bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 578: Plk1 decreases DNA double-strand break (DSB) formation during replication-stalling genotoxic stress.
Authors: Gebreselassie Daniel , Chun-Kost Gina , Leo Elisabetta , Pommier Yves , Saito Erika , Patierno Steven , Ceryak Susan M. 
Published: August 2014

Abstract
Polo-like kinase 1 (Plk1) is a key regulator of mitosis and its over-expression/ deregulation is linked to cellular transformation. Recent studies highlight its role in resumption of cell cycle progression after DNA damage. Plk1 has also been shown to enhance DNA replication under stress of stalled replication forks. We reported Plk1 activation-induced G2/M checkpoint bypass in normal human lung cells (HLFs), in the presence of acute genotoxic stress. The present aim was to determine the effect of Plk1 on DNA double strand breaks (DSBs) during genotoxic stress. In the present study, we measured DNA DSB induction in HLFs by Cr(VI), etoposide, and H2O2 after Plk1 activation using the comet assay and γH2AX immunofluorescence staining. We used equitoxic concentrations of the different genotoxins and found that DNA DSBs increased &gt; 2 fold after exposure to 3 μM Cr(VI), 12.5 μM etoposide, and 150 μM H2O2, respectively, and persisted for at least 4h. Transfection of a Plk1 constitutively active (c/a) mutant (T210D) abrogated both Cr(VI)- and etoposide-induced DNA DSBs as early as 30 min for the duration of treatment, in comparison to the vector-transfected cells. In sharp contrast, Plk1 had no effect on H2O2-induced DNA DSBs. Consistent with DNA DSB formation, Cr(VI) exposure was associated with G1 arrest, at least at 4h, as determined by BrdU incorporation. Moreover, Plk1 enhanced S phase progression during Cr(VI) treatment, which was accompanied by increased replication fork velocity and longer inter-origin distances as determined by using a single-molecule approach based on molecular combing. Expression of a Plk1 “kinase-dead” mutant (K82R) also abrogated DNA DSBs during Cr(VI) treatment, suggesting that this effect may be independent of Plk1 kinase activity. In summary, our data underline the ability of Plk1 to override DNA DSB-induced checkpoints, and to decrease DSBs after replication-stalling genotoxin exposure. We postulate these effects to be due to the replication-enhancing ability of Plk1, which may occur at the expense of genomic stability. This work was supported in part by NIH grants CA107972 and ES017334 (S.C.); ES05304 (S.R.P.); and a PhRMA Foundation predoctoral fellowship (G.C.K.).
Citation Format: Daniel Gebreselassie, Gina Chun-Kost, Elisabetta Leo, Yves Pommier, Erika Saito, Steven Patierno, Susan M. Ceryak. Plk1 decreases DNA double-strand break (DSB) formation during replication-stalling genotoxic stress. [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 578. doi:10.1158/1538-7445.AM2013-578
Abstract 583: Ghrelingene expression avoiding the D-ribose caused HepG2 cell death.
Authors: Shiu Jia Huei , Huang Chin Hao , Lee Tai Lin , Lee Shih Chieh , Liu Shu Ying , Tsai Meng Feng 
Published: August 2014

