bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2476: Acetylated Survivin functions in DNA damage repair
Authors: Cooper Zachary A. , Riolo Matthew , Holloway Michael P. , Altura Rachel A. 
Published: June 2012

Abstract
Survivin is an oncogenic protein that participates in cell division and inhibits apoptosis in cancer cells. These functions are dependent on its interaction with partner proteins within distinct subcellular compartments. Survivin is highly expressed in malignant tumors yet minimally expressed in normal tissues, making it an attractive target for molecular therapy. Inhibition of Survivin function enhances tumor cell sensitivity to radiation, the mechanism of which has been reported to result from a disruption of DNA-double-strand break repair processes. Recently, we demonstrated that Survivin is post-translationally modified by acetylation at numerous lysine residues, one of which is responsible for its subcellular transport. Acetylation at Lys-129 facilitates Survivin homodimerization which prevents its binding to the CRM1 nuclear export protein, inhibiting its translocation from the nucleus to the cytoplasm. The object of this study was to determine the potential relationship between Survivin acetylation and its function in nuclear repair processes. To elucidate the association between Survivin acetylation, nuclear localization and DNA double-strand break repair we subjected HeLa cells to 4Gy γXRT and examined Survivin acetylation at serial time points (20, 40, 60 min) after irradiation. An immediate deacetylation of Survivin was observed at 20 minutes, followed by an increase in both global acetylation and acetylation at Lys-129 at 40 minutes. The increase in Lys-129 acetylation correlated with its nuclear accumulation, as demonstrated by indirect immunofluorescence staining and immunoblotting after subcellular fractionation. Acetylated Survivin was found in endogenous immunoprecipitants with the DNA damage repair protein, Ku70, following γ-irradiation. Indirect immunoflourescence revealed co-localization of Ku70 and acetylated Survivin within the nucleus at similar time points after irradiation suggesting that Survivin acetylation may be required for Ku70 complex formation within the nucleus. These results implicate acetylated Survivin as a regulator of DNA damage repair through the Ku70 DNA repair pathway and further our understanding of Survivin function within the nuclear compartment of cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2011-2476
Abstract 2505: Neurotensin receptor antagonist, SR48692, sensitizes prostate cancer cells to radiation in vitro and in vivo
Authors: Casarez Eli V. , DaSilva John O. , Valerie Nicholas C.K. , Anaganti Suresh , Dunlap-Brown Marya E. , Amorino George P. , Larner James M. , Parsons Sarah J. , Dziegielewski Jaroslaw 
Published: June 2012

Abstract
Prostate cancer (PCa) is one of the major causes of cancer-related deaths in men. Androgen receptor (AR) and androgen sensitivity play a crucial role in the development of the disease. Thus, androgen depletion therapy has become a cornerstone of advanced PCa treatment, with or without radiotherapy. Multiple mechanisms have been proposed for the development of hormone-refractory disease, including an increase in neuroendocrine-like (NE-like) cells, which secrete survival and growth factors for surrounding tumor cells (Deeble et al., Cancer Res 2007). Neurotensin (NT) is secreted by both NE-like and cancer cells, and stimulate proliferation of PCa cells through its interaction with neurotensin receptor 1 (NTR1) (Amorino et al., Oncogene, 2007). In this report we investigate the efficacy of a NTR1 antagonist, SR48692, as a radiosensitizer in an orthotopic PC-3M xenograft model. The role of AR/sensitivity to androgen in response to SR48692 was also investigated using LNCaP and C4-2 cell lines. The latter studies were done to test the hypothesis that AR positive cells may be refractory to the raditherapy, because we had previously shown that neuropeptides from NE-like cells resulted in Src-mediated phosphorylation of AR (DaSilva et al., Cancer Res 2009). The results of the xenograft studies indicate that mice bearing PC-3M tumors and receiving the combination treatment (drug+radiation) showed a statistically significant decrease in tumor growth over radiation or SR48962 treatments alone. SR48692 was also found to radiosensitize PCa cells in vitro, independently of their androgen receptor/androgen sensitivity status. We further demonstrate that NT stimulates accumulation of AR under conditions of reduced androgen and that this activity is blocked by SR48692/radiation co-treatment. These findings suggest that in cells expressing the AR, NT reduces the efficacy of radiation by elevating AR levels and its ensuing pro-growth and -survival signals. Blocking the actions of NT by SR48692 reduces the levels of AR protein and as a result increases cellular sensitivity to radiation. However, in cells lacking the AR, another mechanism(s) of drug action must be operative. Together, our studies suggest that in AR positive or negative PCa cells, NTR1 signaling pathway(s) are novel targets for combined SR48962/radiotherapy of PCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2505. doi:10.1158/1538-7445.AM2011-2505
Abstract 2520: Ku-dependent non-homologous end-joining interferes the efficiency of Mre11 binding to replication related DNA double strand breaks
Authors: Wang Hongyan , Zhang Xiangming , Wang Ya 
Published: June 2012

