bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 767: CXL017 re-sensitizes multidrug resistant leukemia cells to chemotherapy via modulating Bcl-2 family proteins and SERCA proteins
Authors: Das Sonia , Hermanson David , Xing Chengguo 
Published: August 2012

Abstract
Multidrug resistance (MDR) is a major hurdle in the treatment of cancer and there is a pressing need for new therapies. We have recently developed CXL017, derived from a Bcl-2 and SERCA dual inhibitor, with selective cytotoxicity towards MDR cancer cells. In this study, we present new evidence for its therapeutic potential in treatment of MDR cancers and offer mechanistic insights. CXL017 significantly and selectively suppresses the growth of tumors derived from the MDR cancer cell line, HL60/MX2, in vivo. In addition, HL60/MX2 failed to develop stable resistance to CXL017 upon prolonged exposure. In comparison, HL60/MX2 acquired greater than 2000-fold resistance to cytarabine (Ara-C). Remarkably, instead of acquiring cross-resistance, HL60/MX2 cells exposed to CXL017 were re-sensitized to standard therapies (10 to 100-fold). Western blotting analyses revealed that HL60/MX2 has significantly elevated levels of Mcl-1, Bax and Bak relative to HL60. HL60/MX2 also over-expresses SERCA2 and SERCA3 with elevated endoplasmic reticulum (ER) calcium content. CXL017 exposure significantly down-regulates Mcl-1 and Bax but causes up-regulation of Bcl-XL, SERCA2, and SERCA3 proteins, along with a reduction in ER calcium content. Given the well-established functions of Bcl-2 family proteins and ER calcium in drug resistance, our results suggest that the reduction in Mcl-1 and the decrease in ER calcium content are responsible for CXL017 induced chemosensitization of MDR cancer cells. These results support the strategy to develop dual inhibitors of anti-apoptotic Bcl-2 proteins and SERCA to treat MDR cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 767. doi:1538-7445.AM2012-767
Abstract 771: Changes in the subcellular pharmacology of cisplatin, in response to treatment of cells with an anti-Gli1 shRNA
Authors: Fain Jason C. , Amable Lauren , Gavin Elaine , Reed Eddie 
Published: August 2012

Abstract
We have demonstrated that a specific anti-Gli1 shRNA can ablate Gli1 in A2780-CP70 cells, with no effect on Gli2. Upon ablation of Gli1, platinum-DNA adduct repair is inhibited, along with inhibition of ERCC1, XPD, XRCC1, and c-jun. We therefore asked the question of whether there were other subcellular pharmacologic effects, with respect to cisplatin, in these cells. We assessed total cellular accumulation of cisplatin under three conditions: pretreatment with the anti-Gli1 shRNA; pretreatment with a scrambled shRNA control; and pretreatment with Fugene which was used as the transfection agent. We also assessed platinum-DNA adduct levels, at the same time points that total cellular accumulation was measured. All platinum measurements were performed by AAS with Zeeman background correction. In each independent experiment (n=4), we plated cells on day 1; transfected with shRNA 16-18 hours later; treated with cisplatin for 1 hour at 30 μM (the IC50 under these conditions); and, harvested cells at different time points. Those time points were: zero hours (immediately after the 1 hour cisplatin treatment); 6 hours later; or 12 hours later. At zero hours, measured levels of pt-DNA damage were equivalent between the three conditions. At zero hours, measured levels of total cellular platinum were reduced by 40-45% in anti-Gli1 treated cells; suggesting inhibition of cellular accumulation. At 6 hours, scrambled controls showed reductions in total cellular platinum by ∼40%, demonstrating excretion of cisplatin. This is consistent with previously published work (JCI 1991). Cells treated with anti-Gli1 shRNA showed no reductions in total cellular platinum at 6 hrs, nor at 12 hrs; suggesting inhibition of the processes by which cells may eliminate this drug. Cells treated with anti-Gli1 shRNA showed statistically significant inhibition in platinum-DNA adduct repair, as compared to cells treated with scrambled shRNA. Control cells repaired 67.5% of pt-DNA adducts over 12 hours; as compared to 23.7% repair in cells treated with anti-Gli1 shRNA; p2=0.015. We conclude that ablation of Gli1 in cisplatin-resistant A2780-CP70 human ovarian cancer cells, has at least three effects on the subcellular pharmacology of cisplatin. There is inhibition of processes that determine: cellular uptake of drug; cellular elimination of drug; and platinum-DNA adduct repair.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 771. doi:1538-7445.AM2012-771
Abstract 784: Synergistic effect of magnetic nanoparticles and docetaxel on prostate cancer cells in vitro
Authors: Watanabe Masatoshi , Sato Akiko , Kurioka Daisuke , Ishiguro Hitoshi , Uemura Hiroji , Kubota Yoshinobu 
Published: August 2012

