bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4804: Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment
Authors: Pillai Akshita P. , Dasari Subramanyam , Patel Bhavani , Banerjee Souresh , Kornienko Alexander V. , Munirathinam Gnanasekar 
Published: July 2016

Abstract
Major cause for prostate cancer mortality is due to the development of castration-resistant prostate cancer (CRPC) which usually develops when prostate cancer patients undergo standard androgen deprivation therapy. Treatment options currently available for CRPC are not very efficient and have many side effects. Hence, there is an urgent need to identify effective treatment strategies for CRPC. Natural compounds have previously shown to be an effective alternative treatment strategy for cancer. Polygodial (PG) an active constituent of mountain pepper belonging to sesquiterpene dialdehyde family has shown to have several pharmacological benefits including anti-bacterial, anti-fungal, anti-inflammatory, and anti-cancer properties. The objective of this study is to determine the therapeutic effects of PG against CRPC in a pre-clinical study. Cell lines used in this study were androgen dependent LNCaP and CRPC C4-2, DU145, and PC-3 cells. MTT, soft agar, and wound healing assays were performed to evaluate the effects of PG respectively on cell survival, anchorage independent growth, and migration characteristics of prostate cancer cells. PC-3 cells were utilized to determine the anti-cancer mechanisms of PG. Cell viability assay results showed PG effectively inhibited cell proliferation of CRPC C4-2, DU145 and PC-3 cell lines as compared to androgen dependent LNCaP cells. PG treatment significantly reduced the colony growth of CRPC cells in soft agar plates as compared to controls which correlates with its inhibitory effect on anchorage independent growth of these cells. In addition, PG also reduced the migration potential of CRPC cells in a wound healing assay. Inhibition of anchorage independent growth and motility of PCa cells by PG suggests its tumor suppressive and anti-metastatic potential. Western blot analysis showed that PG treatment downregulated the expression of a key cell survival molecule, High mobility group box1 (HMGB1) while promoting PARP-1 cleavage in PC-3 cells. Interestingly, our results also showed that BiP/GRP78, a marker of endoplasmic reticulum (ER) stress was upregulated following PG treatment in PC-3 cells. These findings suggest that PG enforces its tumor suppressive action by inhibiting HMGB1 signaling axis with concurrent activation of ER stress pathway in CRPC cells. Taken together, our study shows that PG might be an effective chemotherapeutic natural compound especially for CRPC.
Citation Format: Akshita P. Pillai, Subramanyam Dasari, Bhavani Patel, Souresh Banerjee, Alexander V. Kornienko, Gnanasekar Munirathinam. Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4804.
Abstract 4808: Identification of a novel compound, MO2455, that induces poly(ADP-ribose) (PAR) accumulation and inhibits the growth of cancer cells in vitro and in vivo
Authors: Shimoyama Tatsu , Sawada Takeshi , Akimoto Mari , Sasaki Yuka , Fujimori Hiroaki , Ishikawa Yoshinobu , Okawara Tadashi , Irie Tetsumi , Takamura Takeji , Matsuno Kenji , Inoue Kengo , Masutani Mitsuko , Koizumi Fumiaki 
Published: July 2016

Abstract
Poly (ADP-ribose) chain (PAR) formed by poly (ADP-ribose) polymerase (PARP) is catabolized mainly by poly (ADP-ribose) glycohydrolase (PARG). PARG is emerging as a therapeutic target for cancer, because its inhibition leads to cell death in some kinds of cancer cell lines.
In order to obtain small molecules that effectively inhibit PARG protein, an in-house collection of ∼10,000 small molecules were screened for their ability to accumulate the PAR in A549 cells at 5 μM. We identified ∼100 hit compounds. Among them, MO2282 and MO2455 induced the most significant accumulation of PAR. MO2455 is an analogue of MO2282 with improved water-solubility. MO2282 and MO2455 were evaluated in vitro for their ability to inhibit the catalytic activity of PARG. MO2282 and MO2455 showed modest inhibition activities against recombinant rat PARG. They also inhibited the growth of various kinds of cancel cell lines in vitro at an IC50 value of 0.05 - 3.0 μM and showed different spectrum of antitumor activity from conventional anticancer drugs, CDDP, ADM, PTX, and CPT-11. Next, we investigated the growth-inhibitory effect of MO2455 on A549 cells in a xenotransplanted model. A significant anti-tumor activity was observed in mice when treated with MO2455 at doses of 25 mg/kg every two days. Although treatment-related body weight loss was observed in mice treated with MO2455, body weight recovered by day 8.
In conclusion, the present data suggest that MO2455 has potential as a cancer drug with different mechanisms of action from conventional anti-cancer drugs.
Citation Format: Tatsu Shimoyama, Takeshi Sawada, Mari Akimoto, Yuka Sasaki, Hiroaki Fujimori, Yoshinobu Ishikawa, Tadashi Okawara, Tetsumi Irie, Takeji Takamura, Kenji Matsuno, Kengo Inoue, Mitsuko Masutani, Fumiaki Koizumi. Identification of a novel compound, MO2455, that induces poly(ADP-ribose) (PAR) accumulation and inhibits the growth of cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4808.
Abstract 4813: Magnetic iron oxide nanoparticles enhance anti-tumor effect of docetaxel on prostate cancer cells via ROS generation and NF-kappa B signaling
Authors: Kojima Kanako , Hashimoto Saho , Sakamaki Rina , Takahashi Sanai , Kasakura Risa , Maruyama Ryo , Nittami Tadashi , Ishiguro Hitoshi , Uemura Hiroji , Watanabe Masatoshi 
Published: July 2016