Abstract
Liver cancer patients could suffer from high saccharide environment due to the malfunction of liver. To mimic this high saccharide environment, HepG2 cells were culture with 30 mM D-riboses.
We found that this high concentration of saccharide cause cell death. Cinnamon was report to reduce glucose in model rats. We hypothesized that the administration of cinnamon extracts may benefit liver cancer patients whose metabolism is defected. To test the hypothesis, three different chemical subtypes of cinnamon extracts were added into the culture medium. The adding of all three cinnamon extracts protected HepG2 cells from D-ribose administration and increased around 20% of surviving cells. These protections were even better than the addition of aminoguanidine hemisulfate salt, a chemical used in the treatment of diabetes. The expressions of ghrelin gene and two ghrelin-related genes was monitored by RT-PCR. Ghrelin gene expression was up-regulated in cinnamon treated cells. Also, the ghrelin modify gene, MBOAT4, and ghrelin process enzyme, furin, gene were all detected in HepG2 cells and cinnnamon treated cells.
These results demonstrated that if ghrelin expressed in HepG2 cell and maybe liver as well, it can be processed properly. Both ghrelin transcript variants 1 and 3 recombinant plasmid were transfected into HepG2 cells and both transcript variants protected HepG2 cells from the addition of D-ribose without the administration of cinnamon extracts. We conclude that the cinnamon avoids HepG2 cell damage from D-ribose induced oxidative stress by inducing ghrelin gene expression, and through the ghrelin signaling increases cell surviving. Since ghrelin level is abnormally regulated in patients with hepatocellular carcinoma and post-hepatitic liver cirrhosis, the understanding of how ghrelin been regulated in liver may benefit liver disease patients.
Citation Format: Jia Huei Shiu, Chin Hao Huang, Tai Lin Lee, Shih Chieh Lee, Shu Ying Liu, Meng Feng Tsai. Ghrelingene expression avoiding the D-ribose caused HepG2 cell death. [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 583. doi:10.1158/1538-7445.AM2013-583
Abstract 585: Salmonella typhimurium A1-R targets quiescent cancer cells.
Authors: Yano Shuya , Zhang Yong , Uehara Fuminari , Hiroshima Yukihiko , Miwa Shinji , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. The cell-cycle phase of each cancer cell in real time was imaged using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-labeled cancer cells in monolayer culture and tumor spheres were treated with Salmonella typhimurium A1-R. Time-lapse confocal imaging showed that A1-R encircled and invaded quiescent cancer cells in monolayer culture, thereby eliminating them. Cancer cells in tumor spheres in serum-free culture become and remain quiescent. A1-R infected and killed quiescent cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill quiescent cancer cells in tumor spheres. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in killing quiescent cancer cells resistant to cytotoxic agents. This study demonstrates that A1-R can kill quiescent cancer cells and suggests a new therapeutic paradigm potentially more effective than current therapeutics which are ineffective against quiescent cancer cells.
Citation Format: Shuya Yano, Yong Zhang, Fuminari Uehara, Yukihiko Hiroshima, Shinji Miwa, Robert M. Hoffman, Ming Zhao. Salmonella typhimurium A1-R targets quiescent 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 585. doi:10.1158/1538-7445.AM2013-585
Abstract 589: NQO1-dependent anticancer action with combination β-lapachone and ionizing radiation in the head and neck cancer.
Authors: Li Long Shan , Reddy Srilakshmi , Gao Jinming , Boothman David A. , Sumer Baran , Yordy John S. 
Published: August 2014

Abstract
The number of new cases of oral cavity, pharynx and larynx cancers is estimated be 52,610 in 2012 with an expected 11,500 deaths. Despite progressive improvements in outcome, current treatment approaches still result in an overall survival rate of approximately 50% at five years for locally advanced head and neck cancer (HNC). Additional therapeutic approaches are needed to further enhance outcomes. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase that reduces quinones to hydroquinones and has been shown to be overexpressed in a number of solid tumors. For the first time, our studies in 45 HNC cell lines identified NQO1 overexpression in more than 70% of HNC cell lines. Furthermore over-expression of NQO1 has been shown to be a critical determinant for tumor-selective therapy using β-lapachone (β-lap), a substrate of NQO1 that undergoes partial reduction and spontaneous reversion, creating a futile cycle that produces very high levels of reactive oxygen species. HNC cell lines that overexpress NQO1 are significantly killed by treatment with β-lap. The anti-cancer action of β-lap in HNC cells is initiated and processed through five essential downstream mediators: (i) reactive oxygen species (ROS), particularly hydrogen peroxide (H2O2); (ii) DNA single strand breaks (SSBs) induced by ROS; (iii) hyperactivation of poly(ADP-ribose)polymerase-1 (PARP1) and accompanying poly(ADP-ribose)-PARP1 (PAR) formation; (iv) dramatic NAD+/ATP depletion; and (v) programmed necrosis (necroptosis). In combination with ionizing radiation (IR), β-Lap radiosensitized NQO1(+) HNC cells under conditions where nontoxic doses of either agent alone did not achieve threshold levels of DNA lesions and /or SSBs required for PARP-1 hyper-activation. Furthermore, combination therapy with β-lap and IR significantly enhanced γ-H2AX and 53BP1 foci formation and PARP-1 hyper-activation which was associated with ATP loss and induction of programmed cell death. Furthermore, the anticancer effects of combination β-Lap and IR were blocked by the NQO1 inhibitor dicoumarol. Our findings offer a strategy for the clinical utilization of β-lap as a radiosensitizer in HNC.
Citation Format: Long Shan Li, Srilakshmi Reddy, Jinming Gao, David A. Boothman, Baran Sumer, John S. Yordy. NQO1-dependent anticancer action with combination β-lapachone and ionizing radiation in the head and neck 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 589. doi:10.1158/1538-7445.AM2013-589
Abstract 590: Enhancing effect of resveratrol on the antileukemic effects of arsenic trioxide.
Authors: Wu Edward J. , Goussetis Dennis J. , Platanias Leonidas C. 
Published: August 2014

