bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 789: Parthenolide sensitizes colorectal cancer cells to TRAIL-induced apoptosis by regulating mitochonrial pathway
Authors: Kim Se Lim , Kim Sang-Wook , Lee Soo-Teik , Kim Seong Hun , Kim In Hee , Lee Seung Ok , Kim Dae Ghon 
Published: May 2015

Abstract
Combination therapy utilizing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in conjunction with other anticancer agents, is a promising strategy to overcome TRAIL resistance in malignant cells. Recently, parthenolide (PT) has proved to be a promising anticancer agent, and several studies have explored its use in combination therapy. Here, we investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. TRAIL inhibited HCT116 cell growth in a dose-dependent manner; however, this reduction did not occur in TRAIL resistant HT-29 cells with an even higher dose of TRAIL. A combination of PT with TRAIL significantly inhibited cell growth of TRAIL resistant HT-29 cells. Consistent with cell growth inhibition, apoptotic cell death was significantly increased by a combination of PT with TRAIL in both of HCT116 and HT-29 cells. Results of flow cytometry analysis demonstrated that TRAIL-sensitive HCT116 cells had much higher death receptor (DR) 5 than TRAIL-resistant HT-29 cells. Interestingly, treatment of PT and/or TRAIL did not affect DR4/DR5, these results indicate that the apoptotic effect of combination is death receptor-independent apoptosis. We observed that the synergistic effect was associated with Bcl-2 family members, p53 and cytochrome C. Moreover, activation of caspase -3, -8 and -9 was increased by combination treatment in both of TRAIL-resistant and -sensitive cells. These results suggest that PT sensitizes TRAIL-induced apoptosis via death receptor-independent and mitochondrial-dependent pathway. Combination treatment using PT and TRAIL might offer an effective strategy to overcome TRAIL resistance in certain CRC cells.
Citation Format: Se Lim Kim, Sang-Wook Kim, Soo-Teik Lee, Seong Hun Kim, In Hee Kim, Seung Ok Lee, Dae Ghon Kim. Parthenolide sensitizes colorectal cancer cells to TRAIL-induced apoptosis by regulating mitochonrial pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 789. doi:10.1158/1538-7445.AM2014-789
Abstract 79: Deletion of STAT3 in a mouse model for metastatic melanoma
Authors: Swoboda Alexander , Sobieszek Isabel J. , Schlederer Michaela , Zahma Safia , Marjanovic Jelena , Poli Valeria , Kenner Lukas , Hengstschläger Markus , Mikula Mario , Moriggl Richard 
Published: May 2015

Abstract
The incidence of metastatic melanoma, a very aggressive type of human skin cancer, has steadily increased over the last years and is associated with high mortality. Activating mutations in the N-Ras proto-oncogene are characteristic for cutaneous melanoma. The most frequent mutation found in N-Ras is a lysine substitution of glutamine at codon 61 (Q61K) constitutively activating the protein. Together with other mutations, especially inactivation of the CDKN2A locus, it is sufficient for spontaneous melanoma formation and subsequent metastasis formation in mice.
STAT3 proteins are highly phosphorylated in melanoma. We identified strong STAT3 expression and activation in 70% of patients that show melanoma brain metastases. Here, we investigated whether deletion of this transcription factor in a mouse model expressing mutant N-RasQ61K transgene under the control of the tyrosinase promoter in combination with a homozygous CDKN2A deletion, leads to modified melanoma formation. Interestingly, we found decreased survival in male mice that do not express STAT3 in melanoma cells. We analyzed primary tumor development, metastasis, and survival using histo-pathological examination between groups of STAT3 positive and negative mice.
To further assess whether the enhanced tumor progression upon loss of STAT3 is a cell autonomous effect we established melanoma cell lines derived from mouse tumors with or without STAT3. These novel cell lines will be used to analyze growth and survival properties. We will also test the influence of a functional immune system to question immunoediting by xenotransplantation experiments.
Citation Format: Alexander Swoboda, Isabel J. Sobieszek, Michaela Schlederer, Safia Zahma, Jelena Marjanovic, Valeria Poli, Lukas Kenner, Markus Hengstschläger, Mario Mikula, Richard Moriggl. Deletion of STAT3 in a mouse model for metastatic melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 79. doi:10.1158/1538-7445.AM2014-79
Abstract 790: A high-throughput chemical screen identifies synergistic activity between neurotransmitter receptor inhibitors and crizotinib in ALK-mutated neuroblastoma
Authors: Moore Nathan , Pukma Srunphut , Gray Nathanael , George Rani 
Published: May 2015

