bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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
Abstract 196: A real-time PCR based long noncoding RNA profiler for cancer research
Authors: Wu Fangting , Mo Yin-Yuan
Published: August 2012

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides, which are abundantly expressed in human and mouse. A recent study indicates that there are at least 16,000 ncRNAs among which over 3,000 are lncRNAs. In particular, accumulating evidence suggests that dysregulation of lncRNAs is associated with many types of human diseases, highlighting their potential as biomarkers and therapeutic targets. However, studies on lncRNA are still at a very early stage and our understanding of lncRNA function is very limited. Thus, investigation of the expression patterns of lncRNAs is a crucial step to understanding of their roles in normal physiological process as well as disease conditions such as cancer. To this end, we developed a qPCR based disease-related human lncRNA profiler, which allows for the quantification of differential expression of 83 individual lncRNAs among various experimental RNA samples. All 83 lncRNAs chosen for the array are based on publications and the majority of them are associated with cancer. To determine the utility of this lncRNA profiler, we profiled their expression in breast cancer specimens compared to matched normal tissue and identified several lncRNAs are dysregulated, suggesting that lncRNAs may function as oncogenes or tumor suppressors. In addition to those that have already been reported in the literature, we also identified dysregulation of a few lncRNAs not yet in the literature. Furthermore, gene expression profiling with this lncRNA profiler in a series of breast cell lines such as MCF10A, MCF7 and MDA-MB-231 cells identified differential expression patterns unique to each cell line, which may provide a basis for future analysis of these differentially expressed lncRNAs. Finally, we identified several lncRNAs that are induced by p53 in HCT-116 and MCF-7 cells. Experiments are underway to further characterize these p53 inducible lncRNAs. Together, these results suggest that this lncRNA profiler is a valuable research tool for cancer research. The features of this profiler are easy, convenient, sensitive and specific. Accordingly, it serves the first step toward the understanding of the role of lncRNAs in cancer.

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 196. doi:1538-7445.AM2012-196
Abstract 1960: Nanosponges as suitable platforms for targeted chemotherapy
Authors: Harth Eva M. , Hariri Ghazal , Stevens David M. , Spears Benjamin R.
Published: August 2012

We will report on the treatment efficacy of a degradable nanosponge drug delivery system. Degradable targeted nanosponges have been developed that are tailored in size and cross-linking density as supramolecular 3-D nano-networks. The organic polyester backbone can be functionalized in convenient ‘click’ chemistries with targeting peptides, dyes and cell penetrating units with particles that are fully soluble in organic solvents but retain their cross-linked architecture like a macromolecule. Furthermore, we found that the tailoring of the cross-linking density of the particles are correlated to the degradation and release properties of the particles to govern a fast, medium and slow linear release of the encapsulated drugs. Drugs can be encapsulated after the nanoparticle is formed and specifically hydrophobic drugs, for example chemotherapeutics, can be encapsulated with high efficiencies. The encapsulation into particle was found to be advantageous towards the solubility of the drug itself and resulted in vivo studies that showed a 3-5 time higher efficacy of the drug in targeted tumor regression studies. Similar efficacies are observed in glioma and lung cancer. We will report on novel combination therapies and efforts towards the delivery of a broad range of therapeutics in non-small lung cancer.

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 1960. doi:1538-7445.AM2012-1960
Abstract 1977: Higher doses of BAMLET may be required to induce cell death in HPV16-infected cancer cells
Authors: Barman Provaboti , Azambuja Katherine Marie De , Toyama Joy A. , Chua Kristofer Magat , Elashoff David , Wiley Dorothy
Published: August 2012

