bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1026: Identify BRD4 as a facilitator of replication stress response signaling
Authors: Zhang Jingwen , Willis Brandon , Hattersley Maureen , Lau Alan , Reimer Corinne , Zinda Michael , Fawell Stephen , Mills Gordon , Dulak Austin , Chen Huawei 
Published: July 2017

Abstract
BRD4 is a member of the BET (bromodomain and extraterminal domain) family of chromatin readers that recognize acetylated-lysines on histones and nuclear proteins. Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. However, whether BRD4 contributes to cancer malignancy through other mechanisms has not been extensively evaluated. Here, we show that BRD4 is important for maintaining an intact DNA replication checkpoint in cancers. Displacement of BRD4 by BET bromodomain inhibitor AZD5153 in cell lines under intrinsic or exogenous replication stress led to a time-dependent reduction in phospho-Chk1 first detected within 30 minutes, and reaching maximum phospho-Chk1 inhibition (~85%) at an hour after AZD5153 treatment in U2OS cells. The decrease in Chk1 phosphorylation was observed without a concomitant decrease in total Chk1, and this was not replicated by treatment with pan-transcriptional inhibitors, suggesting a non-transcriptional mechanism linked to BRD4. Furthermore, BRD4 interacts with the DNA pre-replication complex and inhibition of BRD4 leads to hyperactivation of the pre-replication complex and aberrant DNA replication re-initiation under replication stress conditions. Consistent with a role in S-phase signaling, BETi treatment sensitizes replicating cells to replication stress-inducing agents. Finally, we observed that ovarian cancer cell lines are highly-sensitive to the combined inhibition of BRD4 and ATR. Coadministration of AZD5153 and AZD6738 (ATR inhibitor) significantly inhibited tumor growth in OVCAR3 ovarian xenograft model (TGI after 21 day dosing: AZD5153, 52%; AZD6738, 46%; Combo, 84%). Sustained tumor growth delay was observed after combination treatment cessation. Together, our study uncovered a novel function for BRD4 in regulating DNA replication stress response, and provide mechanistic rational for combining BETi with DNA damage-targeted agents for cancer therapies.
Citation Format: Jingwen Zhang, Brandon Willis, Maureen Hattersley, Alan Lau, Corinne Reimer, Michael Zinda, Stephen Fawell, Gordon Mills, Austin Dulak, Huawei Chen. Identify BRD4 as a facilitator of replication stress response signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2017-1026
Abstract 1048: Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine
Authors: Pluchino Lenora A. , Wang Hwa-Chain R. 
Published: July 2017

Abstract
Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States and is often associated with induction of oncogenic H-Ras. Long-term survival of patients is suboptimal with the current chemotherapeutic regimen of combined cisplatin and gemcitabine and others due to acquired drug resistance and recurrence. Thus, it is urgent to develop new regimens effective in control of tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We used our cellular system, consisting of human urinary bladder cancer J82 cells paired with its derived oncogenic H-Ras-expressing J82-Ras cells, to investigate the efficacy of a novel combination regimen in treating bladder cancer cells. Our studies revealed, for the first time, the ability of a combination of cisplatin and romidepsin with gemcitabine to synergistically and preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. The Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species (ROS), leading to enhanced caspase activation, DNA damage, and DNA oxidation, as well as reduced glutathione, to synergistically increased cell death and reduced drug resistance in cells treated with combined romidepsin, cisplatin, and gemcitabine. Preferentially induced Ras-ERK-Nox-ROS pathway, caspase
activation, and DNA damage/oxidation, as well as reduced glutathione, contributed to the preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. Synergistically induced death and reduced drug resistance were also detected in human bladder cancer SW780 cells treated with combined romidepsin, cisplatin, and gemcitabine. Hence, our results lead us to suggest that a combination of romidepsin, cisplatin, and gemcitabine should be seriously considered as a new therapeutic regimen for controlling the development and recurrence of human urinary bladder cancer, especially Ras-ERK-activated cancers.
Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2017-1048
Abstract 1051: Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer
Authors: Oba Takaaki , Ito Ken-ichi 
Published: July 2017