Abstract
Background: Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces replication related DNA double strand breaks (DSBs). Previously, it was reported that Ku-dependent non-homologous end-joining (NHEJ) deficient DT40 cells were more resistant to CPT-induced killing than wild type cells (JBC, 279:37343, 2004), however, the mechanism remains unclear. We were interested in testing the hypothesis that Mre11 binding to DNA double strand break (DSB) (the first step for initiating homologous recombination repair (HRR)) is interfered by the Ku-dependent NHEJ and the interference was much stronger in S phase.
Methods: Different fork-related DNA structures were designed for testing the efficiency of purified Mre11 protein (kindly provided by Dr. Tainer) in vitro. DT40 cell lines: wild type, Ku70-/, DNA-PKcs-/-, Rad54-/- and Rad51 conditional knock out cells were used in this study. The efficiency Mre11 binding to chromatin DNA in CPT treated the cell lines were detected. The cell cycle distribution was measured by a flow cytometer. The sensitivity of these cell lines to CPT were measured by a clonogenic assay.
Results: Compared with their wild-type counterparts, Rad54−/− and Rad51 conditional knock out cells (essential factors for (HRR)) were much more sensitive to CPT-induced killing but Ku70−/− and DNA-PKcs cells (essential factors for non-homologous end joining (NHEJ)) were much more resistant to CPT-treated killing, which was accompanied by a huge S-phase block in these resistant cells. Mre11 bound to DNA substrates especially to the mimic DNA replication fork substrates. Mre11 bound to chromatin DNA in Ku70-/- and DNA-PKcs-/- cells stronger than that in wild type cells following CPT treatment.
Conclusion: CPT-induced S checkpoint facilitates Mre11 binding and promotes HRR, which protects cells from CPT-induced killing. The Ku-dependent NHEJ block efficiency of Mre11 binding to DNA substrates especially DNA replication related structure, which inhibits HRR and renders sensitivity of the cells to CPT treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2520. doi:10.1158/1538-7445.AM2011-2520
Abstract 2527: Amonafide and its metabolite N-acetyl amonafide are Top2 poisons with differing biochemical properties
Authors: Soans Eroica , Shanmuganatham Karthik , Rogojina Anna , Nitiss John L. 
Published: June 2012

