique features such as well-defined structure, self-assembling capability, and precise controllability over functionalities and high hydrophilicity. To assess the ability of dendron-based copolymers for use in drug delivery, we have synthesized novel, highly PEGylated dendron-coils (PDC) with controlled hydrophilic-lipophilic ratios (HLs) ranging from 52:48 to 91:9. We then systematically compared their self-assembly properties with those of linear-block copolymer (LBC) counterparts at similar HLs. PDCs were synthesized via a multistep synthetic procedure. A hydroxyl-terminated generation 3 (G3) polyester dendron bearing a focal acetylene moiety was conjugated with poly(α-caprolactone) (PCL) by ‘click’ chemistry followed by PEGylation of the dendron surface with multiple methoxy poly(ethylene glycol) (mPEG) moieties. Four types of both PCL-G3-mPEG PDCs and PCL-mPEG LBCs with different block lengths were prepared and their structures were confirmed using 1H NMR, FT-IR, and GPC. The critical micelle concentration (CMC) of PDCs varied from 6.50 × 10-8 to 3.52 × 10-7 M. The CMC values of the LBCs were up to 2 orders of magnitude higher than those of the PDCs at the same HLs demonstrating superior thermodynamic stability of PDC micelles. TEM images revealed that the PDCs formed spherical micelles with diameters less than 100 nm with narrow size distributions, which was further supported by dynamic light scattering measurements. To understand in molecular detail the differences in self-assembly between PDCs and LBCs we utilized atomistic molecular dynamics (MD) simulations. Individual PDC copolymers were observed to adopt a stable conical shape in water, which is ideal for precise packing into spherical structures. Interestingly, the core was more completely covered by PEG in PDC micelles. The higher PEG surface coverage of PDC micelles may result in longer circulation half-lives due to decreased opsonization and enhanced accumulation at the therapeutic target site. Each micelle formulation was found to exhibit controlled release properties over 3 days using indomethacin as a model drug. PDCs exhibited no apparent toxicity up to concentrations as high as 100 μM evaluated by MTS assay. The low CMC of the PDCs at high HLs, controlled micelle morphologies, controlled release properties, and high PEG surface coverage all indicates their superiority over LBC counterparts. We expect PDCs to play a sizeable role in the future of targeted nanomedicine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1954. doi:1538-7445.AM2012-1954