Abstract
Activating mutations in the anaplastic lymphoma receptor tyrosine kinase (ALK) represent important therapeutic targets in neuroblastoma, a common childhood cancer that accounts for 15% of all pediatric oncology deaths. One of the more common mutations, ALKF1174L, is sensitive to the sole FDA-approved ALK inhibitor, crizotinib, only at high doses and mediates acquired resistance to crizotinib in ALK-rearranged cancers. To identify compounds that would synergize with crizotinib to increase cytotoxicity in neuroblastoma cells, we devised a high-throughput small molecule synergy screen using the ALKF1174L-dependent SH-SY5Y cell line to compare cell viability between screen compound alone and screen compound in combination with crizotinib. Compounds ranged from those with clinical approval and known therapeutic indications to those with only predicted bioactivity. Of ∼10,000 compounds screened, the most recurrent hits included adrenergic and dopaminergic neurotransmitter receptor inhibitors. Validation studies with a candidate dopamine receptor D2 antagonist, chlorpromazine, resulted in increased cytotoxicity when combined with crizotinib over that of either single agent alone. These studies support further pre-clinical efforts to explore the therapeutic potential of combining crizotinib with neurotransmitter receptor inhibitors in ALKF1174L-mutated neuroblastoma.
Citation Format: Nathan Moore, Srunphut Pukma, Nathanael Gray, Rani George. A high-throughput chemical screen identifies synergistic activity between neurotransmitter receptor inhibitors and crizotinib in ALK-mutated neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 790. doi:10.1158/1538-7445.AM2014-790
Abstract 792: Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: A shorter drug-free interval leads to more efficient antitumor effects
Authors: Komura Toshihiro , Ohnuma Shinobu , Miura Koh , Shirasaka Tetsuhiko , Kajiwara Taiki , Kudoh Katsuyoshi , Haneda Sho , Toshima Masahide , Kohyama Atsushi , Musha Hiroaki , Naitoh Takeshi , Katayose Yu , Unno Michiaki 
Published: May 2015

Abstract
[Background] A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. The aim of this study was to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.
[Methods] Mice were treated with S-1/LV either in a daily group (two weeks of administration followed by two weeks of withdrawal) or an alternate-day group (administration on alternate days for four weeks), then the mice of both groups were sacrificed and the xenograft tumors were resected. To assess the adverse reactions, the body weight changes, the condition of feces, mucosal injury of small intestine and myelosuppression were compared between both groups. Furthermore, tumor volume, tumor growth inhibition (TGI) and the expression of Ki67, TUNEL, cIAP2 and XIAP were analyzed to evaluate the antitumor activity and tumor apoptosis.
[Results] Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, no adverse reactions were observed in the alternate-day group, except slight myelosuppression. The TGI in the alternate-day group was better than that in the daily group, possibly resulting from apoptosis of tumor cells due to the suppression of cIAP2.
[Conclusion] Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve higher antitumor activity without severe adverse reactions. Therefore, we propose that clinical trials with this regimen should be conducted in CRC patients.
Citation Format: Toshihiro Komura, Shinobu Ohnuma, Koh Miura, Tetsuhiko Shirasaka, Taiki Kajiwara, Katsuyoshi Kudoh, Sho Haneda, Masahide Toshima, Atsushi Kohyama, Hiroaki Musha, Takeshi Naitoh, Yu Katayose, Michiaki Unno. Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: A shorter drug-free interval leads to more efficient antitumor effects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2014-792
Abstract 795: Metronomic chemotherapy with cyclophosphamide and metformin inhibits tumor and metastasis growth M-406 murine mammary adenocarcinoma
Authors: Asad Antonela S. , Basualdo Jesús , Micheletti Lucía , Gardenal María C. Capello , Perroud Herman A. , Rico María J. , Rozados Viviana R. , Scharovsky O. Graciela 
Published: May 2015