Introduction: Recent experiments showed that BAMLET (Bovine Alpha lactalbumin Made LEthal to Tumor cells), biochemically equivalent to HAMLET, administered at doses shown to induce volume reduction and clearance of cutaneous wart in humans was insufficient to clear DMBA-induced skin papillomas in C57/Bl6 mice expressing HPV16 E7 transgene on a K14 promoter. Gustufsson et al., reported >75% subjects and 96% of warts reduced lesion volume when 0.7 mM HAMLET solution was topically administered. Thus, BAMLET's limited effect on papilloma reduction led to an in vitro dose-response experiment evaluating exponentially increasing doses of BAMLET on HPV16-infected CaSki cells, a well described cancer cell line. Five doses were selected versus normal saline controls and the cell viability was evaluated at 4, 24 and 72 hours using trypan blue exclusion assay. Methods: Caski cells were cultured in 6-well plates, 2 x 105 cells/well were initialized and allowed to grow to confluence. The initiating dose was based on published data as the exposure dose for our initial mouse studies. Exponential extrapolations of the baseline dose were evaluated: BAMLET administered at 0, 17.5µM (1.0-fold), 31.1µM (1.8-fold), 55.3µM (3.2-fold), 98.4µM (5.6-fold) and 175.0µM (10-fold) at time 0 and allowed to grow. At 4, 24, and 72 hours, cells were typsinized, pelleted, and resuspended in 1 ml PBS. A 10µL aliquot of Trypan-blue (0.4% v/v) was mixed with 10 µL of resuspended cells and incubated for 3 minutes. Duplicate specimens were evaluated under microscopy (10X) using a hemocytometer. Viable (white) and non-viable (blue) cells were counted and the average prevalence of viable cells was estimated for each dose. Results: For 0, 17.5µM, 31.1µM and 55.3µM doses, viability at 4, 24, and 72 hours were closely approximated: 74-92%, 81-91% and 67-88%, respectively. However, at 98.4µM and 175.0µM doses, a significant reduction in viability was observed in a time-dependent manner. Specifically, 95% vs. 91%, 68% vs. 0% and 6% vs. 2% viability were each observed at 4, 24 and 72 hours for these doses, respectively. Conclusions: These data suggest that the sensitivity of HPV16 infected cells to BAMLET may differ significantly from low-risk viruses that often cause cutaneous warts. While these data sheds light on the ineffectiveness of BAMLET in our ongoing animal experiment, they should be similarly considered in trials of BAMLET in humans where more pathogenic HPVs are the causal agent.

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 1977. doi:1538-7445.AM2012-1977
Abstract 1979: Sweet wormwood-derived artesunate causes cell cycle arrest in ovarian cancer cell lines
Authors: Greenshields Anna , Hoskin David
Published: August 2012

Introduction: Artesunate is a semi-synthetic derivative of artemisinin, a natural compound from the herb sweet wormwood (Artemisia annua L). Artemisinin has been used for centuries in traditional Chinese medicine while artesunate has recently been used as an anti-malarial drug. Artesunate is also cytotoxic to human cancer cells. Since the use of artesunate as an anti-malarial agent is associated with few adverse effects, artesunate may represent a less toxic alternative to conventional chemotherapy. This study investigates the effects of artesunate on ovarian cancer cell lines and the mechanism(s) underlying its activity. Methods and Results: Artesunate had a time- and dose-dependent growth inhibitory effect on all ovarian carcinoma cell lines examined (SKOV3, OVCAR3, IG-OV-1, HEY) using an MTT assay. Further examination of artesunate-treated SKOV3 and HEY cells using Oregon Green-488 and Annexin-V-FLUOS/propidium iodide staining indicated that artesunate had a strong anti-proliferative effect but was not cytotoxic towards the ovarian cancer cells. Cell cycle arrest occurred in the G1 and G2 phases of the cell cycle, and western blot analysis showed artesunate-induced changes in the expression and phosphorylation of a range of cell cycle proteins including the retinoblastoma protein, p21, and cyclin B1. Pretreatment with holotransferrin increased artesunate's anti-proliferative activity. Conclusions: These data show that artesunate possess a strong anti-proliferative activity in ovarian cancer cell cultures and therefore warrants further investigation as a possible treatment for ovarian cancer. Research supported by NSERC.

