bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3397: Synergistic activity of the Akt inhibitor perifosine and 5-fluorouracil in 5-FU resistant gastric cancer.
Authors: Hyo Song Kim , Shin You Keun , Zhang Xianglan , Kim Jung Min Kim , Kim Tae Soo , Park Chan Hee , Jang Woo Ick , Engel Juergen , Rha Sun Young Rha 
Published: August 2014

Abstract
Purpose
Akt/PI3K pathway has been known to confer resistance to conventional chemotherapy. Perifosine is a synthetic novel alkylophospholid which inhibits Akt activation. Because 5-fluorouracil (5-FU) is a common cytotoxic agent used in gastric cancer, we evaluated the role of perifosine overcoming 5-FU chemoresistance.
Experimental design
We checked the correlation between pAkt expression and 5-FU sensitivity in 25 gastric cancer cell lines. Cytotoxic effects of 5-FU and perifosine combination were assessed using in vitro assays (cell growth and apoptosis analysis). Whether this synergistic combination of two drugs has significant effect on their downstram targets and on biochemical markers were also tested with western blotting analysis. Tumor inhibition and pAkt expression were measured using xenograft mice treated with perifosine and 5-FU combination.
Results
More 5-FU resistant cell lines demonstrated higher pAkt expression levels (mean 1.35 IU vs 0.49 IU, p=0.019). Among the 14 5-FU resistant cell lines, majority of the cell lines (57.1%) showed synergistic effect with perifosine combination. Perifosine and 5-FU combination caused marked Akt and extracellular signal-regulated kinase (Erk) 1/2 dephosphorylation in synergistic cell line. Moreover, combination results in a substantial induction of apoptosis by JNK pathway activation in synergistic cell line. In vivo model, treatment with tolerated doses of 5-FU derivatives, capecitabine and perifosine resulted in significantly enhanced antitumor efficacy relative to that of either agent alone (P=0.006). Histopathologic analysis of pAkt expression also revealed prominent pAkt reduction in combination groups. In the gene expression profiling analysis, Akt1 and MAPK4K genes were up-regulated in synergistic cell lines implicating those genes as predictive markers for restoring 5-FU resistance in combination treatment.
Conclusions
These results indicate that activated Akt pathway confers 5-FU chemoresistance. In addition, perifosine and 5-FU combination restored those chemoresistance via pAkt, pErk dephosphorylation and JNK activation. Taken together, 5-FU and perifosine combination may be a promising therapeutic strategy to improve patient outcome in gastric cancer patients.
Citation Format: Kim Hyo Song, You Keun Shin, Xianglan Zhang, Jung Min Kim Kim, Tae Soo Kim, Chan Hee Park, Woo Ick Jang, Juergen Engel, Sun Young Rha Rha. Synergistic activity of the Akt inhibitor perifosine and 5-fluorouracil in 5-FU resistant gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3397. doi:10.1158/1538-7445.AM2013-3397
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3403: A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib.
Authors: Tyson Darren R. , Peng Chengwei , Hardeman Keisha N. , Paudel Bishal , Quaranta Vito 
Published: August 2014

Abstract
Patients with melanomas expressing B-RafV600E benefit from treatment with B-Raf-targeted therapeutics, such as vemurafenib. Initial responses to these agents are occasionally profound, but the duration of response is variable from patient to patient, with some tumors recurring within a few weeks and others requiring months before tumors progress. The source of this variability of response is under intense investigation. A number of acquired resistance mechanisms have been described, but it is not known whether they pre-exist or develop after treatment initiation. To address this question, we tracked the cellular response to PLX4720 (the vemurafenib research compound) over 96 hours in the A375 and SK-MEL-5 cell line models of B-RafV600E-expressing melanoma. Both cell lines exhibited a significant early reduction in cell number compared to control, but after 60 hours of treatment cells numbers began to increase even in the presence of 8 μM drug, albeit at a slow rate. This “rebound” proliferation effect was not due to drug decay since re-administration of the drug did not prevent it. We further examined the rebound effect at the single cell level using our newly described Fractional Proliferation assay (Tyson et al., Nat Methods, 2012, 9(9):923-928, doi:10.1038/nmeth.2138). The rebound corresponded to a dividing cell subpopulation whose size and rate of division depend on the concentration of drug. This subpopulation does not represent rare non-responding variants within the cell lines, but rather it arises stochastically as sibling cells do not always exhibit the same phenotypic response. Investigation of the molecular correlates of this dividing subpopulation, which may act as the reservoir from which the resistant cells arise, are ongoing.
Citation Format: Darren R. Tyson, Chengwei Peng, Keisha N. Hardeman, Bishal Paudel, Vito Quaranta. A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3403. doi:10.1158/1538-7445.AM2013-3403
Abstract 3406: Evaluation of (E)-Styrylsulfonyl methylpyridine: A novel kinase inhibitor targeting mitotic pathways.
Authors: Lu Tiangong , Wang Shudong , Laughton Charles , Bradshaw Tracey 
Published: August 2014