Abstract
Current chemotherapy approaches to prostate cancer need to be improved because of limitations by lack of specificity and systemic toxicity although docetaxel-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease. Nanotechnology has prompted new and improved materials for biomedical applications with particular emphasis in therapy and diagnostics. Especially, magnetic nanoparticles (Fe3O4) have potential applications in drug delivery, cancer diagnosis and therapy. We have shown that magnetic nanoparticles would modify the effect of chemotherapy in cancer cells. In this study, we analyzed the combined effects of docetaxel and magnetic nanoparticles on prostate cancer cell lines (LNCaP, DU145, and PC3) and their mechanisms. The combination of docetaxel and magnetic nanoparticles more effectively inhibited cancer cell growth and induced apoptosis. Only magnetic nanoparticles produced reactive oxygen species (ROS), however did not inhibit cancer cell growth significantly. Magnetic nanoparticles were also found to have the effect on the expression of ABC transporter genes, and have the possibility to inhibit the PI3K-Akt-mTOR pathway. These results suggest that magnetic nanoparticles may result in favorable development of current chemotherapy for the advanced disease and leading to new tumor ablation therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 784. doi:1538-7445.AM2012-784
Abstract 788: CK2α regulates MRP1 mediated multidrug drug resistance in cancer via phosphorylation of Thr249
Authors: Stolarczyk Elzbieta I. , Reiling Cassandra J. , Pickin Kerry A. , Coppage Ryan , Knecht Marc , Paumi Christian M. 
Published: August 2012

Abstract
We have previously shown that the function of Ycf1p, yeast ortholog of MRP1, is regulated by yeast casein kinase 2α (Cka1p) via phosphorylation at Ser251. In this study we explore whether CK2α, the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semi-conserved site, Thr249. Knockdown of CK2α in MCF7-derived cells expressing MRP1 (MRP1 CK2β(−)) resulted in increased doxorubicin sensitivity. MRP1-dependent transport of LTC4 and E217αG into vesicles derived from MRP1 CK2β(−) cells was decreased compared with MRP1 vesicles. Moreover, Thr249 to alanine mutation (MRP1-T249A) also resulted in decreased MRP1-dependent transport, while a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings showing increased intracellular doxorubicin accumulation in MRP1 CK2β(−) and MRP1-T249A cells compared to MRP1 cells. Inhibition of CK2 kinase by DMAT resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2β(−), MRP1-T249A or MRP1-T249E cells, suggesting that CK2α regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2α and MRP1 interact physically and recombinant CK2 phosphorylates MRP1 derived peptide in vitro in Thr249 dependent manner, while knockdown of CK2α results in decreased phosphorylation at MRP1-T249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin. This study supports a model in which CK2α potentiates MRP1 function via direct phosphorylation of Thr249. We believe that addition of CK2 inhibitors to cancer treatments will improve therapeutic outcome in part due to reversal of MRP1- mediated drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 788. doi:1538-7445.AM2012-788
Abstract 808: Endocrine resistance: The influence of stromal-epithelial interaction on intracrine pathways of oestrogen synthesis
Authors: Purohit Atul , Odendaal Joshua M. , Palmieri Carlo 
Published: August 2012