Abstract
Chemotherapy is one of treatment options for castration-resistant prostate cancer. Especially, docetaxel-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease. However, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. Magnetic iron oxide nanoparticles (MgNPs, Fe3O4) have been investigated for nanomedicine such as drug delivery, cancer diagnosis and therapy. We have also shown that MgNPs would modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and non-/carboxyl-modified magnetic nanoparticles (MgNPs/MgNPs-COOH) on a prostate cancer cell line, DU145 and clarify their mechanisms. While only MgNPs produced reactive oxygen species (ROS) and 8-OHdG, MgNPs-COOH did neither produce ROS nor 8-OHdG. The combination of docetaxel and MgNPs-COOH more effectively inhibited cancer cell growth and induced apoptosis compared with combination of docetaxel and MgNPs. Although docetaxel induced NF-kappa B expression, combination of docetaxel and MgNPs inhibited NF-kappa B expression compared with combination of MgNPs-COOH and docetaxel. However, both combinations increased p-Akt expression. These results suggest that MgNPs/MgNPs-COOH may enhance effect of docetaxel on prostate cancer cells via NF-kappa B signaling, however different factors may be involved in these phenomena, leading to new tumor ablation therapies.
Citation Format: Kanako Kojima, Saho Hashimoto, Rina Sakamaki, Sanai Takahashi, Risa Kasakura, Ryo Maruyama, Tadashi Nittami, Hitoshi Ishiguro, Hiroji Uemura, Masatoshi Watanabe. Magnetic iron oxide nanoparticles enhance anti-tumor effect of docetaxel on prostate cancer cells via ROS generation and NF-kappa B signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4813.
Abstract 4821: The WEE1 inhibitor AZD-1775 has synergic activity with trabectedin or lurbinectedin in ovarian cancer cells
Authors: Uboldi Sarah , Carrassa Laura , Frapolli Roberta , Ubezio Paolo , Erba Eugenio , D’Incalci Maurizio 
Published: July 2016

Abstract
AZD-1775 is a small molecule that selectively inhibits the tyrosine kinase WEE1, with a reported antineoplastic activity in ovarian cancer. WEE1 is a tyrosine kinase key regulator of DNA damage surveillance pathways that controls G2/M transition and ensures faithful DNA replication. WEE1 is required during normal S phase to avoid deleterious DNA breakage and prevent loss of genome integrity in the absence of exogenous DNA damage.
Trabectedin is a drug approved in 2007 by EMA and 2015 by FDA for the treatment of soft tissue sarcomas and in 2009 by EMA for the treatment of ovarian cancer patients, who have relapsed after 6 months from Platinum-based therapy, in combination with pegylated liposomal doxorubicin. Lurbinectedin (PM01183) is a trabectedin analog with a similar mechanism of action and, according to ongoing clinical investigations, less toxic and thus suitable for combinations of potential clinical interest. Since both trabectedin and lurbinectedin cause a G2/M block and AZD-1775 is able to inhibit the WEE1 activity with consequent disruption of G2/M checkpoint, we hypothesized that the combined treatment with AZD-1775 could be synergistic in ovarian cancer cells.
The sensitivity of the ovarian cancer cell lines OVCAR-5, A2780 and IGROV-1 to trabectedin, lurbinectedin and AZD-1775 alone or in combination (72h of continous treatment) was evaluated by a cell proliferation assay. The cytotoxic effect induced by the simultaneous administration of trabectedin with AZD-1775 or lurbinectedin with AZD-1775 was evaluated by a combination index analysis.
The results obtained showed that the combination trabectedin with AZD-1775 or lurbinectedin with AZD-1775 is synergic in all the ovarian cancer cell lines analyzed (Combination Index &lt;1). The combination lurbinectedin with AZD-1775 seems to be better than trabectedin with AZD-1775, in OVCAR5 cell line. The analysis of cell cycle and apoptosis are in progress in order to investigate the mechanism of the observed synergism. These positive results prompted us to study these combinations in vivo, in ovarian cancer xenografts derived from the cell lines used for the in vitro studies.
If the synergism observed in vitro will be confirmed in vivo, there will be a strong rationale to test these combinations in ovarian cancer patients.
Citation Format: Sarah Uboldi, Laura Carrassa, Roberta Frapolli, Paolo Ubezio, Eugenio Erba, Maurizio D’Incalci. The WEE1 inhibitor AZD-1775 has synergic activity with trabectedin or lurbinectedin in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4821.
Abstract 4824: Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models
Authors: Pundt Krista , Baldino Camern , Caserta Justin , Adjei Alex , Lee Kelvin , Zhu Xu , Verone-Boyle Alissa , Engler Frank , Pitzonka Laura , Fetterly Gerald 
Published: July 2016