Abstract
Naphthalimides derivatives have been extensively studied as anti-cancer agents. Amonafide (5-amino-2-[2-(dimethylamino)ethyl]-1H-benzo[de]isoquinoline-1,3(2H)-dione) showed clinical activity especially in some groups of AML patients. Amonafide has been shown to target topoisomerase II (Top2), and to stabilize Top2 covalent complexes. Therefore, the agent is a Top2 poison, however, the compound shows some unusual properties. Unlike most Top2 poisons, the action of amonafide against Top2 is largely ATP independent; In addition, amonafide leads to cleavage of DNA at a very restricted set of sites compared to other Top2 poisons such as mitoxantrone or etoposide. These findings have led to suggestions that amonafide may target Top2 in an unconventional way. Another obstacle to the clinical use of amonafide is variable drug metabolism. Felder and colleagues showed that amonafide is metabolized by N-acetyl transferase 2 (NAT2) to form N-acetyl amonafide (NAA). Toxicity of amonafide regimens is associated with higher levels of NAT2 activity 2. The mechanism of NAA toxicity has not been reported. We have used the ICE assay developed by Muller and colleagues to assess Top2 covalent complex levels in cells treated with either amonafide or NAA. We found that amonafide induces Top2 mediated DNA cleavage, and that covalent complexes formed by both Top2 alpha and Top2 beta were seen. Interestingly, NAA induced higher levels of Top2 covalent complexes than the parent compound. In addition, the level of Top2 covalent complexes increased with increasing NAA dose, whereas a plateau in the level of Top2 covalent complexes was seen with amonafide at relatively low doses. We are currently comparing the action of amonafide and NAA against purified human topoisomerases. We suggest that NAA is a Top2 poison, and a plausible hypothesis is that NAA may act more like a conventional Top2 poison, while amonafide may show a better therapeutic index because it has more limited potential for forming Top2 covalent complexes. These results may be useful in the further development of amonafide derivatives with a favorable therapeutic profile.
(1) Felder, T. B.; McLean, M. A.; Vestal, M. L.; Lu, K.; Farquhar, D.; Legha, S. S.; Shah, R.; Newman, R. A. Drug Metab Dispos 1987, 15, 773.
(2) Ratain, M. J.; Rosner, G.; Allen, S. L.; Costanza, M.; Van Echo, D. A.; Henderson, I. C.; Schilsky, R. L. J Clin Oncol 1995, 13, 741.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2527. doi:10.1158/1538-7445.AM2011-2527
Abstract 2540: Evaluation of novel bis-amidine osmium complex as anti-proliferative agents
Authors: Ajay Matta , DeSouza Leroi V. , Lau T. C. , Siu K.W. Michael 
Published: June 2012

Abstract
Introduction. Despite improvement in current treatment strategies, including surgery, chemotherapy (CT) and radiotherapy (RT), survival of cancer patients in advanced stages has not improved significantly over the last decade. Organometallic complexes of platinum (cisplatin, carboplatin and oxaliplatin) are in use as chemotherapeutic agents worldwide. However, acquired drug resistance to these platinum complexes has necessitated the search for novel strategies to overcome this limitation, which includes combination therapies and the development of novel platinum or non-platinum complexes as drugs.
Methods. Anti-proliferative effects of a bis-amidine complex (Os-Sh1) was determined by measuring the inhibition of cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry-based cell-cycle analysis, annexin V dye binding assay and TUNEL assay in endometrial cancer (Hec1A and KLE) and cervical cancer (HeLa) cells.
Results: Cell viability (MTT) assays revealed inhibition of cell proliferation on treatment with the bis-amidine osmium complex (Os-Sh1) in HEC1A, KLE and HeLa cell lines in a dose- (1μM – 50μM) and time-dependent manner (24h – 96h). Cell-cycle analysis showed increased cell death, i.e. the sub-G0 fraction, with G0/G1-arrest and reduction in the G2/M phase of cell cycle on treatment with the Os-Sh1 in these cell lines. Results of annexin V assay suggested apoptosis as the mechanisms of Os-complex induced cell death. Apoptosis was further confirmed by TUNEL assay using flow cytometry analysis. Western blot analysis showed cleavage of caspase 9, caspase 3 and poly-ADP ribose polymerase (PARP), suggesting activation of the intrinsic mitochondrial pathway of apoptosis. Interestingly, Os-Sh1 was more effective in inhibiting cell proliferation at a lower dose and shorter period of time (LD50=20 μM, 48h) in comparison to cisplatin, carboplatin and oxaliplatin in HEC1A, KLE and HeLa cell lines.
Conclusions: Our in vitro data clearly demonstrated anti-proliferative effects of a novel bis-amidine osmium complex in endometrial and cervical cancer cells at a lower dose and in shorter period of time in comparison to platinum drugs. Based on these results, we hypothesize that such osmium complex has the potential as effective cytotoxic agents wherein cancer cells acquire resistance to commonly used platinum drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2540. doi:10.1158/1538-7445.AM2011-2540
Abstract 2541: Inhibition of DNA repair by trifluoperazine sensitizes human lung cancer cells to apoptosis associated with lysosomal dysfunction following prolonged G2-M checkpoint arrest
Authors: Zong Dali , Hååg Petra , Lewensohn Rolf , Viktorsson Kristina 
Published: June 2012

