bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2528: Enhanced sensitivity of pancreatic cancer cells to the concurrent inhibition of aberrant Stat3 and EGFR or Src
Authors: Soumya Jaganathan , Yue Pei Bin , Turkson James 
Published: February 2011

Abstract
Pancreatic cancer is a lethal disease with little understanding of the etiology and no effective therapies. While aberrant epidermal growth factor receptor (EGFR), Src and Stat3 are detected in pancreatic cancer and implicated in the disease, their exact roles in the support of the disease phenotype remain poorly defined. Moreover, the potential for a cross-talk between EGFR, Src and Stat3 poses a challenge to any therapy that targets only one of these entities. In this study, we sought to define the EGFR, Src and Stat3 signaling integration and to investigate the contributory roles of the three entities to the pancreatic cancer phenotype. We found in Panc-1 and Colo-357 lines that phospho-Y845EGFR, pY1068EGFR and pY1086EGFR levels are responsive to c-Src inhibition, in contrast to pY1173EGFR that is solely EGFR kinase-dependent. Treatment of Panc-1 and Colo-357 cells with the EGFR inhibitor, Iressa (ZD 1839) or the Src inhibitor, Dasatinib (Das) suppressed the constitutively-active Stat3 activity, suggesting that both EGFR and Src activities promote aberrant Stat3 activation in pancreatic cancer cells. However, the early suppression of aberrantly-active Stat3 by the EGFR and Src inhibition in Panc-1 cells is countered by a Janus kinase (Jaks)-dependent re-activation, suggesting that Jaks activity could represent a compensatory mechanism for Stat3 induction. The abrogation of c-Src activity by either Das treatment or the over-expression of a kinase-dead c-Src mutant suppressed the levels of phospho-FAK, phospho-p130Cas, phospho-cortactin, phospho-p120catenin, and phospho-paxillin, suggesting that Src activity induces the mediators of motility and migration in pancreatic cancer cells. By contrast, neither EGFR nor Src inhibition modulated the baseline enhanced phospho-ErkMAPK or phospho-Akt levels in Panc-1 and Colo-357 cells, consistent with the observation that the inhibition of EGFR or Src alone only weakly suppressed cell growth and survival of pancreatic cancer cells. By contrast, the concurrent inhibition of Stat3 and EGFR or Src induced greater viability loss and apoptosis, and diminished the migration/invasion of pancreatic cancer cells in vitro. Of therapeutic significance, the concurrent inhibition of Stat3 and EGFR or Src, as compared to mono-targeting modality, induced a stronger human pancreatic tumor growth inhibition in xenografts models. We infer that the large tumor growth inhibition in vivo is due to the simultaneous suppression of the abnormal functions of Stat3 and EGFR or Src. These studies strongly suggest that the concurrent targeting of Stat3 and EGFR or Src could be a beneficial therapeutic approach for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2528.
Abstract 2536: Therapeutic testing of a novel PKC inhibitor GAP-107B8 on ovarian cancer cells
Authors: Yan Fu J. , Steffensen Isabella , Garson Kenneth , Vanderhyden Barbara C. 
Published: February 2011