Abstract
ON01910.Na, a styryl benzylsulfone, is a Phase III stage, non-ATP competitive anti-cancer agent. It is multi-targeted, promoting selective mitotic arrest and apoptosis in cancer cells. Extensive Phase II/III trials conducted in patients with solid tumors and hematological cancers have proved its excellent efficacy and impressive safety profile. However, incomplete understanding of mechanisms of action and relatively low drug oral bioavailability remain obstacles to development. By modifying the structure of ON01910.Na, a novel class of (E)-Styrylsulfonyl methylpyridines was designed and synthesized. We report herein the evaluation of a selected compound, TL-77, (E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide, as a potent small molecule inhibitor targeting mitotic pathways.
MTT assays were performed to assess in vitro anti-proliferative effects. In a panel of 10 tumor and 2 non-transformed human cell lines following 96 h exposure, TL-77 gave consistent GI50 values in the sub-micromolar range in tumor cells, whereas, it was non-toxic to non-transformed human mammary endothelial cells (HMECs). Cell cycle was analyzed by flow cytometry. TL-77 caused significant G2/M arrest ≥ 6 h, whereas ON01910.Na caused the same effect after longer exposure periods (≥ 12 h). An OD-based tubulin polymerization assay allowed us to explain obstruction of cell division caused by TL-77. TL-77 retarded tubulin polymerization between 1μM and 6μM, intriguingly, microtubules were stabilizes at TL-77 concentrations &gt; 8μM. Western blot analyses of cell lysates following treatment of cells with TL-77 revealed dose-dependent reduction of phosphorylated Cdc25c, a known substrate of Plk1 and/or Chk1/2, indicating Plk1 and/or Chk1/2 inhibition. Finally, dose- and time-dependent apoptosis triggered by TL-77, detected by Annexin-V assays, was closely associated with induction of caspase 3/7 activity. Importantly, pharmacokinetics studies in mice revealed that the oral bioavailability of TL-77 was optimized to 56% compared with 9% for ON01910.Na.
In summary, TL-77 is a potent anti-cancer agent. It disturbs tubulin during cell division, resulting in G2/M cell cycle arrest, followed by caspase-dependent apoptosis. TL-77 appears to share an analogous mechanism of action with ON01910.Na, but exhibits greater selectivity towards cancer cells and possesses superior oral bioavailability. Therefore, further evaluation of TL-77 as a promising anti-tumor agent is justified.
Citation Format: Tiangong Lu, Shudong Wang, Charles Laughton, Tracey Bradshaw. Evaluation of (E)-Styrylsulfonyl methylpyridine: A novel kinase inhibitor targeting mitotic pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3406. doi:10.1158/1538-7445.AM2013-3406
Abstract 341: In vivo model of non-small cell lung cancer metastasis to the brain.
Authors: Chung Su I. , Tobin Lisa A. , Xie Yili , Wunderlich John R. , Kwong King F. 
Published: August 2014