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 1979. doi:1538-7445.AM2012-1979
Abstract 1982: Turmeric oil inhibits hepatocellular carcinoma through abolishing EpCAM expression
Authors: Li Yan , Dunki-Jacobs Erik , Li Suping , Martin Robert C.G
Published: August 2012

Background: In previous study, we found that turmeric oil, a volatile oil from turmeric, can prevent hepatocellular carcinoma (HCC) in an orthotopic HCC mouse model. Epithelial cell adhesion molecule (EpCAM), a marker of cancer stem cells (CSC), is correlated with HCC initiation, progression, and prognosis. Our resent data showed that turmeric oil can decrease EpCAM expression in esophageal cancer and HCC cell lines. Since the role of EpCAM in HCC carcinogenesis is becoming clarified, it is likely that turmeric oil prevents HCC through EpCAM signaling. Aim: To investigate the mechanism of turmeric oil for HCC prevention. Method: EpCAM expression in the specimens from HCC patients (n=25) was evaluated by immunohistochemical staining. Red fluorescent protein (RFP)-labeled H4IIE cells were inoculated into liver lobe of ACI rats. The rat HCC tumor tissues from RFP-H4IIE cell inoculation were evaluated for the subpopulation cells, which co-expressed RFP and EpCAM. The HCC rats by H4IIE cell inoculation were treated with turmeric oil (100mg/kg, i.p, every 2 days) for 2 weeks. The H4IIE cells treated with turmeric oil as well as with EpCAM siRNA, and then inoculated at 106 into the right flank of nude BALB/c mice for 1 week. Three HCC cell lines from human (HepG-2), mouse (hepal-6), and rat (H4IIE) cells, were treated with turmeric oil to evaluate the cell viability EpCAM expression, and β-catenin in vitro. Results: In human samples, a strong EpCAM expression was found HCC tissues, while EpCAM was barely detected in the healthy controls. In HCC animal models, RFP+ EpCAM+ cells were detected in the formed tumor tissue and in circulation. The incidence of HCC by H4IIE cells inoculation was significantly decreased in rats treated with turmeric oil. Abolishing of EpCAM by turmeric oil caused the H4IIE cells unable to form tumor in nude mice. In cell culture study, turmeric oil significantly decreased EpCAM expression in all three HCC cell lines. Turmeric oil caused relocalization of β-catenin, a component in Wnt/β-catenin pathway, in nuclear and cytosol (Figure 1). Conclusion: 1) EpCAM-positive HCC cells contribute to HCC initiation in animal models; 2) The inhibition of HCC by turmeric oil is through decreasing EpCAM expression; 3). The regulation of EpCAM expression by turmeric oil is associated with Wnt/β-catenin pathway.

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 1982. doi:1538-7445.AM2012-1982
Abstract 1983: Thymoquinone induces cell killing in glioblastoma cells through generation of DNA damage and cell cycle arrest
Authors: Racoma Ira O. , Snapka Robert M. , Wani Altaf A.
Published: August 2012

Glioblastoma (GBM) is the most aggressive and common type of brain tumor in humans. Surgical resection followed by radiation and chemotherapy is the current standard treatment; however, due to the upregulation of several survival pathways, tumor recurrence is quite common with a median survival of 12 to 15 months. Therefore, there is an urgent need for more effective therapeutic strategies for the treatment of glioblastoma. Naturally occurring phytochemicals have steadily received much scientific attention, owing to the fact that many of these compounds have potent action against tumors. Thymoquinone (TQ) is the bioactive compound of the volatile oil extracted from the black seed, Nigella sativa. TQ has shown anti-oxidant, anti-inflammatory and anti-neoplastic actions with a selective cytotoxicity for human cancer cells compared to several normal cells. Here, we show that TQ is able to dose-dependently inhibit colony formation in three distinct glioblastoma cell lines (T98, U87 and Gli36), with the highly tumorigenic Gli36 being the most sensitive to the anti-proliferative effects of TQ. We also show that TQ induces persistent γ-H2AX activation, a marker of DNA double strand breaks, in a time- and dose-dependent manner. TQ also causes G2/M cell cycle arrest in GBM cells to a degree that correlates with the cells’ relative clonogenic sensitivity. Moreover, co-treatment with TQ and N-acetyl cysteine, a simple thiol nucleophile and antioxidant, prevented cell death, DNA double strand breaks, and cell cycle arrest. Taken together, our findings demonstrate that TQ is a potent inhibitor of GBM cell proliferation and growth, and that this effect may be mediated by generation of reactive oxygen species.