Abstract
Background: Ovarian cancer is the most fatal gynaecologic disease in the western world. In 2009 in North America, an estimated 23,896 women will develop ovarian cancer and an estimated 15,24050 women will die from this disease. Current treatments are limited to surgery or chemotherapy, but the disease often recurs. Thus, the development of novel cancer therapeutics remains important. The protein kinase C (PKC) family of serine/threonine kinases is involved in cellular proliferation, differentiation, apoptosis and cell polarity. One PKC isoform, PKC iota, has recently been identified as a human oncogene and has been shown to be overexpressed in serous epithelial ovarian cancers and is thus a potential therapeutic target for ovarian cancer. Objective: We have tested a novel PKC inhibitor GAP-107B8 (PharmaGap Inc., Ottawa) in vitro on a panel of nine ovarian cancer cell lines to determine its potential to inhibit cell proliferation, proliferation in soft agar, and migration. Methods: Nine ovarian cancer cell lines were treated with three different concentrations of GAP-107B8 and then screened using high throughput assays to measure the proliferation of cells in adherent and anchorage independent (soft agar) cultures. The ability of cells to migrate in the presence of GAP-107B8 was also determined. Results: We observed significant reduction in cell proliferation in 6 of 9 ovarian cancer cell lines tested, including two cell lines resistant to the standard chemotherapy. GAP-107B8 inhibited cell proliferation by 30% to 79% compared with untreated cells, with more than 50% inhibition in 4 of 7 cell lines. Treatment with GAP-107B caused a reduction in growth in soft agar in 7 of the 9 cell lines tested in vitro. GAP-107B8 inhibited growth in soft agar by 50% to 94% compared with untreated cells, with 80% or greater inhibition in 6 of 7 cell lines. Finally, 5 of 8 cell lines tested showed significant inhibition of mobility following treatment with GAP-107B8. There was 50% or greater inhibition in all 5 cell lines compared with untreated cells. Conclusion: The novel PKC inhibitor GAP-107B8 displays good efficacy in vitro in suppressing several cancer cell characteristics in a variety of ovarian cancer cell lines. Further experiments are underway to investigate the therapeutic potential of GAP-107B8 in xenograft models of ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2536.
Abstract 2547: Caveolin-1 inhibits survivin and increases sensitivity to paclitaxel in breast cancer cells
Authors: Jafar Nadia , Shajahan Ayesha N. , Clarke Robert 
Published: February 2011

Abstract
Breast cancer is the second leading cause of death due to cancer in women and approximately 194,280 new cases of breast cancer were diagnosed in 2009. The chemotherapeutic drugs known as taxanes disrupt the microtubule function and arrest cell cycle. Paclitaxel (Taxol) is a taxane that is commonly used to treat patients with breast cancer as well as other types of cancer. However, resistance to paclitaxel remains a hindrance to successful treatment. Previously, we have shown that signaling associated with caveolin-1 (CAV1), a structural protein, is an essential determinant of paclitaxel sensitivity in MCF-7 breast cancer cells. CAV1 is part of this family of proteins that has multiple functions in different cancers but it has been proposed to function as a tumor suppressor in breast cancer. Here we show that CAV1 may promote cell death in response to paclitaxel by inhibiting the function of a pro-survival protein called survivin. Survivin is encoded by the BIRC5 gene and is part of the inhibitors of apoptosis (IAP) family. This protein has numerous functions including inhibition of apoptosis and regulation of the cell cycle. Evidence shows that survivin inhibits cell apoptosis by preventing the activation of caspases, which are proteases associated with cell-mediated apoptosis. Up-regulation of survivin is associated with cancer and usually indicates a poor prognosis. We show that while over-expression of CAV1 down-regulates survivin, over-expression of survivin down-regulates CAV1 in MCF-7 cells. Moreover, MCF-7 cells that over-express survivin show decreased inhibition of cell proliferation in response to 10 nM paclitaxel compared to MCF-7 cells expressing the empty vector (EV, control). Thus, our work highlights the role of CAV1 expression in breast cancer cells as an essential determinant of paclitaxel sensitivity. Findings from this research can help researchers and clinicians to evaluate whether CAV1 expression in breast tumors can help predict its responsiveness to taxanes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2547.
Abstract 2549: Histone deacetylase regulation of hypoxia-inducible factor 1α may play a key role in cancer drug resistance
Authors: Lautz Timothy B. , Holub Janette L. , Clark Sandra H. , Qiu Yi-Yong , Madonna Mary Beth , Chu Fei 
Published: February 2011