Abstract
Background: Non-small cell lung cancer (NSCLC) has a high rate of metastasis to distant sites such as the brain. Previous reports have suggested that exogenously expressed EMT transcription factors lead to EMT-induced migration, invasion, and anchorage-independent growth of cancer cells in vitro. In other cancer types, increased EMT transcription factors leads to promotion of metastatic tumor cell dissemination but simultaneously can also inhibit distant colonization by circulating metastatic cells. Methods: To investigate the role of EMT in brain metastasis in NSCLC, we established an in vivo model of brain metastasis through the isolation of brain metastatic clones from iterative rounds of systemic cancer cell inoculation in immunodeficient mice. Results: With each round, an increasing frequency of brain metastasis characterized the metastatic pattern and earlier onset of brain tumor formation was seen in select animals. In the metastatic cell lines established from the explanted brain metastases, we observed elevation of EMT markers such as TWIST, vimentin, and fibronectin compared to the parental cells. In addition, metastatic clones to the brain demonstrated markedly increased migration and EGFR expression. Conclusion: Iterative in vivo passaging of cancer cells facilitated isolation of subclones demonstrating increased brain metastasis. Also, these data suggests that the increased expression of EMT markers does not inhibit the formation of brain metastasis in NSCLC.
Citation Format: Su I. Chung, Lisa A. Tobin, Yili Xie, John R. Wunderlich, King F. Kwong. In vivo model of non-small cell lung cancer metastasis to the brain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 341. doi:10.1158/1538-7445.AM2013-341
Abstract 3410: Inhibitors of Skp2 E3ligase stabilize nuclear p27kip1 for regain of growth regulation in cancer.
Authors: Pavlides Savvas C. , Huang Kuang-Tzu , Wu Lily , Rueda Bo R. , Blank Stephanie V. , Mittal Khushbakhat R. , Cardozo Timothy , Gold Leslie I. 
Published: August 2014

Abstract
In many human cancers, the tumor suppressor, p27kip1 (p27), a cyclin-dependent kinase inhibitor critical to cell cycle arrest, undergoes perpetual ubiquitin-mediated proteasomal degradation by the E3 ligase complex SCF-Skp2/Cks1 and/or cytoplasmic mislocalization; lack of nuclear p27 causes aberrant cell cycle progression and cytoplasmic p27 can mediate cell migration/metastasis. We previously showed that estrogen (E2) induces Skp2-dependent degradation of p27 and cell proliferation in primary endometrial epithelial cells (EECs) and endometrial carcinoma (ECA) cell lines (e.g., ECC-1) suggesting a pathogenic mechanism for type I endometrial carcinoma (ECA), an estrogen (E2)-linked cancer. The current studies show that treatment of ECC-1 cells with small molecule inhibitors of Skp2/Cks1 E3 ligase activity (Skp2E3LIs) increase protein levels of p27, increase p27 half-life by 6 hours and inhibit cell proliferation (IC50 10μM). Two of five SKP2E3LIs, designated as C2 and C20 specifically increase p27 in the nucleus while decreasing p27 in the cytoplasm in both ECC-1 cells and primary ECA cells. In addition, C2 and C20 prevent both E2-induced proliferation and degradation of nuclear p27. These data suggest that Skp2E3LIs can function in the nucleus to prevent E2-induced degradation of p27 in primary ECA cells to regain growth control by directly blocking p27 ubiquitylation and subsequent degradation. Skp2E3LIs enable a chemical biology approach to understanding the functional significance of the ubiquitin pathway in p27-mediated cell cycle regulation and importantly, are the first specific proteasome inhibitors that pharmacologically target the binding interaction between the E3ligase, SCF-Skp2/Cks1 and p27 to prevent its ubiquitylation and subsequent degradation. These targeted inhibitors represent a major therapeutic advancement over general proteasome inhibitors for cancers characterized by SCF-Skp2/Cks1-mediated destruction of p27.
Citation Format: Savvas C. Pavlides, Kuang-Tzu Huang, Lily Wu, Bo R. Rueda, Stephanie V. Blank, Khushbakhat R. Mittal, Timothy Cardozo, Leslie I. Gold. Inhibitors of Skp2 E3ligase stabilize nuclear p27kip1 for regain of growth regulation in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3410. doi:10.1158/1538-7445.AM2013-3410
Abstract 3412: Imaging of methioninase-induced S/G2-phase-trapping for subsequent effective chemotherapy.
Authors: Yano Shuya , Tome Yasunori , Digman Michelle , Momiyama Masashi , Suetsugu Atsushi , Gratton Enrico , Hoffman Robert M. 
Published: August 2014