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 1983. doi:1538-7445.AM2012-1983
Abstract 1986: GBM cell migration and proliferation is inhibited by crude Rosa canina plant extracts
Authors: Idassi Ombeni , Cagle Patrice , Goktepe Ipek , Martin Patrick M.
Published: August 2012

Glioblastoma multiforme (GBM) are aggressive and malignant tumors that develop in the brain. These tumors are characterized by increased rates of proliferation and invasive migration as well as angiogenesis. To date few therapeutic options exist for the treatment and management of GBMs, therefore we decided to investigate the anti-oncogenic properties of extracts from the rosehip plant. Rosehip extracts have been used for centuries as alternative therapies. Currently, rosehip extracts are being used as over the counter supplements and recent studies demonstrate that it has an anti-tumor effect. Therefore, we tested the anti-migratory and antiproliferative capacity of extracts from the rosehip (Rosa canina) plant in GBM cell lines. Three human GBM cell lines, U-251 MG, U-1242MG and A-172, were treated with rosehip extracts (1 mg/mL - 25ng/mL) and demonstrated a decrease in cell proliferation. The rosehip extract-mediated decrease in cell proliferation was equal to the decrease of cell proliferation observed when U0126 (10µM), a know inhibitor of GBM cell proliferation was utilized. Utilizing a fluorescent-based labeling strategy (Live-Dead Assay), we examined whether rosehip extracts prevented cell proliferation by initiating apoptosis. Pretreatment of the GBM cells with rosehip extracts (1 mg/mL - 25ng/mL) induced the inhibition of cell proliferation without promoting apoptosis; whereas, cells treated with staurosporine (1 µM), a known inducer of apoptosis, showed an increase in cell apoptosis. Additional studies demonstrated that rosehip extracts prevent GBM cell proliferation by decreasing the active state of MAPK and AKT. Furthermore, rosehip extract-treated GBM cells also prevent cell migration by regulating actin remodeling. Taken together, these data suggest that rosehip extracts inhibit cell proliferation via a cytostatic mechanism that does not by induce apoptosis while also serving as a migration inhibiting agent. These data suggest that, rosehip extracts may serve as an alternative, or supplement, to current therapeutic regimens for GBMs.

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 1986. doi:1538-7445.AM2012-1986
Abstract 1997: Resveratrol modifies the activity and expression of antioxidant enzymes in somatic cancer cells
Authors: Khan Md. Asaduzzaman , Chen Han-chun , Wan Xin-xing , Xu Ai-hua , Zhang Dian-zheng
Published: August 2012