Abstract
Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that mediates the downstream expression of genes controlling the cellular response to hypoxic conditions. Overexpression of HIF-1α has been implicated in promoting angiogenesis and a more invasive phenotype in a variety of cancer cells. HIF-1α expression may also promote chemoresistance and increased expression of the MDR gene. Previous work from our laboratory has implicated class II histone deacetylases (HDACs) as key mediators of chemoresistance, however the mechanism for this observation remains unclear. It is known that HDACs decrease HIF-1α acetylation, preventing proteosomal degradation and increasing HIF-1α activity. We hypothesized that class II HDAC modulation of HIF-1α activity may contribute to the development of resistance to anti-cancer therapy. In the present study, HDAC4 and HDAC6 expression were upregulated in doxorubicin-resistant human breast (MCF-7-DoxR), human osteosarcoma (SaOS2-DoxR) and human neuroblastoma (SK-N-SH-DoxR) cells compared to their parental cells by western blot and RT-PCR. Likewise, after treatment with deferoxamine mesylate (DFO) to prevent HIF-1α degradation under normoxic conditions, HIF-1α expression was found to be upregulated in MCF-7-DoxR and SaOS2-DoxR cells. Inhibition of HDACs with suberoylanilide hydroxamic acid (SAHA), sodium butyrate (NaB), or siRNA against HDAC4 or HDAC6 resulted in decreased HIF-1α expression and restoration of sensitivity to anti-cancer agents in both drug resistant cell lines. The percentage of viable drug-resistant cells was lower after treatment with doxorubicin plus SAHA or NaB, compared to doxorubicin, SAHA or NaB alone. In summary, HDAC regulation of HIF-1α expression may be an important mediator of tumor resistance to anti-cancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2549.
Abstract 2553: Characterization of the UDP-Glucuronosyltransferases in melanocytes and melanoma
Authors: Dellinger Ryan W. , Matundan Harry H. , Meyskens Frank L. 
Published: February 2011

Abstract
The UDP-glucuronosyltransferase (UGT) family of enzymes catalyzes the glucuronidation of a variety of endogenous compounds such as bilirubin and steroid hormones, as well as xenobiotics including chemotherapeutic agents and environmental carcinogens. Glucuronidation of these substrates inactivates them by making them more hydrophilic and easily excreted. UGTs are expressed primarily in the liver, but are also expressed in several extra-hepatic tissues including prostate, breast, colon, lung, brain, kidney, bladder and ovary. However, there have been no reports measuring UGTs in melanocytes or melanoma.
We screened several primary melanocyte cultures from neonatal foreskin as well as several primary and metastatic melanoma cell lines for UGT expression by RT-PCR. Three UGT family members, UGT2B7, UGT2B10 and UGT2B15, were found to be expressed in melanocytes. Interestingly, of all the melanoma cell lines screened only WM115, a primary melanoma, had UGT expression. Again, only UGT2B7, UGT2B10 and UGT2B15 were detected. UGT expression was not detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression.
Treatment of WM3211 cells with temozolomide, currently indicated for treatment of metastatic melanoma, induced expression of UGT2B7, UGT2B10 and UGT2B15. Similar induction of these UGTs was observed in response to adriamycin or epirubicin treatment of WM3211 cells. Furthermore, induction of UGT2B7, UGT2B10 and UGT2B15 in response to epirubicin was also observed in the metastatic melanoma cell line SKmel28. Since the UGTs are Phase II xenobiotic metabolism enzymes, we hypothesize that the upregulation of the UGTs in melanoma cells in response to chemotherapeutic agents is a potential mechanism for the well documented drug resistance observed in this malignancy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2553.
Abstract 2556: Granulin-epithelin precursor modulates chemo-resistance in liver cancer
Authors: Wong Chung Lim , Cheung Fung Yi , Cheung Siu Tim 
Published: February 2011