Abstract
Resistance to endocrine therapy, both de novo and acquired, poses a significant clinical challenge. Two primary pathways, the aromatase and steroid sulphatase (STS) pathways, exist for the production of estrogenic steroids from androstenedione and DHEAS, respectively. Numerous studies have demonstrated an upregulation of these pathways in breast tumour tissue compared to normal breast tissue. Therapies targeting oestrogenic pathways form the mainstay of the pharmacological approach to breast cancer treatment. The SERM, Tamoxifen, and aromatase inhibitors (AI) such as Letrozole, have shown substantial clinical benefit in hormone-dependent breast cancer patients. Additionally, to date one STS inhibitor has entered clinical trials. Despite this success, a proportion of hormone-receptor positive patients do not respond to hormone therapy with 40% of patients who initially show a response to Tamoxifen relapsing. As little is known about the influence of the tumour microenvironment, particularly stromal-fibroblasts, on these pathways in the development of endocrine resistance, we have examined the influence of stromal-epithelial interactions on the expression of enzymes of steroidogenesis in endocrine resistant cells. Wild type and tamoxifen-resistant MCF-7 breast cancer cells (MCF-7wt and MCF-7TamR, respectively) were indirectly co-cultured with primary fibroblasts derived from breast tumour and reduction mammoplasty samples, using 0.4μm 6-well inserts. Expression levels of 17α-hydroxysteroid dehydrogenase types 1 (17α-HSD1) and 2, (17α-HSD2), aromatase, oestrogen receptor ≤ (ERα) and β, progesterone receptor, steroid sulphatase (STS), and steroid sulphotransferase were assessed basally and in co-culture using RT-PCR. Significantly higher basal expression of STS (p&lt;0.001), aromatase (p=0.012) and 17α-HSD2 (p=0.032) was seen in fibroblast versus epithelial lines. On co-culture a 2.5 - 5 fold up-regulation of aromatase expression was seen in MCF-7wt and MCF-7TamR (p=0.009, p=0.046 respectively). The expression of STS (p=0.150, p=0.05) and 17α-HSD1 (p=0.001, p=0.071) was also increased. Epithelial lines showed a significant down-regulation in ERα on co-culture. Both malignant and normal fibroblast lines demonstrated up-regulation of aromatase expression on co-culture (p=0.037). These data suggest that stromal-fibroblasts make a significant contribution to the tumour hormonal environment through both expression and modulation of the pathways associated with intracrine oestrogen production. The differential effect of cell-type combinations implicates these interactions in both oestrogen sensitivity and insensitivity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 808. doi:1538-7445.AM2012-808
Abstract 812: Identification of novel anticancer drugs as substrates of organic anion transporting polypeptide 1B3 using a cell viability assay
Authors: Obaidat-Hays Amanda L. , Hagenbuch Bruno 
Published: August 2012

Abstract
Organic anion transporting polypeptide 1B3 (OATP1B3) belongs to a superfamily of transport proteins that mediate the uptake of a wide range of endogenous and exogenous compounds into cells. Under normal conditions OATP1B3 is selectively expressed at the basolateral membrane of human hepatocytes. Recently, OATP1B3 expression has been detected in a variety of different cancers and because of its multispecificity OATP1B3 is thought to be a potential therapeutic target to enhance drug delivery into cancer cells. Thus far, only a few anticancer drugs have been identified as substrates of OATP1B3 including docetaxel, paclitaxel, methotrexate and imatinib. Given that OATP1B3 can potentially be used as a target for anticancer drug delivery we need to identify additional anticancer drug substrates of OATP1B3. Therefore, we aimed at establishing a cell based high throughput assay to screen the NCI approved oncology drug set for novel cytotoxic substrates of OATP1B3. Using a luminescent cell viability assay, we measured the viability of wild-type and OATP1B3-expressing Chinese Hamster Ovary (CHO) cells in the absence or presence of the anticancer drugs. After we identified positive hits we further characterized them with respect to concentration dependencies. We identified etoposide, bleomycin, oxaliplatin and plicamycin as compounds that kill OATP1B3-expressing CHO cells at much lower concentrations than wild-type CHO cells suggesting that these compounds are substrates of OATP1B3. Using secondary assays we confirmed that etoposide is a substrate of OATP1B3 and we are currently testing the remaining compounds for direct uptake by OATP1B3. In conclusion, this cell-based viability assay is a good tool to identify novel cytotoxic OATP1B3 substrates that can potentially be used to treat OATP1B3-expressing cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 812. doi:1538-7445.AM2012-812
Abstract 815: The role of spleen tyrosine kinase (SYK) in paclitaxel resistant ovarian cancer
Authors: Gaillard Stephanie , Stoeck Alexander , Davidson Ben , Wang Tian-Li , Shih Ie-Ming 
Published: August 2012

Abstract
The development of resistance to paclitaxel represents a general challenge in clinical oncology, particularly in ovarian serous carcinomas (OSCs), the most common and lethal form of ovarian cancer. Initial treatment with a taxane and platinum combination regimen is standard and while the majority of women will achieve a major response to this treatment, the mortality of ovarian cancer is directly related to the tumor's development of chemoresistance. Using a proteomic approach to comprehensively compare the protein expression profiles of primary and recurrent OSC clinical samples, our laboratory previously identified several novel candidate proteins associated with the development of recurrent OSC. In this study, we focus on evaluating one of these proteins, spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, and its role in the maintenance of paclitaxel resistance in OSC. We have determined that increased expression of SYK in OSC tumor cells obtained from ascites and/or pleural effusion fluid is associated with a poorer response to chemotherapy. Using a cell culture system, we found that two OSC cell lines show an increased expression of SYK after development of in vitro resistance to paclitaxel treatment. More importantly, we demonstrate that SYK small compound inhibitors significantly resensitize the tumor cells to paclitaxel. Our results suggest that SYK plays a role in maintaining paclitaxel resistance in OSC. Recently an oral SYK inhibitor was found to be safe and effective in treating rheumatoid arthritis and non-Hodgkin lymphoma; our results suggest a potential translational use for this inhibitor as a chemosensitizing agent in patients with OSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 815. doi:1538-7445.AM2012-815
Abstract 826: Yes-associated protein increases hepatocellular carcinoma chemosensitivity by modulating p53
Authors: Bai Nan , Zhang Chunyan , Chang Antao , Zhang Zhuhong , Yin Jing , Xiang Rong , Liu Chenghu 
Published: August 2012