Abstract
Standard therapy for acute myeloid leukemia (AML) results in significant mortality and morbidity with an overall cure rate of only 25%. Implementation of novel therapeutic options is needed in order to significantly improve patient survival and outcome. PIM serine/threonine kinases are overexpressed in hematological malignancies and regulate cell cycle, survival and drug resistance pathways—thus providing viable therapeutic targets. We hypothesized that targeted or cytotoxic therapy will enhance anti-tumor activity in combination with JP-11646, a novel PIM2 inhibitor, in preclinical AML models.
Preclinical data has shown JP-11646 exerted potent inhibition of AML cells in vitro and in vivo in subcutaneous AML xenograft models. An in vitro MTT assay was used to determine the overall anti-proliferative effects of single and combination therapies with respect to the downstream effects of PIM kinase and mechanism of action of JP-11646 in leukemia. First, the single agent efficacy in human AML (HEL, and MV(4;11)) cell lines were examined after 72 hours of exposure to JP-11646, rapamycin, daunorubicin and cytarabine. Overall potency, IC50, (0.17 μM (0.15-0.19), 0.003 μM (0.002-0.004), 0.067 μM(0.065-0.0699) and 0.31 μM (0.294-0.345), respectively) and maximal inhibition, Imax, of the various therapies was determined. Potential synergistic effects were first tested by treating AML cell lines with JP-11646 and daunorubicin, cytarabine, or rapamycin (an inhibitor of a pathway that regulates downstream molecules of the PIM kinase pathway). To quantify the synergy or interaction of JP-11646 in combination, a simple inhibitory non-competitive interaction model with an interaction parameter (Ø) as well as a three dimensional interaction surface was employed (Ø&lt;1 synergism, Ø&gt;1 antagonism). The intensity of the interaction (Ø) of JP-11646 with rapamycin (0.819 (0.395-0.543)), daunorubicin (0.469 (0.665-0.975)) or cytarabine (0.173 (0.118-0.229)) demonstrated synergistic effects across all combinations.
Here, we demonstrate that novel drug targets and drugs for AML treatment alone, and in combination with pre-existing therapies, may lead to improved strategies for AML treatment and these findings support future development of JP-11646 in novel combinatorial regimens for AML therapy.
Citation Format: Krista Pundt, Camern Baldino, Justin Caserta, Alex Adjei, Kelvin Lee, Xu Zhu, Alissa Verone-Boyle, Frank Engler, Laura Pitzonka, Gerald Fetterly. Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4824.
Abstract 4834: Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma
Authors: Morgan Katherine M. , Lee Francis , Michaud Erin , Fischer Bruce S. , Pine Sharon R. 
Published: July 2016

Abstract
Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer (NSCLC) cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among NSCLC patients whose tumors are wildtype for TP53. Here, we characterized the interaction between BMS-906024, a clinically relevant gamma secretase inhibitor (GSI) that inhibits Notch activation, and front-line chemotherapy in preclinical models of NSCLC. MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy were performed on a panel of human NSCLC cell lines, most of which were derived from adenocarcinomas. Analysis of the drug effects with CalcuSyn yielded significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. Treatment of lung adenocarcinoma xenografts in NOD scid gamma mice confirmed enhanced antitumor activity for the combination treatment of BMS-906024 and paclitaxel by mechanisms currently under investigation. These results are a step toward identification of the optimal combination of the GSI BMS-906024 with standard chemotherapies, as well as potential biomarkers that could be used to predict patient response to Notch-targeted therapy.
Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Bruce S. Fischer, Sharon R. Pine. Preclinical analysis of the Notch gamma secretase inhibitor BMS-906024 in combination with chemotherapy in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4834.
Abstract 4853: BMVC specifically binds the major G-quadruplex structure formed in the c-MYC promoter to lower c-MYC levels
Authors: Liu Wenting , Wu Guanhui , Lin Clement , Onel Buket , Chen Ding , Chang Ta-Chau , Yang Danzhou 
Published: July 2016