Abstract
Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have already demonstrated that MCT, as an intervention strategy, of metronomic Cy combined with celecoxib or doxorubicin inhibits mammary tumors growth. Our present aim was to analyze the antitumor and antimetastatic effects of MCT of Cy combined with Met. Inbred CBi mice were s.c. or i.v. challenged with M-406 tumor (Day 0), and treated when the tumors reached a volume of 100 a 150 mm3 (s.c.) or from Day 3 (i.v.) on, with: I) no further treatment (controls); II) Cy in the drinking water (20-30 mg/kg body weight/day); III) Met 3 times/week by gavage (100 mg/kg); IV) Treated as II + III. Tumors were measured and animals weighed twice a week and blood samples for glycemia determination were taken. On day 36 tumor volume in group IV (mm3, mean ± SEM: 929.7 ± 213.8) was lower than in groups I (2880.0 ± 1530.0), II (2896.4 ± 976.9) and III (3772.0 ± 68.0). On day 46, with only two groups remaining, tumor volume in group IV was lower than that in group II (p=0.032). All the groups differed in tumor volume doubling time (days, mean ± SEM; I: 3.8 ± 0.3, II: 5.3 ± 0.7, III: 3.6 ± 0.4, IV: 5.4 ± 0.2) (p&lt;0.05). All the groups differed in survival (days, median, I: 30.5; II: 44; III: 29; IV: 50) (p=0.0063), showing group IV the highest one. There were neither weight losses nor changes in the glycemia with respect to basal values both in s.c. and i.v. experiments. In the i.v. experiment, animals were sacrificed on day 13, when the first mouse showed signs of metastatic illness. The number and diameter of lung metastasis were determined and total metastatic volume (TMV) was calculated. The experimental groups differed in TMV (p&lt;0.0001), being those of groups II (mm3, mean ± SEM: 162.1 ± 41.4) and IV (218.6 ± 31.3) significantly lower (p&lt;0.001 and p&lt;0.01, respectively) than those in groups I (491.3 ± 80.6) and III (432.3 ± 54.5). These results clearly show that metronomic chemotherapy with a combination of cyclophosphamide and metformin significantly inhibits tumor growth and increase survival, also decreasing the development of metastasis of a murine mammary adenocarcinoma, while being devoid of toxicity.
Citation Format: Antonela S. Asad, Jesús Basualdo, Lucía Micheletti, María C. Capello Gardenal, Herman A. Perroud, María J. Rico, Viviana R. Rozados, O. Graciela Scharovsky. Metronomic chemotherapy with cyclophosphamide and metformin inhibits tumor and metastasis growth M-406 murine mammary adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 795. doi:10.1158/1538-7445.AM2014-795
Abstract 796: Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy
Authors: Cruickshanks Nichola A. , Hamed Hossein A. , Booth Larry A. , Tavallai Seyedmehrad , Sajithlal G B. , Grant Steven , Poklepovic Andrew , Dent Paul 
Published: May 2015

Abstract
Detachment of cells from the extracellular matrix (ECM) results in a form of cell death referred to as anoikis. Anoikis resistance (AR), frequently acquired by malignant cells, is required for tumor metastases. The present study focused on identifying the mechanisms by which drug sensitivity is restored in previously resistant AR breast cancer cells. AR breast cancer cells display reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA and PUMA. In contrast, expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. It has previously been noted that AR cells display resistance to several currently available anti-tumor cell therapies, including a combinational approach with Lapatinib (ERBB1/2 inhibitor) and Obatoclax (MCL-1 inhibitor, exhibiting reduced autophagic flux, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL in AR cells resulted in apoptosis to a greater extent than in their wild-type counterparts. Pre-treatment of AR cells with Valproate (histone deacetylase inhibitor (HDACIs)); for 24hrs increased the levels of toxic BH3 domain proteins whilst simultaneously reducing levels of MCL-1 and re-sensitising AR cells to therapy-mediated cell death. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored chemo-sensitivity and prolonged animal survival. These data argue that pre-treatment with HDACIs may provide a mechanism to enhance the anti-tumor effect of chemotherapy in AR breast cancer cells.
Citation Format: Nichola A. Cruickshanks, Hossein A. Hamed, Larry A. Booth, Seyedmehrad Tavallai, G B. Sajithlal, Steven Grant, Andrew Poklepovic, Paul Dent. Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2014-796
Abstract 798: Androgen receptor, PI3K/mTOR and PSMA: Exploring and exploiting the interplay between therapeutic targets in prostate cancer
Authors: Murga Jose D. , Magargal Wells W. , Moorji Sameer M. , DiPippo Vincent A. , Olson William C. 
Published: May 2015