Abstract
Methionine-dependence of cancer cells may be due to excessive methylation reactions in cancer cells. Deprivation of methionine α,γ lyase (methioninase or METase) selectively arrests cancer cells during late S-phase, where they are highly sensitive to DNA-damaging chemotherapy. Fluorescent ubiquitination-based cell cycle indicator (FUCCI)), was used to monitor the onset of the S/G2-phase block due to methionine deprivation effected by METase. The S-phase-blocked cancer cells fluoresced yellow or green, in contrast to cancer cells in G1 which fluoresced red. Cancer cells, synchronously blocked in S-phase by METase and identified by their yellow-green fluorescence, were administered DNA-damaging chemotherapy drugs such as doxorubicin, cisplatin, or 5-fluorouracil. Treatment of cancer cells with drugs only without methioninase-effected S-phase synchrony, led to the majority of the cancer cell population being blocked in G0/G1 phase (red fluorescent) where they were resistant to the drugs. In contrast, METase treatment, followed by chemotherapy when FUCCI indicated the S/G2 block was highly effective for killing cancer cells. Color-coded chemotherapy, whereby the cell cycle of cancer cells is selectively and synchronously blocked in S-phase as identified by fluorescent reporters, may be a general approach to effective cancer treatment.
Citation Format: Shuya Yano, Yasunori Tome, Michelle Digman, Masashi Momiyama, Atsushi Suetsugu, Enrico Gratton, Robert M. Hoffman. Imaging of methioninase-induced S/G2-phase-trapping for subsequent effective chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3412. doi:10.1158/1538-7445.AM2013-3412
Abstract 3414: Disruption of CREB-CREBBP association by 2-Naphthol AS-E phosphate induces cell cycle arrest and apoptosis in non-small cell lung cancer cells .
Authors: Lee Jong Woo , Park Hee Sun , Ryu Seung-Hee , Koch Patricia , Boyer Julie , Morgensztern Daniel , Herbst Roy S. , Koo Jaseok Peter 
Published: August 2014

Abstract
The cyclic-AMP response element-binding protein (CREB) plays a critical role in the growth and survival of cancer cells as well as cell metabolism. Our previous studies have shown that enhanced CREB activity correlates with increased growth and survival of non-small cell lung cancer (NSCLC) cell lines. In addition, 2-naphthol AS-E phosphate (NASEp), a small molecule inhibitor of CREB, restricted growth of NSCLC cell lines which was associated with reduced expression of pro-angiogenic factors. NASEp distrupts binding of CREB binding protein (CREBBP) to CREB, however, the mechanism which CREB inhibition by NASEp regulates NSCLC cell growth and survival is not fully understood. Here, we found that NASEp inhibited cell growth, survival, anchorage-independent cell growth and invasion, and also completely blocked the expression of Ki-67 and PCNA, markers of cell proliferation in NSCLC cells. Mechanistically, NASEp caused cell cycle arrest at the sub-G1 or G2 phase through down-regulation of several cyclins (cyclin A2, cyclin B1, cyclin D1 and cyclin E2) and led to apoptosis in NSCLC-derived cell lines. Suppression of cyclin D1 was closely related to decreased expression of activator protein-1 (AP-1). Furthermore, in a murine xenograft model, NASEp significantly reduced tumor burden not only by down-regulating of cyclin E2 and PCNA, but also by induction of apoptosis. Taken together, these results suggest that inhibition of CREB activity through dissociation of CREB-CREBBP by NASEp may be a potent new therapeutic in NSCLC.
Citation Format: Jong Woo Lee, Hee Sun Park, Seung-Hee Ryu, Patricia Koch, Julie Boyer, Daniel Morgensztern, Roy S. Herbst, Jaseok Peter Koo. Disruption of CREB-CREBBP association by 2-Naphthol AS-E phosphate induces cell cycle arrest and apoptosis in non-small cell lung cancer cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3414. doi:10.1158/1538-7445.AM2013-3414
Abstract 3425: Chk1 inhibitor targets replicative stress in melanomas.
Authors: Gabrielli Brian G. , Brooks Kelly , Edwards Brooke , Chen James , Pavey Sandra 
Published: August 2014