Abstract
Purpose:
There is an urgent need to develop novel therapeutic strategies for triple negative breast cancer (TNBC). To explore the antitumor effect of combination of eribulin (ERI) and paclitaxel (PTX) for TNBC, we conducted preclinical experiments.
Materials & methods:
Combinational effects of ERI and PTX were analyzed both in vitro and in vivo using two TNBC cell lines (MDA-MB-231, Hs578T).
Results:
When ERI was added simultaneously with PTX to TNBC cells, the sensitivity to PTX was increased synergistically. On the other hand, synergistic increase of sensitivity to ERI was observed in the presence of PTX. When the TNBC cells were treated with each drug subsequently, pretreatment with ERI for 96 hours enhanced the sensitivity to PTX administrated subsequently. In contrast, pretreatment of TNBC cells with PTX enhanced the sensitivity to the subsequently administrated ERI. When the TNBC cells were treated with ERI, the expression of epithelial marker, E-cadherin was increased, while the expression of mesenchymal markers, pSmad2, ZEB1, Slug, and vimentin were decreased. In contrast, when the cells were treated with PTX, the expressions of mesenchymal markers were increased. When epithelial-mesenchymal transition (EMT) was induced by TGF-β in the TNBC cells, the sensitivity to ERI was enhanced, while TGF-β receptor inhibitor (LY2157299) reduced the sensitivity to ERI. Furthermore, knockdown of ZEB1 by small interfering RNA conferred resistance to ERI in both TNBC cell lines. In the mouse xenograft model bearing MDA-MB-231, ERI plus PTX combination therapy significantly inhibited tumor growth compared with either PTX or ERI monotherapy. Furthermore, prior treatment with ERI significantly enhanced the antitumor activity of PTX in the mouse xenograft model.
Conclusions:
Our findings demonstrate an EMT-mediated synergistic antitumor effect by combination of two tubulin inhibitors. This combination therapy may serve as a novel therapeutic strategy for TNBC.
Citation Format: Takaaki Oba, Ken-ichi Ito. Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1051. doi:10.1158/1538-7445.AM2017-1051
Abstract 1054: Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway
Authors: Kato Kazunori , Yamazaki Takumi , Honma Masaaki 
Published: July 2017

Abstract
Nobiletin is a citrus polymethoxy flavonoid that suppresses cell proliferation, angiogenesis and metastatic properties in various cancer cells. In this study, we investigated the combined effects of nobiletin and various chemotherapeutic agents on the cytotoxicity of human colon and esophageal cancer cells. We cultured cancer cells at serial dilution of chemotherapeutic agents with or without nobiletin and assessed cell cytotoxicity at 5 days after drug treatment. The addition of a suboptimal dose of nobiletin did not alter the growth of cancer cells, however cytotoxic effect of antimetabolites (gemcitabine and 5-FU) and DNA-platinating agent (cisplatin) were markedly attenuated by nobiletin. By contrast, nobiletin markedly enhanced antitumor effect of antimicrotubule agents such as docetaxel, paclitaxel, vincristine and MMAE. Moreover, enhanced cytotoxicity by nobiletin was also verified in the combination with MMAE- or DM1-conjugated antibodies to EpCAM and EphA2. We found the inhibition of phosphorylation and nuclear translocation of Pin1 (peptidyl-prolyl isomerase) by nobiletin, suggesting a rational molecular target of nobiletin is Pin1. Overall, these data suggest that nobiletin might useful for the chemotherapeutic treatment of microtubule inhibitors.
Citation Format: Kazunori Kato, Takumi Yamazaki, Masaaki Honma. Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2017-1054
Abstract 1061: Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas
Authors: An Yi , Sun Lillian , Derakhshan Adeeb , Carlson Sophie , Das Rita , Chen Zhong , Waes Carter Van 
Published: July 2017