Abstract
Background and Objective: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for 80% of the primary liver tumors in adults. HCC is found to be resistant to most current chemo-therapeutic agents, making the disease as one of the most mortal in the world. There is therefore an urgent demand for better therapeutic approaches. Granulin-epithelin precursor (GEP) was identified as a potential therapeutic target from our genome-wide expression profiles study for HCC. It was an autocrine growth factor with over-expression in most HCCs, and involved in HCCs proliferation, invasion and tumorigenicity. The aim of the current study is to examine the role and signaling mechanism of GEP in chemo-resistance, and if chemo-resistant HCC would response to GEP targeted therapy using GEP monoclonal antibody (mAb).
Methods: HCC cells Hep3B was stably transfected with GEP cDNA for overexpression, and antisense fragment for suppression studies, respectively. Chemo-resistant HCC populations were obtained by selection and expansion of Hep3B cells under different class of chemo-therapeutic agents, including cisplatin, doxorubicin and fluorouracil. The cells were examined for chemotherapy induced apoptosis with chemo-therapeutic agents alone, or in combination with GEP targeted therapy using GEP mAb. The ERK signaling molecules were examined by western blot, and caspases activity by the Caspase-Glo luminescent assay.
Results: The Hep3B transfectants with GEP overexpression demonstrated increased resistance to apoptosis under different class of chemo-therapeutic agents with reference to the parental population. Hep3B cells with GEP suppression resulted in enhanced sensitivity to the chemotherapy induced apoptosis. The Hep3B cells with acquired resistance demonstrated an increment of 8-16 folds in IC50 to cisplatin, doxorubicin and fluorouracil, respectively, with reference to the parental population. The chemoresistant Hep3B cells were responsive to GEP targeted therapy, and combined chemotherapy with GEP targeted therapy demonstrated synergistic effect on apoptosis induction. GEP regulated the ERK pathway including the activation of p-p38 and p-p44/42. GEP targeted therapy alone did not affect the caspases activities, however, combination treatment using the GEP mAb and chemo-therapeutic agents provided a synergistic effect on activation of caspase 3, and magnified the apoptotic effect.
Summary: The present study demonstrated that GEP regulated chemoresistance, and GEP mAb could sensitize both the parental and chemoresistant liver cancer cells to chemo-therapeutic agents. The GEP targeted therapy indicated a new therapeutic approach for chemo-resistant liver cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2556.
Abstract 2558: CEBPD induces SOD1 and cisplatin resistance in urothelial carcinoma
Authors: Huang A-Mei , Lai Yan-Liang , Kuan Ching-I , Sterneck Esta , Wu Wen-Jeng , Pu Yeong-Shiau , Hour Tzyh-Chyuan 
Published: February 2011

Abstract
Bladder cancer is the fourth most common type of cancer in men (ninth in women) in the United States. Cisplatin is an effective agent against the most common subtype, urothelial carcinoma. However, the development of chemotherapy resistance is a severe clinical problem for the successful treatment of cancers. A better understanding of the cellular and molecular events in response to cisplatin treatment and the development of resistance are critical to improve the therapeutic options for patients. Here, we report that expression of the CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ, NFIL-6β) is induced by cisplatin in the human bladder urothelial carcinoma NTUB1 cell line and is specifically elevated in a cisplatin resistant subline. Expression of CEBPD reduces cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter trans-activation. Several reports have implicated CEBPD as a tumor suppressor gene. This study reveals a novel role for CEBPD in conferring drug resistance, suggesting that it can also be pro-oncogenic. Furthermore, our data suggest that SOD inhibitors, which are already used as antiangiogenic agents, may be suitable for combinatorial chemotherapy to prevent or treat cisplatin resistance in bladder and possibly other cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2558.
Abstract 2564: High-throughput siRNA library screen for discovery and identification of new melanoma therapeutic targets in combination with antioxidant pretreatment
Authors: Deng Wuguo , Poindexter Nancy J. , Ekmekcioglu Suhendan , Kwon John , Kinney Sandra A. , Grimm Elizabeth A. 
Published: February 2011