Abstract
There are few effective treatments for metastatic melanoma. Chk1 inhibitors are being trialed for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is relatively unexplored. We have examined the effectiveness of two novel Chk1 selective inhibitors, AR-323 and AR-678, in a large panel (40) of melanoma cell lines and normal cell types in vitro, and investigated the mechanism promoting their cytotoxicity in the drug-sensitive cell lines. We demonstrate that these drugs display single agent activity, with IC50s in the nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is related to inhibition of S phase Chk1 which drives cells prematurely from late S phase, resulting in apoptosis either prior to or during an aberrant mitosis. Time lapse imaging has shown that the timing of cell death is related to the drug sensitivity of the cell line. The sensitivity to the Chk1 inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress, and increasing endogenous replicative stress increased drug sensitivity. Chk1 inhibitors are viable single agent therapies which target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that Chk1 is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to Chk1 inhibitors as single agents.
Citation Format: Brian G. Gabrielli, Kelly Brooks, Brooke Edwards, James Chen, Sandra Pavey. Chk1 inhibitor targets replicative stress in melanomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3425. doi:10.1158/1538-7445.AM2013-3425
Abstract 3427: The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction.
Authors: Menon Vijay , Peterson Erica , Deb Sumitra , Povirk Lawrence , Farrell Nicholas 
Published: August 2014

Abstract
BBR3610-DACH, a long-chain, bifunctional dinuclear PTII complex with a similar DNA binding mode to the Phase II clinical drug, BBR3464 and its potent analogue, BBR3610, was shown previously to be resistant to metabolic decomposition by sulfur-containing nucleophiles. Initial observations utilizing the alkaline comet assay indicate that BBR3610-DACH forms interstrand crosslinks. Cell cycle analysis using flow cytometry showed that BBR3610-DACH inhibited cell proliferation and caused G1/S and G2/M cell cycle arrest in HCT116 colorectal cells in a time dependent manner accompanied with significant s phase depletion. Similar experiments with synchronized cells showed a distinct G1 phase arrest elicited by the drug following release from arrest. Immunoblotting revealed a stabilization of p53 between 6-24hr after treatment with 20μM (IC90) BBR3610-DACH, with a concomitant increased levels of the cyclin dependent kinase inhibitors, p21 and p27. Cell proliferation assay using MTT and subsequent cell cycle studies with HCT116 p53-/- and HCT116 p21-/- indicated that the cytotoxicity profile of BBR3610-DACH was p21 dependent and partially dependent on the p53 status. However, no change was observed in the protein levels of cyclin E, CDK2, and CDC25A which are G1 phase regulators. Decrease in the levels of cyclin A and cyclin B1 at 24hrs suggested a G2/M block indicative of a possible mitotic catastrophe. Next, we examined whether the DNA damage sensor protein kinases, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and RAD3 related (ATR) had a role in the cell cycle regulation after drug treatment. Studies using the ATM inhibitor, KU-60019 and caffeine (inhibits both ATM and ATR) revealed no apparent role of ATM but a possible dependence on ATR. Following the cell cycle effects, BBR3610-DACH induced cell death as seen from cleaved poly (ADP-ribose) polymerase-1 (PARP-1) levels as early as 6hrs after drug treatment. Interestingly, no cleaved caspase 3 was seen suggesting a caspase-independent PARP cleavage. Together these findings suggest that BBR3610-DACH is a major cell cycle inhibitory DNA binding platinum agent that could be further developed as a major chemotherapeutic.
Citation Format: Vijay Menon, Erica Peterson, Sumitra Deb, Lawrence Povirk, Nicholas Farrell. The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3427. doi:10.1158/1538-7445.AM2013-3427