Abstract
The c-MYC proto-oncogene is one of the most deregulated genes in human cancers. Transcriptional repression of c-MYC is considered as one of the attractive strategies in targeting c-MYC. Previous studies revealed that the c-MYC promoter nuclease hypersensitive element (NHE) III1 region, which regulates 80-95% of total c-MYC transcription, can form DNA G-quadruplex (G4) and that stabilization of the c-MYC G4 could repress c-MYC gene expression. We have previously determined the molecular structure of the major G-quadruplex formed in the c-MYC promoter NHE (MycG4), which is an intramolecular parallel-stranded structure. BMVC, a carbazole derivative, was designed as a fluorescent probe for recognizing telomeric G4. However, we found that BMVC binds to MycG4 with much greater affinity and specificity. Cellular studies showed that BMVC was enriched in the nucleus at 48 hr after treatment, leading to markedly reduced c-MYC expression levels. Promoter-driven luciferase assays revealed that BMVC could enhance the inhibitory effects of MycG4, suggesting BMVC can repress c-MYC expression in vivo through stabilization of MycG4. To understand the molecular interactions between BMVC and MycG4, we have determined the molecular structure of the complexes of BMVC with MycG4 by NMR. BMVC appears to bind the 5’-end of the MycG4 with very high affinity, as shown by the slow-exchange binding on the NMR timescale. The structure of the 5’-end complex of BMVC and MycG4 shows that BMVC is paired to the flanking adenine with specific hydrogen bonding interactions, while the BMVC-adenine plane stacks nicely on the 5’-end G-tetrad of MycG4. Compared to the previous MycG4 complex with a quindoline compound, the tighter and more specific binding of BMVC appears to be imparted by the novel arched shape of BMVC and specific pairing recognition of BMVC with the flanking bases of MycG4. BMVC can also bind to the 3’-end of MycG4 with lower affinity to form a second complex. However, the 3’-end complex shows much more dynamic conformation and less specific interactions. Our results indicated that the cellular targets of BMVC include not only telomeric G4, but also the c-MYC promoter G4. Because of the inherent fluorescence and novel binding mode of BMVC, our study provides useful information for future design of improved carbazole-based anticancer agents or specific cellular fluorescent probes, as well as insights into specific recognition of MycG4 by small molecules.
Citation Format: Wenting Liu, Guanhui Wu, Clement Lin, Buket Onel, Ding Chen, Ta-Chau Chang, Danzhou Yang. BMVC specifically binds the major G-quadruplex structure formed in the c-MYC promoter to lower c-MYC levels. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4853.
Abstract 4854: Bazedoxifene inhibits ESR1 somatic mutants with improved potency compared to tamoxifene and raloxifene
Authors: Fanning Sean W. , Dharmarajan Venkat , Mayne Christopher G. , Toy Weiyi , Carlson Kathryn E. , Martin Teresa A. , Nowak Jason , Nwachukwu Jerome , Hosfield David J. , Tajkhorshid Emad , Chandarlapaty Sarat , Griffin Patrick , Shen Yang , Katzenellenbogen John A. , Greene Geoffrey L. 
Published: July 2016

Abstract
Despite continued administration of antiestrogen therapies, approximately 50% of all estrogen receptor alpha (ERalpha) positive breast cancers will present new metastatic lesions. The acquisition of secondary hormone-resistant metastatic breast cancers represents a significant clinical barrier towards life-long disease free survival for the patient. Somatic mutations to the ERalpha gene (ESR1) Y537S and D538G represent a novel mechanism of acquired antiestrogen resistance because they confer hormone-free transcriptional activity and reduced selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) potency. Fulvestrant, a SERD, was the only molecule that could completely ablate mutant ERalpha activity. Unfortunately, fulvestrant possesses poor pharmacologic profiles that limit its therapeutic utility. Bazedoxifene (BZA) is a potent mixed SERM/SERD and has improved pharmacokinetics and oral bioavailability compared to fulvestrant. We show that BZA inhibits Y537S and D538G ESR1 somatic mutation transcriptional activity with a greater potency than the SERMs 4-hydroxytamoxifen (TOT) and raloxifene (RAL). Further investigations into the biophysical and structural basis for BZA action suggest that BZA increases the conformational dynamics of helix 12, a key molecular switch that governs ERalpha action resulting in SERD-like properties and improved potency against the somatic mutations compared to TOT and RAL.
Citation Format: Sean W. Fanning, Venkat Dharmarajan, Christopher G. Mayne, Weiyi Toy, Kathryn E. Carlson, Teresa A. Martin, Jason Nowak, Jerome Nwachukwu, David J. Hosfield, Emad Tajkhorshid, Sarat Chandarlapaty, Patrick Griffin, Yang Shen, John A. Katzenellenbogen, Geoffrey L. Greene. Bazedoxifene inhibits ESR1 somatic mutants with improved potency compared to tamoxifene and raloxifene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4854.