Abstract
Introduction: Androgen receptor (AR), the PI3K/mTOR signaling pathway and prostate-specific membrane antigen (PSMA) represent significant potential targets for prostate cancer therapy. The present study examined the cross-regulation and co-targeting of these molecular pathways.
Methods: Cytotoxicity and the kinetics of antigen expression were evaluated in prostate cancer cell lines (LNCaP and C4-2) that vary according to androgen dependence. Expression of PSMA, prostate-specific antigen (PSA), and AR was evaluated in cells cultured in rapamycin and AR inhibitors. Cells were tested for susceptibility to PI3K/mTOR inhibitors used alone and in combination with PSMA ADC, a fully human PSMA monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE). Potential drug synergy or antagonism was evaluated using the Bliss independence method.
Results: In androgen-dependent LNCaP cells, rapamycin exerted antiproliferative effects that were accompanied by an increase in AR expression and signaling in the absence of any significant effect on PSMA expression. In androgen-independent C4-2 cells, rapamycin increased AR expression/signaling and PSMA expression in the absence of any significant anti-proliferative effect. AR inhibitors synergized with PSMA ADC in LNCaP and C4-2 cells, but PI3K/mTOR pathway inhibitors synergized with PSMA ADC in C4-2 cells only. More modest synergy was observed by combining non-targeted microtubule inhibitors with inhibitors of AR or mTOR. Compared with rapamycin, GDC0941 (PI3K inhibitor) and MK-2206 (Akt inhibitor), both upstream of mTOR, synergized less strongly with PSMA ADC in C4-2 cells.
Conclusions: In this study, AR and PI3K/mTOR pathways exhibited cross-regulation impacting PSMA expression. PSMA ADC synergized with AR and mTOR inhibitors via a multimodal mechanism involving increased PSMA expression and disruption of microtubule function. The findings support clinical exploration of regimens combining PSMA-targeted therapies with inhibitors of the AR and/or PI3K/mTOR signaling pathways.
Citation Format: Jose D. Murga, Wells W. Magargal, Sameer M. Moorji, Vincent A. DiPippo, William C. Olson. Androgen receptor, PI3K/mTOR and PSMA: Exploring and exploiting the interplay between therapeutic targets in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 798. doi:10.1158/1538-7445.AM2014-798
Abstract 80: Activated SHP2 collaborates with MYCN in neuroblastoma tumorigenesis
Authors: Zhang Xiaoling , Yang Guang , Look A.Thomas , Neel Benjamin G. , Zhu Shizhen (Jane) 
Published: May 2015

Abstract
Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed a transgenic line in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69K synergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland (IRG), the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish coexpressing MYCN and ptpn11E69K. Coexpression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. In addition, coexpression of ptpn11E69K and MYCN induced adrenal neuroblastic hyperplasia in the IRG of all the transgenic fish at 5 weeks of age, a phenotype that has only been observed in about 50% of transgenic fish overexpressing activated ALK and MYCN or MYCN alone. Thus, these results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying genetic alterations identified in integrative genomic studies.
Citation Format: Xiaoling Zhang, Guang Yang, A.Thomas Look, Benjamin G. Neel, Shizhen (Jane) Zhu. Activated SHP2 collaborates with MYCN in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 80. doi:10.1158/1538-7445.AM2014-80
Abstract 800: Synergistic effects of CBL0137 and gemcitabine against non-small cell lung and pancreatic cancer xenografts
Authors: Burkhart Catherine , Kohrn Rachael , Walker Brittany , Meyer David , Gurova Katerina , Gudkov Andrei 
Published: May 2015

Abstract
CBL0137 represents a novel class of small molecules that simultaneously activate p53 and inhibit cancer-associated stress response pathways, such as NF-κB and HSF-1. The effects of CBL0137, culminating in tumor cell death, are mediated by the inhibition of FACT, a chromatin remodelling factor complex composed of SSRP1 and SPT16 subunits, that is involved in the transcription of genes with highly ordered chromatin structure, replication, and mitosis. FACT is expressed during early embryogenesis and in undifferentiated progenitors and stem cells of adult tissues while protein levels of both FACT subunits are almost undetectable in differentiated cells and tissues. FACT is expressed in several tumor types compared to equivalent normal tissues. In particular, SSRP1 is expressed in a high proportion of lung and pancreatic cancers (∼45-63%). FACT positive tumors are associated with an aggressive malignant phenotype (high grade, metastatic disease, worse overall survival). Therefore, FACT represents a potentially important target for cancer therapy. We investigated the effect of CBL0137 and its combination with gemcitabine a nucleoside analog used in treatment of non-small lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDA). We found that CBL0137 had significant antitumor activity against a H1975 NSCLC xenograft model (89.6% growth inhibition) as well as a patient-derived PDA (PDA#2) model (70.4% growth inhibition). Furthermore, CBL0137 acted synergistically with gemcitabine against both tumor types as evidenced by increased median survival time compared to each drug administered as a single agent (increase in survival time: H1975- &gt;47 days combination vs 24 days CBL0137 only, 32.5 days gemcitabine only; PDA#2- &gt;42 days combination vs 28 days CBL0137 only, 30.5 days gemcitabine only). Preliminary investigation into the mechanism underlying the synergy of this combination suggest that CBL0137 may enhance gemcitabine activity in part by abrogating the expression of modulators of gemcitabine response, such as cytidine deaminase and ribonucleotide reductase. Together, these data indicate that CBL0137 may provide a clinical benefit for the treatment of both NSCLC and PDA when combined with standard agent gemcitabine.
Citation Format: Catherine Burkhart, Rachael Kohrn, Brittany Walker, David Meyer, Katerina Gurova, Andrei Gudkov. Synergistic effects of CBL0137 and gemcitabine against non-small cell lung and pancreatic cancer xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 800. doi:10.1158/1538-7445.AM2014-800