Abstract
Head and neck squamous cell carcinomas (HNSCC) induced by human papilloma virus (HPV) have increased recently in the US, and exhibit a different prognosis and response to therapies from HPV(-) cancers. Analysis of HNSCC TCGA datasets provide evidence for distinct alterations in expression of components of the NF-κB and death pathways in HNSCC with different HPV status. Previously, we have found that birinipant, a novel SMAC mimetic that inhibits inhibitor of apoptosis proteins (IAPs), sensitizes a subset of HPV(-) HNSCC cell lines to death agonists like TNF-α and TRAIL. In this study, we have observed that birinipant also sensitizes most HPV(+) cell lines to TRAIL and TNF-α in vitro. The IC50 of birinipant was under 50nM for HPV(+) UPCI-SCC-90 and UM-SCC-47 cell lines, when combined with TNF-α or TRAIL. To explore the therapeutic potential of enhancing TRAILR mediated death signaling in HPV(+) HNSCC cells, we investigated the effects of an agonistic polyclonal TRAILR2 antibody. Treatment of cells with TRAILR2 antibody alone shows little or no inhibitory effect on UPCI-SCC-90 and UM-SCC-47 cells in vitro. However, a combination of birinipant and TRAILR2 antibody, or triple combination of birinipant, TRAIL, and TRAILR2 antibody shows additive or synergistic effects to inhibit cell proliferation and induce cell death in a dose dependent manner. In addition, our preliminary data suggested that the non-canonical NF-κB pathway is predominately activated in HPV(+) HNSCC cells, and that NF-κB inducing kinase (NIK) is a key component of this pathway. When we tested the NIK inhibitor 4H-isoquinoline-1,3-dione in UPCI-SCC-90 cells, we found it reduced cell proliferation in a dose-dependent manner (IC50 =1.5 μM). Taken together, these results indicate that TNF-α, TRAIL, and TRAILR2 agonist antibody sensitized birinipant anti-tumor activity, and triple combination exhibited synergistic effects in HPV(+) HNSCC cell lines. NIK inhibitor alone inhibits cell proliferation of HPV(+) cells, supporting the hypothesis of aberrant activation of alternative pathway in HPV(+) HNSCC cells. (Supported by NIDCD intramural projects ZIA-DC-000016, 73, 74).
Citation Format: Yi An, Lillian Sun, Adeeb Derakhshan, Sophie Carlson, Rita Das, Zhong Chen, Carter Van Waes. Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1061. doi:10.1158/1538-7445.AM2017-1061
Abstract 1069: Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells
Authors: Chi Ru-pin , Wei Wei , Birrer Michael , Leaner Virna D. 
Published: July 2017

Abstract
Elevated expression of members of the nuclear transport protein family has been reported in multiple cancers and presents as novel anticancer therapeutic targets. Using a cervical cancer model system, we have previously shown that inhibition of the nuclear import receptor, KpnB1 by siRNA and a novel small molecule, Inhibitor of Nuclear Import (INI-43) resulted in cancer cell death via apoptosis. In this study, we investigated the cancer cell killing effects of KpnB1 inhibition in combination with Cisplatin (CDDP), a first-line chemotherapeutic agent used in the treatment of many cancers. KpnB1 siRNA and INI-43 treatment at sub-lethal concentrations enhanced cancer cells' sensitivity to CDDP. Our data shows that the combination treatment of INI-43 and CDDP significantly decreases CDDP IC50 compared to CDDP treatment alone. Increased PARP-cleavage was observed in combination treated cells and this correlated with increased γH2A.X, indicating increased apoptosis and DNA damage. Furthermore, INI-43 treatment reduced the nuclear import of NFκB, a stress-regulated response transcription factor known to be a KpnB1 cargo protein that promotes cancer cell survival. Decreased levels of downstream pro-survival and DNA-repair targets of NFκB were observed, including cyclinD1, c-Myc and XIAP, which correlated with increased DNA damage and apoptosis. Taken together, results suggest increased Cisplatin sensitivity of cervical cancer cells when nuclear import via KpnB1 is inhibited.
Citation Format: Ru-pin Chi, Wei Wei, Michael Birrer, Virna D. Leaner. Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2017-1069
Abstract 109: Effects of trifluoperazine analogue on A549 human lung cancer cells
Authors: Jeong Joo Yeon , Ryu Jinhyun , Yoon Nal Ae , Kang Seokmin , Seong Hyemin , Fudhaili Ahmad , Park Juyeong , Sim Jimin , Lee Jiyeon , Hwang Soohyun , Kang Sang Soo 
Published: July 2017