Abstract
The function of the yes-associated protein (YAP) transcription co-activator remains an enigma since reports indicate that YAP either acts as an oncogene or enhances apoptosis. In this study, we found that YAP expression occurs in 51% of human hepatocellular carcinoma (HCC) biopsies while phosphorylated YAP (pYAP) expression occurs in 33% of Grade II and III HCCs. In addition, we found that YAP and p53 expression/ nuclear translocation increase in chemo-treated HepG2 cells. In chemo-treated HepG2 cells transfected with WT-YAP or blank (control), the chemosensitivity of the HepG2 + WT-YAP cells increases compared to HepG2+blank cells. In chemo-treated HepG2 cells transfected with Flag-S94A (TEAD binding domain mutant), Flag-W1W2 (WW domain mutant), or blank (control), the chemosensitivity and p53 expression/ nuclear translocation of the HepG2+Flag-S94A cells and HepG2+Flag-W1W2 cells decrease compared to HepG2+blank cells. In chemo-treated HepG2 cells transfected with Flag-5SA-S94A or Flag-5SA-W1W2, the chemosensitivity and p53 expression/ nuclear translocation of the HepG2+Flag-5SA-S94A cells and HepG2+Flag-5SA-W1W2 cells increase again compared to HepG2+Flag-S94A cells or HepG2+Flag-W1W2 cells respectively. These results indicate that YAP promotes chemosensitivity by modulating p53 during chemo-treatment, and YAP-modulated p53 activity requires the TEAD binding domain and the WW domain. In summary, our data indicate that YAP functions as a tumor-suppressor that enhances apoptosis by modulating p53 activity during chemo-treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 826. doi:1538-7445.AM2012-826
Abstract 841: CCL2 and interleukin-6 regulate EMT-mediated chemo-resistance in prostate cancer
Authors: Zou Chunlin , Lu Yi , Mizokami Atsushi , Keller Evan T. , Pienta Kenneth J. , Zhang Jian 
Published: August 2012

Abstract
Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death in western countries. In China, the incidence has increased, unexpectedly and sharply, for the past 20 years. Chemo-resistance, in various types of tumor including PCa, is one of the critical problems in cancer therapy. In PCa, for example, the resistance to taxanes (DTX) accounts for tumor relapse and progression resulting in skeletal metastasis and high mortality. Epithelial-mesenchymal transition (EMT) has been suggested as a key process that dominates chemo-resistance through unknown mechanisms. In the current study, we reported that CCL2 and interleukin-6 (IL-6) serve as key molecules in EMT-mediated chemo-resistance in PCa cells using previously established paclitaxel-resistant cells, DU145-TxR and PC-3-TxR. Parental DU145 and PC-3 cells were used as controls. We observed that DU145-TxR and PC-3-TxR cells produced significantly higher amount of CCL2 and IL-6 compared to their parental cells, determined by cytokine array. In addition, DU145-TxR and PC-3-TxR cells demonstrated EMT phenotypes including hall maker changes in E-cadherin and Vimentin expression and transcriptional factor (Snail, ZEB1, and Slug) alterations. These changes were reversed partially by adding neutralizing antibodies against either CCL2 or interleukin-6. Interestingly, synergistic effects were observed by adding both reagents. Finally DU145-TxR, PC-3-TxR, or their parental cells were implanted into SCID mice and the mice were given DTX (10mg/kg, biweekly) and tumor growth was monitored for 4 weeks. Both DU145-TxR and PC-3-TxR tumors grew faster than the parental tumors. Tumor tissues were collected and total RNAs were isolated. Levels of CCL2 expression in these tumors were significantly higher in DU145-TxR and PC-3-TxR tumors. IHC analysis confirmed corresponding staining of EMT markers such as E-cadherin and Vimentin expression. Together we concluded that CCL2 and IL-6 regulates EMT-mediated chemo-resistance in prostate cancer. These results are of high impact of human prostate cancer chemotherapy. Supported by U.S. Department of Defense PC061231 (J. Zhang), National Natural Sciences Foundation Key Project (81130046, J. Zhang) and National Natural Science Foundation Project (81171993, Y. Lu).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 841. doi:1538-7445.AM2012-841