Abstract
Arsenic trioxide (As2O3) has been approved by the FDA for the treatment of APL, in which it has major clinical activity. However, the requirement of high doses to generate antileukemic effects has been a limitation for As2O3‘s potential use in other subtypes of AML. Given As2O3‘s potent antileukemic properties in vitro, approaches to enhance its effects are of clinical and translational relevance. Resveratrol (RSV), a phytoalexin found naturally in grapes and other plants, has wide-ranging health benefits, and in leukemias, has been shown to induce apoptosis and act synergistically with other agents. In studies to examine the influence of RSV on As2O3‘s antileukemic effects, we found that RSV enhances As2O3-induced cell death in KT1 cells as shown by flow cytometric and MTT analyses to assess apoptosis and cell viability. Our studies demonstrate that combined As2O3 and RSV treatment significantly reduces leukemic progenitor colony formation in a dose dependent manner by K562, KT1, and U937 cell lines. It also results in enhanced suppressessive effects on primary leukemic progenitors from patients with myeloid leukemias. Altogether, our results suggest that use of RSV may provide an approach to enhance the antileukemic effects of As2O3 treatment by potentiating the effects of lower As2O3 doses.
Citation Format: Edward J. Wu, Dennis J. Goussetis, Leonidas C. Platanias. Enhancing effect of resveratrol on the antileukemic effects of arsenic trioxide. [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 590. doi:10.1158/1538-7445.AM2013-590
Abstract 596: Low-dose 1,25-dihydroxyvitamin D3 combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis.
Authors: Ji-Yeon Bae , Kim Ji-Won , Kim Inho 
Published: August 2014

Abstract
Arsenic trioxide (As2O3) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia (APL). However, since not all patients can achieve remission after treatment, it is necessary to investigate a novel method to overcome the problem. We investigated the anti-leukemic effect of low-dose 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in combination with As2O3 on HL-60 and K562 cells. The cell viability was in reverse proportion to As2O3 or 1,25(OH)2D3 concentration. In both HL-60 and K562 cells, after the combination treatment with As2O3 and 1,25(OH)2D3 at a 10:1 ratio, the combination index values were less than 1 in all treatment groups. In the RT-PCR and Western blot analysis, the combination treatment decreased Bcl-2 expression and increased Bax and Caspase-3 expressions more prominently than the single treatment. In the flow cytometric analysis performed in HL-60 cells, the proportion of late apoptosis was 4.9% in control, 30.0% in 1.0 μM As2O3, 8.1% in 100nM 1,25(OH)2D3, and 64.3% in 1.0 μM As2O3 plus 100 nM 1,25(OH)2D3. In conclusion, low-dose 1,25(OH)2D3 combined with As2O3 synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single-drug treatment.
Citation Format: Bae Ji-Yeon, Ji-Won Kim, Inho Kim. Low-dose 1,25-dihydroxyvitamin D3 combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis. [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 596. doi:10.1158/1538-7445.AM2013-596
Abstract 597: The combination of valproic acid and fludarabine treatment induces a synergistic apoptotic response in chronic lymphocytic leukemia (CLL) patients involving the lysosomal protease cathepsin B.
Authors: Yoon Ju Yoon , Szwajcer David , Ishdorj Ganchimeg , Benjaminson Pat , Kumar Rajat , Johnston James B. , Gibson Spencer B. 
Published: August 2014

Abstract
Chronic Lymphocytic Leukaemia (CLL) is the most common hematological malignancy in the western world. Fludarabine, a nucleoside analogue, is commonly used in combinational treatments for CLL. However, patients commonly develop resistance to fludarabine based therapies. Valproic Acid (VPA), an inhibitor of histone deacetylases (HDACs), showed synergistic apoptotic responses when combined with fludarabine in human leukemic cells and primary CLL cells. The mechanism for this synergistic apoptotic response is unknown. We found that fludarabine and VPA treatment increased activates caspases-8, -9, -3, and caspase-2 and a decreased in expression of anti-apoptotic proteins Mcl-1 and XIAP. Treatment with fludarabine alone or in combination with VPA led to the loss of lysosome integrity suggesting a leakage of the lysosomal content into the cytosol in response to these drugs. Chemical inhibition of a specific lysosomal protease, cathepsin B, using CA074-Me was sufficient to stabilize Mcl-1 and XIAP while reducing caspase activation and apoptosis. Addition of purified cathepsin B to leukemic cell lysates led to the reduction in protein levels of Mcl-1, XIAP and pro-caspase-2, thus suggesting that the re-localization of cathepsin B into the cytosol is sufficient to degrade these proteins. VPA treatment increased cathepsin B levels in both leukemic cell lines and primary CLL cells. VPA also increased cathepsin B activity. In addition, six relapsed CLL patients who had received at least one prior therapy with fludarabine were treated with VPA alone or in combination with fludarabine. No responses were seen after 28 days using VPA alone but in five patients who continued on VPA with fludarabine, three patients showed reduced lymphocyte count after receiving at most five cycles of the combination therapy. When the CLL cells from VPA-treated CLL patients were examined, VPA administration induced increased levels of histone-3 acetylation and cathepsin B expression in vivo. Thus, VPA and fludarabine synergistic apoptotic response is mediated by cathepsin B activation leading to a decrease in anti-apoptotic proteins in CLL cells and likely contributes to the clinical response observed in relapsed, fludarabine-refractory CLL patients.
Citation Format: Ju Yoon Yoon, David Szwajcer, Ganchimeg Ishdorj, Pat Benjaminson, Rajat Kumar, James B. Johnston, Spencer B. Gibson. The combination of valproic acid and fludarabine treatment induces a synergistic apoptotic response in chronic lymphocytic leukemia (CLL) patients involving the lysosomal protease cathepsin B. [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 597. doi:10.1158/1538-7445.AM2013-597
Abstract 60: The MedBook network for cancer precision medical care.
Authors: Goldstein Theodore C. , Baertsch Robert , Febbo Phillip G. , Stuart Josh , Haussler David 
Published: August 2014