Abstract
Although there have been great advancement in technology, molecular diagnosis, therapeutics, lung cancer is still the leading cause of cancer related mortality all over the world. Recently, some antipsychotic drugs have been shown to possess the anticancer activity. Thus the present study was designed to evaluate the anticancer effects of trifluoperazine (TFP), a commonly used antipsychotic drug, and its synthetic analogs on human lung cancer cell lines. To this end, effects of TFP and its selected analog on A549 cells were investigated in vitro as well as in vivo experiments. Synthetic TFP analogs were evaluated by the viability of A549 cells following drug treatment and compared to TFP. KCFC51, a selected TFP analog, significantly inhibited the proliferation of A549 cells. Further experiment showed that TFP and KCFC51 had activities to inhibit the migration, and anchorage dependent/independent colony formation of A549 cells. Western blot analysis revealed that TFP and KCFC51 affect the protein expression levels related to cell apoptosis and cell cycle. KCFC51 showed stronger anticancer effects in all the experiment than TFP. Flow cytometric analysis showed that KCFC51 induced sub-G1 population and reduced cell population in S and G2/M phase. In addition, the two in vivo experimental models, KCFC51 also showed powerful anticancer effect in skin xenograft tumor growth and orthotropic lung cancer development than TFP. Thus present study demonstrates that a synthetic TFP analog has anti-lung cancer activity and provides a potential therapeutic candidate for lung cancer.
Citation Format: Joo Yeon Jeong, Jinhyun Ryu, Nal Ae Yoon, Seokmin Kang, Hyemin Seong, Ahmad Fudhaili, Juyeong Park, Jimin Sim, Jiyeon Lee, Soohyun Hwang, Sang Soo Kang. Effects of trifluoperazine analogue on A549 human lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 109. doi:10.1158/1538-7445.AM2017-109
Abstract 1095: A combination of suberoylanilide hydroxamic acid and quinacrine is an effective therapeutic approach in preclinical settings of upper gastrointestinal cancers
Authors: Zhu Shoumin , El-Rifai Wael 
Published: July 2017