Abstract
Clinical therapy resistance severely limits the efficacy of DNA damaging chemotherapy in human lung non-small cell lung carcinoma (NSCLC). Here we show that chemosensitization can be achieved in NSCLC by combining clinically-relevant DNA damaging agents with trifluoperazine (TFP). Colony formation assays demonstrated that TFP significantly potentiated the cytotoxicity of bleomycin and cisplatin in NSCLC cell lines. TFP impaired the repair of bleomycin- and cisplatin-induced DNA double strand breaks (DSBs), and consequently delayed the recovery from DNA damage-induced G2-M checkpoint (12 h vs at least 24 h). At later time points (&gt; 24 h), NSCLC cells co-treated with TFP and bleomycin or cisplatin were able to overcome the initial G2-M checkpoint arrest, as evidenced by the reappearance of the mitosis markers and reduction in CFSE fluorescence. However, these cells showed increased micronucleation, apoptosis and gradual loss of proliferative capacity due to secondary G2-M arrest. Notably, TFP co-treated NSCLC cells underwent limited lysosomal membrane permeabilization (LMP) prior to Bak/Bax activation and mitochondrial depolarization. In turn this led to robust activation of caspase-3 preferentially in cells residing in the G2-M phase. In conclusion, our data supports the notion that by antagonizing DSB repair, TFP forces NSCLC cells into prolonged checkpoint arrest (whether initial or secondary) which sensitizes them to apoptosis associated with lysosomal dysfunction.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2541. doi:10.1158/1538-7445.AM2011-2541
Abstract 2546: AXL targeted therapy blocks tumor progression and prevents tumor metastasis in pancreatic cancer
Authors: Rajeshkumar N.V. , Karikari Collins , DeOliveira Elizabeth , de Wilde Roeland F. , Holland Sacha J. , Payan Donald G. , Maitra Anirban 
Published: June 2012

Abstract
Background: Metastasis and drug resistance are the major causes of mortality in patients with pancreatic ductal adenocarcinoma (PDA). Once developed, the progression of PDA metastasis is virtually unstoppable with current therapies. Accumulating evidence suggests important roles for the receptor tyrosine kinase AXL in cancer progression, invasion, metastasis, drug resistance, and patient mortality. Given the critical influence of metastasis on the clinical history of PDA, we hypothesize that pharmacological inhibition of AXL might inhibit tumor growth and prevent PDA metastasis.
Methods: We investigated the AXL expression in a panel of human pancreatic cancer xenografts using Affymetrix gene array as well as qRT-PCR. We conducted a comprehensive preclinical trial to determine whether AXL targeted monotherapy, and in combination with gemcitabine, was effective in blocking PDA tumor progression and metastasis using subcutaneous as well as orthotopic pancreatic cancer models.
Results: R428, a potent selective small molecule inhibitor of AXL, inhibited proliferation of pancreatic cancer cell lines in a concentration-dependent manner. A combination of R428 with gemcitabine could significantly inhibit primary tumor growth compared to gemcitabine treated mice. Notably, R428 alone and in combination with gemcitabine was remarkably effective in preventing the development of metastasis to organs and lymph nodes as compared to gemcitabine treatment in a highly aggressive orthotopic model.
Conclusions: The data presented here provide strong evidence for the therapeutic development of AXL inhibitors as anti-metastatic agents in pancreatic cancer. A combination treatment of R428 and gemcitabine was highly effective in controlling the primary tumor growth and preventing metastatic spread. The novel therapeutic approach tested here has potential therapeutic implications for improving the current standard of care for PDA patients and to contribute towards making PDA a more manageable disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2011-2546
Abstract 2553: Inhibition of γ-secretase in combination with Lapatinib induces tumor regression in vivo
Authors: Pandya Kinnari , Meeke Kathleen , Rogowski Allison , Clementz Anthony , Osipo Clodia 
Published: June 2012