Abstract
Precision cancer care will connect clinical information to genomic information. To facilitate this connection, we are creating MedBook, a social networking system that links patients, physicians, and researchers in the battle against cancer. The Stand Up To Cancer West Coast Dream Team is first creating a bioinformatic platform that will run statistical and machine learning data analysis in a cloud-computing environment applied first to castration resistant prostate cancer and then share the data analysis results with oncologists and their patients. Patients, physicians, and researchers can also share sample data, high-throughput genomic discoveries, and their personal experiences in a safe structured environment covering research, disease course, and treatment. All data will be extracted from HIPAA repositories and anonymized and retain institutional review board controls. The social media model allows both the capture of unstructured information as well as collaborative discussions, annotation, and editing of structured information, to learn from each patient. Eventually, MedBook will collect knowledge about the experience of the disease from individual patients, from their treatments, and from their outcomes, and store them alongside relevant genomic molecular data. Our approach allows a variety of high-throughput genomic information to be generated and shared in a wiki-style collaborative network. This presentation will summarize the current state of MedBook and its utilization by a team of doctors and researchers across five medical centers and many university laboratories.
Citation Format: Theodore C. Goldstein, Robert Baertsch, Phillip G. Febbo, Josh Stuart, David Haussler. The MedBook network for cancer precision medical care. [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 60. doi:10.1158/1538-7445.AM2013-60
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 602: Ascorbic acid combined with a cytostatic inhibitor of glycolysis synergistically induces apoptosis in non-small lung cancer cells.
Authors: Vuyyuri Saleha B. , Rinkinen Jacob , Worden Erin , Davis Keith R. 
Published: August 2014

Abstract
Purpose An exceptional characteristic of many cancer cells is increased glucose uptake and elevated glycolysis with a concomitant reduction in oxidative respiration, also known as the Warburg effect. The increase in basal levels of reactive oxygen species (primarily, H2O2) and their increased dependence on glycolysis for their survival make tumor cells more susceptible than normal cells to treatment with a combination of pro-oxidant agents and chemotherapy. This common feature of tumor cells has been targeted for the development of new cancer therapeutics. Ascorbic acid (AA) has been shown to have cancer curative potential, at clinically achievable doses that have minimal or no toxic effects on normal cells. We have previously shown that some cancer cell lines are significantly more sensitive to treatment with ascorbic acid at concentrations where it may function as a pro-oxidant. In the present case, we investigated the effects of AA alone or in combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO) on the viability of three non-small lung cancer (NSCLC) cell lines vs immortalized lung epithelial cell line.
Results Cell viability assays showed that combined treatment of AA and 3-PO caused a synergistic increase in cell death in all the NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone, while no synergistic cytotoxic effect was observed in immortalized lung epithelial cells. Key markers such as DNA fragmentation, PARP cleavage, annexin-V binding, and caspase activity indicated that AA-induced cell death is caused via the activation of apoptosis. Metabolomic analysis revealed a decrease in NAD/NADH in the combination treatment that correlated well with the synergistic cell death observed in the viability results. The importance of NAD/NADH depletion in the synergistic response was confirmed by rescue experiments showing addition of NAD to the culture protected cells from the combination treatment. The major significance of these studies is that, we show for the first time that AA selectively synergizes with a glycolytic inhibitor in killing NSCLC cells and that pharmacologic AA treatment (either alone or combined with any other chemotherapeutic agent or glycolytic inhibitors used in the treatment of cancer) may be a promising therapy for non-small lung cancer and other challenging to-treat cancers.
Citation Format: Saleha B. Vuyyuri, Jacob Rinkinen, Erin Worden, Keith R. Davis. Ascorbic acid combined with a cytostatic inhibitor of glycolysis synergistically induces apoptosis in non-small 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 602. doi:10.1158/1538-7445.AM2013-602