Abstract
Background: Quinacrine (QC), an antimalarial drug, has been shown to possess anticancer effects. Suberoylanilide hydroxamic acid (SAHA) inhibits class I and class II HDACs and is approved for cancer therapy. Developing novel approaches to overcome cancer drug resistance could significantly enhance current therapeutic approaches and improve patient care.
Methods: ATP-GLO, clonogenic survival, Annexin-V apoptosis assay, comet assay and DNA double-strand breaks (DSB) kits were used. The mRNA and protein levels were evaluated by quantitative real-time PCR and Western blot analyses.
Results: A combination of QC/SAHA significantly increased cell death in all cancer cell lines and had no effect on immortalized non-cancer cell lines (HFE145, NIH-3T3 and EPC2) (P&lt;0.01). Clonogenic survival assay indicated that QC/SAHA co-treatment led to significantly lower number of cancer cell colonies, as compared to single agents and controls (P&lt;0.01). Of note, the QC/SAHA combination led to an increase in the the sub-G0 population in AGS (9-fold), MKN-28 (14-fold), FLO1 (5.6-fold), and SNU1 (4-fold) cells (P&lt;0.01). These results were confirmed using the Annexin V apoptosis induced significantly higher levels of apoptosis (10 - 20 fold) as compared to single agent and control (P&lt;0.01). Treatment with QC/SAHA combination induced high levels of DSB (&gt;20 fold, P&lt;0.01). Comet assay data showed increased DNA damage compared with vehicle-treated cells (8-fold, P&lt;0.01). Western blot analysis demonstrated a notable increase in activation of PARP, caspases 3, 9 and γ-H2AX following QC/SAHA co-treatment in all cancer cell lines. Interestingly, the combination of QC/SAHA substantially decreased the protein levels of both wtP53 and mutP53 in these cells. Tumor xenograft data confirmed that a combination of QC/SAHA is more effective than a single agent in abrogating tumor growth (P&lt;0.05).
Conclusion: Our novel findings show that QC and SAHA have a synergistic effect on cancer cell death. The results provide compelling evidence that increased DNA damage mediates the cytotoxic effect of combined QC/SAHA. Such effect is likely related to mutP53 and wtP53 protein degradation induced by QC/SAHA combination. Our findings provide a rationale for a clinical evaluation of combined QC/SAHA therapy in gastro-esophageal cancers. Ongoing studies are currently being undertaken to understand mechanisms that regulate the degradation of wtp53 and mutp53 proteins.
Citation Format: Shoumin Zhu, Wael El-Rifai. A combination of suberoylanilide hydroxamic acid and quinacrine is an effective therapeutic approach in preclinical settings of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1095. doi:10.1158/1538-7445.AM2017-1095
Abstract 1098: Delta-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem cells
Authors: Husain Kazim , Sebti Said M. , Malafa Mokenge P. 
Published: July 2017

Abstract
Background: Pancreatic cancer, a lethal malignancy is the fourth leading cause of cancer-related deaths in the United States. The standard chemotherapy with gemcitabine is ineffective in patients with metastatic tumors. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the chemosensitization of pancreatic tumor metastasis by δ-tocotrienol to gemcitabine in vitro as well as in vivo.
Methods: In vitro human metastatic pancreatic cancer cells L3.6pl and pancreatic cancer stem cells (PCSC) were treated with gemcitabine (5 μM) and δ-tocotrienol (50 μM) alone and in combination. Treated cells used for epithelial to mesenchymal transition (EMT), migration/invasion, microsphere/spheroid, and signaling markers assays. PCSC expressing luciferase was orthotopically implanted into pancreas of Athymic nude mice (n = 20) and after one week they were randomized into four groups: 1) vehicle control (ethanol extracted olive oil), 2) gemcitabine (100 mg/kg, IP, twice a week), 3) δ-tocotrienol (200 mg/kg, orally twice a day) and 4) gemcitabine + δ-tocotrienol. The treatment was continued for 4 weeks. The tumor volume, tumor weight, metastasis were recorded.
Results: Gemcitabine slightly inhibited the growth, migration/invasion of L3.6pl and PCSC in vitro and PCSC tumor growth (tumor volume and weight) in vivo. δ-tocotrienol significantly inhibited the growth, microsphere/spheroid, migration/invasion, EMT(E-cadherin to vimentin), angiogenesis (VEGF), PCSC transcription factors (Nanog, Oct4, and Sox2), tumor growth and liver/lung metastasis compared to control. The combination of both drugs synergistically inhibited the cancer and stem cell growth, EMT, migration/invasion, microsphere/spheroid, metastasis, angiogenesis, and PCSC transcription factors in vitro as well as in vivo.
Conclusion: Vitamin E δ-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell self-renewal, tumor growth and metastasis.
Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Delta-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2017-1098