Background & Objectives: Resveratrol has been reported as a potent anti-cancer compound, but it's mode of action is not completely understood. In this study, we investigated the effects of resveratrol treatment on the activity and expression of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) in three somatic cancer cell lines: PC-3 (prostate cancer), MCF-7 (breast cancer) and HepG2 (hepatocellular cancer). Methods: The cells were treated with different concentration (0-200 μM) of resveratrol for 24, 48 and 72 hours.Cell growth was studied by cell counting; cell homogenate was taken for the measurement of enzyme activities; proteins were isolated for western blotting to measure the genetic expression. Results: Resveratrol showed dose-dependent growth inhibitory activity in all cells. It was significantly effective against PC-3 and HepG2 even in 10 μM, and 25 μM concentration, but not in MCF-7 cells. However 50 μM showed significant growth inhibitory effect in MCF-7, and also in HEK293T (human embryonic kidney cell line as control) cells. 25 μM was identified as most effective dosage against PC-3 and HepG2 cells, without affecting HEK293T cells. Treatment of 25 μM for 48 hours increased the activity of SOD enzymes by 3-4 folds in PC-3; 2-3 folds in HepG2; 1.5-1.8 folds in MCF-7; and 1.2-1.5 folds in HEK293T cells. Resveratrol treatment also significantly increased the activity of CAT in HepG2, moderately in MCF-7, but non-significantly in PC-3 and HEK293T cells. However, the treatment of resveratrol showed no significant change in GPX activity in any cell line. Western blotting also revealed the increased expression of SOD2 in PC-3, and HepG2 cells at 25 μM resveratrol treatment. CAT expression was moderate, but no change in GPX1 expression was found in the tested cancer cells. Conclusions: The results of this study could confirm the dose dependent growth inhibitory potential of resveratrol; however, the dose of resveratrol in treatment of the cancer cells should be limited, as higher dose (Δ50 μM) has also been found dangerous for normal cells (HEK293T). Resveratrol at low dose (25 μM) potentially increases the activity and expression of SOD enzyme in cancer cells while inhibiting cell growth. Moderate increase of CAT activity and expression is also observed, but no significant change in GPX activity and expression in cell lines used in this study. These findings may contribute to understanding the mechanisms of resveratrol action in treatment of cancer. The work was supported by the National Basic Research Program of China (No. 2011CB910700-704)

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 1997. doi:1538-7445.AM2012-1997
Abstract 2001: Caffeic acid phenethyl ester inhibits growth of human lung adenocarcinoma cells with an epidermal growth factor receptor T790M mutation susceptible property
Authors: Huang Wen-Chien
Published: August 2012

Purpose: Target therapeutics targeting epidermal growth factor receptor (EGFR) effectively kills non-small cell lung cancer cells along with a high proportion acquires T790M mutation of EGFR, an amino acid alteration likely causing drug resistance. Caffeic acid phenethyl ester (CAPE), a naturally occurring small molecule isolated from honeybee propolis, is known to possess preferential bioactivity against lung cancer cells. Materials and Methods: In this study, we evaluated the effect of CAPE on A549 (EGFR wild-type) and H1975 (EGFR T790M mutation) human lung adenocarcinoma cells by using assays as follows: MTS for viability, DNA histogram for hypoploidy and cell cycle analysis, DiOC6(3) staining for mitochondrial transmembrane potential, and Western blotting for caspase-3 cleavage Results: We found that CAPE inhibited the growth of lung adenocarcinoma H1975 cells with an extent greater than A549 (IC50 approximate 5 versus 10 mg/mL) after 24 - 48 h treatment. This differential growth inhibition was accompanied by much higher percentages of sub-G1 (7.5 folds) and G2/M arrest (2.6 folds) in H1975 cells. No significant difference could be seen for changes in mitochondrial transmembrane potential and caspase-3 cleavage, indicating a mitochondria-independent and caspase-3-inependent pathway involved. Conclusion: It suggests that CAPE may have potential to be developed as a small-molecule therapeutics against lung adenocarcinoma cells harboring wild-type epidermal growth factor receptor and, more effectively, the T790M-mutated clone.

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 2001. doi:1538-7445.AM2012-2001
Abstract 2021: ONO-WG-307, a novel, potent and selective inhibitor of Bruton's tyrosine kinase (Btk), results in sustained inhibition of the ERK, AKT and PKD signaling pathways
Authors: Yasuhiro Tomoko , Yoshizawa Toshio , Daub Henrik , Weber Christoph , Narita Masami , Kawabata Kazuhito
Published: August 2012