Abstract
Amplification, over-expression, and/or hyperactivity of ErbB-2 occur in 15-30% of breast tumors which include both luminal B and the HER2+ subtypes. Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab. Lapatinib, a dual EGFR/ErbB-2 tyrosine kinase inhibitor, is approved for the treatment of ErbB-2-positive breast cancer that has advanced during or after trastuzumab treatment. However, resistance to lapatinib occurs in cell culture models in vitro. We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors of ErbB-2, trastuzumab or a tyrosine kinase inhibitor. Furthermore, we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor (MRK-003, GSI). Additionally, in an independent study we showed that GSI also prevented resistance to lapatinib. Since lapatinib is a very potent inhibitor of ErbB-2 tyrosine kinase activity in vitro, we asked whether a combination therapy based on lapatinib and GSI can prevent the resistant phenotype by using a pre-clinical in vivo model. BT474 breast tumor xenografts were generated in athymic mice and randomized to vehicle, GSI, lapatinib, or lapatinib plus a GSI. Tumor size was measured up to 13 weeks with treatments. The xenograft studies using BT474 lapatinib sensitive cells demonstrated that lapatinib treatment alone inhibited tumor growth by 40%. GSI alone had no effect on growth of tumors compared to vehicle control. However, GSI plus lapatinib significantly reduced tumor growth where regression was observed. Tumor histology of lapatinib plus GSI-treated tumors displayed a significant decrease in Ki67, a proliferation marker, and an increase in apoptotic cells as measured by TUNEL. Furthermore, both ERK1/2 and AKT1 phosphorylated proteins were undetectable by western blot in tumors treated with lapatinib plus GSI. These results suggest that both ErbB-2 and Notch activities must be inhibited to induce tumor regression of ErbB-2 positive breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2553. doi:10.1158/1538-7445.AM2011-2553
Abstract 2554: Synergistic antitumor effect of AUY922 in combination with sorafenib in hepatocellular carcinoma cells
Authors: Lau Chi-Keung , Yang Z F. , Ho D W. , Lam C T. , Pang R , Fan S T. , Poon R T. 
Published: June 2012

Abstract
PURPOSE: Molecularly targeted therapy is of particular importance for HCC due to a lack of efficacy with currently approved chemo-toxic therapies. It is of interest to investigate the combined effect of two molecular targeted drugs, sorafenib (a multi-kinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity) and a highly potent non-geldamycin HSP90 inhibitor, NVP-AUY922 on HCC treatment. EXPERIMENTAL DESIGNS: Cell viability after different treatments was measured by both 3,[4,5-dimethylthiazol-2-yl] -2,5-diphenyl-tetrazolium bromide (MTT) assay and cytofluorometric annexin-V apoptotic assay to compare the apoptotic cells induced by single versus combined treatment. Cell cycle analysis was also performed, and Western blotting was employed to determine the effects on MEK signaling, and in vivo efficacy was determined in nude mice with PLC/PRF/5 xenografts. RESULTS: Combined drugs treatment produced a synergistic effect on decreased HCC cell viability shown by MTT assay. An increase in the number of apoptotic cells were observed by apoptotic assay in combined drugs group when compared with single agents sorafenib or NVP-AUY922. Also, sorafenib combined with NVP-AUY922 induced S-phase arrest which was demonstrated by cell cycle analysis. Sorafenib alone decreases phospho-Erk1/2 expression, and this effect was further enhanced in combination treatment with NVP-AUY922. Finally, sorafenib plus NVP-AUY922 significantly suppressed PLC/PRF/5 xenograft tumor growth when compared with single (NVP-AUY922 or Sorafenib) treatment alone. CONCLUSION: The combination therapy of sorafenib and NVP-AUY922 can be a new and promising therapeutic approach to the treatment of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2011-2554