Abstract
Melanoma is one of the most prevalent cancers in the United States, having the fifth highest cancer incidence in males and sixth highest incidence in females. Primary cutaneous melanoma can often be cured by surgery, but for those patients in whom metastasis has occurred, mortality is high in part due to numerous chemoresistance mechanisms. Thus, there is an urgent need to discover and identify novel therapeutic targets for the efficient treatment of this lethal disease. Gene silencing by RNA interference (RNAi) is a powerful tool to identify novel genes involved in specific biological processes. In our study, we used high-throughput druggable siRNA library (Dharmacon) targeting 6028 human genes to screen metastatic melanoma cell lines and found that knockdown of gene expression by siRNA pools targeting 885 genes significantly inhibited melanoma growth (p&lt;0.005). Among them, 67 siRNA pools resulted in &gt;50% inhibition of cell viability in the melanoma A375 cells which we employed for the screening analysis. We validated the top-six cancer-related genes (RRM2, BCAR3, PSMA2, UBB, RRM1, TCP1) as potential melanoma therapeutic target candidates, as knockdown of these 6 genes significantly inhibited cell growth and induced apoptosis in multiple melanoma cell lines. We have hypothesized that antioxidant treatment relieves resistance mechanisms, and showed that among the screened &gt;6000 siRNA pools, treatment with 20 pools significantly increased the growth inhibition in the presence of nontoxic levels of bardoxolone methyl (p&lt;0.005), a novel semi-synthetic triterpenoid (previously known as CDDO-Me) with potent antioxidant activity generously provided by Reata Pharmaceuticals. We also selected 5 additional cancer-related genes (GNPAT, SUMO1, SPINT2, FLI1 and SSX1) for further analysis and validated them as additional candidates for therapeutic targeting in the presence of antioxidant. Our results thus demonstrate the feasibility of the high-throughput siRNA library screen system in discovering new melanoma therapeutic targets and shows that these new candidate genes are promising for the development of novel therapeutic targets for melanoma treatment, many of which are revealed by antioxidant pretreatment. Results from our study provide the basis for significant advances in identifying targets for the treatment of melanoma patients. (This study was partially supported by the grant from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the NIH Melanoma SPORE grant P50, CA093459).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2564.
Abstract 2565: Targeting the p38 MAPK pathway inhibits drug resistance in colon adenocarcinoma cells
Authors: Paillas Salomé , Boissière Florence , Causse Annick , Denis Vincent , Vezzio-vie Nadia , Arsa Imade Ait , Martineau Pierre , Bibeau Frederic , Rio Maguy Del , Gongora Céline 
Published: February 2011

Abstract
Despite the recent advances achieved in the treatment of colon cancer, tumour resistance is a frequent cause of chemotherapy failure. Our work was aimed to determine the molecular mechanisms involved in the resistance to irinotecan (SN38), an anticancer agent widely used in colorectal cancer treatment. To this end, we have established an SN38-resistant cellular model from the colon adenocarcinoma cell line HCT-116 and we have obtained 5 resistant clones. In all these five clones we have observed an activation of the MAPK p38 compared to the sensitive cell line called HCT116-s. We have shown in the HCT116-SN6 clone that the p38 pathway is responsible for the resistance to SN38. The family of MAPK p38 counting four isoformes α, β, γ and δ, we have generated cells lines overexpressing each isoforms or inhibiting each isoform expression, and we have demonstrate that the α and β forms are involved in SN38 resistance. In a xenograft model we have shown that the HCT116-SN6 cell line is also resistant to Campto treatment in vivo, and that the α and β isoforms are still responsible for drug resistance. Finally, we have also detected phosphorylated p38 in colon cancer cells of patients resistant to Irinotecan-based chemotherapy. These results show for the first time that the p38 pathway is implicated in the drug sensitivity of colon cancer cells and that targeting p38 could be a good alternative to decrease drug resistance.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2565.