Purpose: Btk is a key regulator of B cell receptors (BCR) which play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BCR signaling is implicated in the survival of malignant B cells and recent studies indicate that targeting Btk may be effective in the treatment of B-cell lymphoma. Response between cell survival and BCR signaling is implicated in different types of B-cell lymphoma. Therefore, we evaluated the inhibitory effect of ONO-WG-307 on Btk-dependent signal transduction by large-scale and quantitative phosphoproteome analysis to a depth of more than 10,000 phosphorylation sites. Methods: Two tumor cell lines (sensitive and non-sensitive) were treated with ONO-WG-307. After 72h, cell viability was determined by the CellTiter-Glo Luminescent Cell Viability Assay. P-Btk was used as a marker for Btk activity determined by Western blot and Flow Cytometry. Quantitative phosphoproteomics were enabled by differential SILAC labeling of lymphoma cells. After 1 hr incubation with ONO-WG-307, the total cellular proteins were digested and phosphopeptides were enriched by a combination of strong cation exchange and immobilized metal affinity chromatography. Site-specific phosphorylations were identified and by LC-MS analysis on a LTQ-Orbitrap-Velos mass spectrometer followed by bioinformatic processing. Results: Btk is potently and selectively inhibited by ONO-WG-307 in an in vitro Btk kinase assay, with an IC50 in the subnanomolar range whereas IC50 values for other tyrosine kinases (Lck, Lyn and Fyn) were above 1 µM. The concentration required for growth inhibition for the sensitive cells was 3.59 nmol/L (IC50), whereas considerably higher concentrations were required to suppress growth of non-sensitive cells. Surprisingly, inhibition of cellular Btk and ERK phosphorylation by ONO-WG-307 levels of P-Btk and P-ERK were similar in both sensitive and non-sensitive cells. However, our quantitative phosphoproteome studies revealed selective suppression of Akt-mediated signaling and cellular protein kinase D activity in sensitive compared to non-sensitive cells.Conclusion: These results suggest that the selective ONO-WG-307 inhibition of “responder” cell growth might be due to a critical role of Btk-mediated signaling through Akt and protein kinase D. These data shed new light on the cellular mode-of-action of Btk inhibition and support the potential clinical utility of ONO-WG-307 in B cell malignancies.

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 2021. doi:1538-7445.AM2012-2021
Abstract 2101: Differential mtDNA sequence variants in primary tissues of colorectal adeno-polyps
Authors: Adams Gregory , Mehrabi Sharifeh , Vatcharapijarn Yupha , Akwe Joyce A. , Yao Xuebiao , Aikhionbare Felix O.
Published: August 2012

Introduction: Increasing evidence suggest that mitochondrial alterations involved in cellular signal pathways have been associated with tumorigenesis. Differentially diagnosing progressive stages of colorectal adenomatous polyps is important for therapeutic intervention and surveillance. We hypothesized that Mitochondrial DNA (mtDNA) variants in colorectal adenomatous polyps are stage-specific genetic changes. We aimed to identify the genetic mtDNA mutations present in the early stages of colorectal cancer. Methods: MtDNA sequence variants among the different types of colorectal adenomatous polyps: Tubular, Tubulovillous and Villous adenomatous were analyzed from sixty-four tissue samples (33 tumor 31 matched surrounding normal tissue (NST)) with patients mean age 57.1±7. Two mtDNA regions were screened from each sample with two primer pairs spanning 8282-to-10107 and 11673-to-13950bp comprised of the MT-NC7, MT-TK, MT-ND3, ATPase 6, ATPase 8, COX III, ND3, ND4L, ND4 and ND5 genes. The presence of polymorphisms and other sequence variants of mtDNA were also evaluated using the high-resolution restriction endonucleases and PCR based sequencing. Results: Forty-two variants were observed of which 18 of 42 (42%) were not previously reported in the MITODAT reference database. The distribution of observed mutations included, 31% (13/42) Tubular, 52% (22/42) Tubulovillous, 45% (19/42) Villous, 45% (19/42) colorectal cancer (including FAP and JVP). Notably, unreported germline variant, G8573A, in the ATPase 8 gene region was found in 100% tubulovillous adenomas, but not any other samples. A heteroplasmic variant A11873G, in the MTND4 gene was detected in 67% tubular, 78% tubulovillous, 71% villous and 38% cancer subtypes. Given that mutations in ATPase 8 genes inhibits the production of ATP from ADP, and mutations in MTND4 genes prevent the normal interactions of complex I with ubiquinone, affecting the generation of ATP, these observed variants may influence the early stages of colorectal tumor. Conclusion: Therefore, our findings suggest that certain mtDNA sequence variants may contribute as a framework for further differentiation studies of stages of colorectal adeno-polyps.

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 2101. doi:1538-7445.AM2012-2101
Abstract 2142: Dietary grape polyphenol resveratrol regulates Rac activity to increase mammary tumor growth and metastasis
Authors: Castillo-Pichardo Linette , Cubano Luis A. , Dharmawardhane Suranganie
Published: August 2012

Resveratrol is a natural compound from grapes and peanuts that is structurally similar to estrogen and can act as an estrogenic or antiestrogenic compound, depending on the concentration. In vitro, high concentrations of resveratrol can have proapoptotic, antigrowth, anti-inflammmatory, antiangiogenic, and anti-invasive properties in cancer cells. However, we reported that resveratrol at low, physiologically relevant, concentrations acts similar to estrogen and promotes breast cancer cell migration via actin cytoskeletal changes regulated by Rac; a small GTPase that plays a pivotal role in cancer cell migration/invasion, and thus, metastasis. Herein, we investigated the effects of dietary resveratrol on mammary tumor growth and metastasis in immunocompromised mouse models of cancer metastasis. Interestingly, our findings suggest promotion of mammary tumor growth and metastasis to lung, liver, and kidney by resveratrol in tumors derived from the low metastatic estrogen receptor (ER)α(−), ERα(+) MDA-MB-231 and the highly metastatic ER(-) MDA-MB-435 cancer cell lines. To determine the role of Rac in resveratrol-mediated mammary tumor progression, the activity of Rac was measured in tumors from resveratrol-treated mice. Our results show a significant increase in tumoral Rac activity, consistent with the concentration of resveratrol that induced the highest metastatic efficiency. Taken together, our findings demonstrate a cancer-promoting role for dietary concentrations of resveratrol in metastatic cancer via Rac activation. Therefore, this study illuminates the importance of further delineating resveratrol's concentration dependent molecular mechanisms, particularly in breast cancer, before it can be tested in the clinic or used as a dietary supplement for cancer patients. This study was supported by DoD/BCRP W81XWH-08-1-0258 to LCP, DoD/BCRP W81XWH-07-1-0330 to SD, the UCC Pilot Project Program, and the UCC Postdoctoral Program sponsored by the PR Science, Technology and Research Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Universidad Central del Caribe or the PR Science, Technology and Research Trust.

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 2142. doi:1538-7445.AM2012-2142
Abstract 2259: Oncolytic attenuated measles virus exploits autophagy for its replication and spreads by suppressing Rig-1 like receptors (RLRs) in non-small cell lung cancer cells
Authors: Xia Mao , Gonzalez Patrick , Li Chunyan , Meng Gang , Wang Hongwei , Luehl Nike , Beltinger Christian , Wei Jiwu
Published: August 2012

Both autophagy and RLRs are involved in response to microbial infection, including oncolytic attenuated measles viruses, which are being tested in several clinical trials in advanced cancer patients. As little is known about the role of autophagy in measles virus infection and oncolytic activity as well as the crosstalk with RLRs, these mechanisms require further investigation. In this study, we show for the first time that measles virus of the Edmonston strain (MV-Edm) exploits autophagy for its replication and spreads by suppressing RLRs in non-small cell lung cancer cells (NSCLCs). MV-Edm rapidly induced autophagosomes formation in NSCLCs. Inhibition of autophagy by RNAi led to a hampered viral replication/spread accompanied by robustly increased production of type-I interferons. Conversely, overexpression of autophagic genes massively reduced production of type-I interferons and enhanced viral replication. Expression of RIG-I and MDA5 was enhanced in MV-Edm infected NSCLCs and massively increased when autophagy was concomitantly inhibited, suggesting that virus-induced autophagy participated in modulating RLR-mediated anti-viral response. As enhancing viral replication and spread within tumors could improve oncolytic efficiency, our work may lead to improve clinical therapeutic efficacy of oncolytic MV-Edm when combined with autophagy inducers.

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 2259. doi:1538-7445.AM2012-2259