bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1717: Selective induction of breast adenocarcinoma cell death via inhibition of the transient receptor potential melastatin-2 (TRPM2) cation channel
Authors: Koh David W. , Powell Daniel P. , Blake Steven D. , Hoffman Joy L. , Feng Xiaoxing 
Published: August 2015

Abstract
Transient receptor potential melastatin-2 (TRPM2) is a plasma membrane cation channel with important physiologic roles in noncancerous cells. However, in MCF-7 and MDA-MB-231 human breast adenocarcinoma cells, we previously demonstrated that TRPM2 was present in the nucleus, and pharmacologic inhibition or RNAi silencing of TRPM2 led to decreased proliferation. In this study, we evaluated the ability of TRPM2 inhibition to produce cell death in normal breast epithelial cells and breast adenocarcinoma cells. Further, we analyzed the cell death pathways induced. Treatment with the DNA alkylating agent, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), or doxorubicin (Dox) led to increased levels of cell death in MDA-MB-231 breast adenocarcinoma cells pretreated with TRPM2 inhibitors, but not in noncancerous mammary epithelial cells after pretreatment. Similar increases in cell death were observed after RNAi silencing of TRPM2 in both MDA-MB-231 and MCF-7 breast adenocarcinoma cells after Dox or tamoxifen treatment, respectively. Investigation of apoptosis after TRPM2 inhibition demonstrated decreased levels of caspase activity and no significant effect of Q-VD-OPh, a pan-caspase inhibitor, on cell death induced by TRPM2 inhibition. Further, pretreatment with 3-methyl adenine, an inhibitor of autophagy, also produced no significant effect on cell death induced by TRPM2 inhibition. These studies indicate that apoptosis or autophagy are not the primary cell death pathways induced by TRPM2 inhibition in breast cancer cells. Also, RNAi silencing of poly(ADP-ribose) glycohydrolase (PARG) and apoptosis-inducing factor (AIF), two proteins involved in initiating or facilitating alternative pathways of cell death, produced minimal changes in cell death induced by TRPM2 inhibition. Taken together, this study demonstrated that TRPM2 inhibition selectively increases cell death in breast adenocarcinoma cells. Further, the data suggests that apoptosis, autophagy, and PARG/AIF-mediated cell death are not the primarily cell death pathways involved in the cytotoxicity caused by TRPM2 inhibition. The results therefore suggest that TRPM2 is a potential target in breast cancer, where its inhibition may cause the selective eradication of breast adenocarcinoma cells.
Citation Format: David W. Koh, Daniel P. Powell, Steven D. Blake, Joy L. Hoffman, Xiaoxing Feng. Selective induction of breast adenocarcinoma cell death via inhibition of the transient receptor potential melastatin-2 (TRPM2) cation channel. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1717. doi:10.1158/1538-7445.AM2015-1717
Abstract 1721: Moving beyond in vitro models and addressing the challenges of pooled RNAi screens in mouse xenografts
Authors: Diehl Paul , Tedesco Donato , Bonneau Kyle , Makhanov Mikhail , Deng Debbie , Sun Peiqing , Chenchik Alex 
Published: August 2015

Abstract
RNAi loss-of-function screening with pooled shRNA expression libraries has proven to be a useful tool to identify essential cancer genes and drug resistance mechanisms in numerous cell lines in vitro. The effects of knocking down large numbers of genes on cancer cell growth and viability can be measured simultaneously using this approach. Now there is considerable interest to adapt RNAi viability screens to ex vivo xenograft mouse models. However, small take rates, growth rate variance of cells, and differing cell microenvironments in these more complex tumor models impose significant challenges to this sort of assay. We have developed a novel approach based on the use of pooled shRNA libraries with clonal barcodes that enables proliferation measurements of clonal populations produced by the individual shRNA-expressing founder cells that produce the tumor. This RNAi clonal analysis provides a basis to separate, across large cell populations, the external parameters that strongly influence cell growth rates from shRNA-induced growth inhibition in these systems. We will present in vivo RNAi screening validation data for several cancer models.
Citation Format: Paul Diehl, Donato Tedesco, Kyle Bonneau, Mikhail Makhanov, Debbie Deng, Peiqing Sun, Alex Chenchik. Moving beyond in vitro models and addressing the challenges of pooled RNAi screens in mouse xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1721. doi:10.1158/1538-7445.AM2015-1721
Abstract 1726: CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment
Authors: Gao Weimin , Lu Chuanwen , Chen Lixia , Keohavong Phouthone 
Published: August 2015

Abstract
In spite of extensive investigations, the molecular mechanisms of lung tumorigenesis have not been completely understood, and the effective therapy for lung cancer is in great demand. Studies have shown that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated ‘cargo’ proteins, overexpressed in several human cancers. The objectives of the present study are to evaluate the involvement of CRM1 in lung carcinogenesis and lung cancer treatment. First, we have analyzed the importance of CRM1 overexpression in lung cancer development. We showed that CRM1 was overexpressed in lung tumor tissues from lung cancer patients and lung adenocarcinoma in mice induced by a tobacco carcinogen, as well as lung cancer cell lines. The increased CRM1 expression levels in these lung cancer tissues and cells were associated with an increased phosphorylation level at threonine residue 55 of the p53 protein. Furthermore, CRM1 overexpression in lung cancer cells seemed to be p53-dependent. Stable overexpression of CRM1 in BEAS-2B cells led to malignant cellular transformation and p53 cytoplasmic localization. Moreover, as compared to A549 cells, cancer-related genes significantly altered in A549 cells with stable CRM1 knockdown. Second, we have evaluated targeting CRM1 as an adjuvant therapy for lung cancer treatment using both in vitro and in vivo models. We found that CRM1-siRNA could inhibit A549 cell growth and A549 cells with stable CRM1 knockdown showed more pronounced cytotoxic effects to cisplatin than A549 cells. In addition, A549 cells treated with cisplatin and a low non-toxic dose of leptomycin B (a CRM1 inhibitor) had a remarkably enhanced cytotoxicity compared to cisplatin. This increased therapeutic effect from leptomycin B and cisplatin was further validated using an in vivo xenograft mouse model. The findings of this study reveal the significance of CRM1 in lung carcinogenesis and lung cancer adjuvant therapy.
Citation Format: Weimin Gao, Chuanwen Lu, Lixia Chen, Phouthone Keohavong. CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1726. doi:10.1158/1538-7445.AM2015-1726
Abstract 1729: Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy
Authors: Bao Rudi , Pan Zhongzong , Zhao Zhiming , Yu Hongping , Xu Yaochang 
Published: August 2015

Abstract
HSP90 is a major heat shock protein involved in the proper folding of its client proteins including many onco-proteins. HSP90 is elevated in tumor cells with a more active configuration, making it a potential target for cancer drug development. Utilizing structure-base design, we discovered a small molecule compound that inhibits HSP90 activity with an IC50 at low- nanomolar concentration. Cell proliferation was inhibited by this compound at a IC50 of single-digit nanomolar concentration across many different cancer cell lines. Mechanism of action studies demonstrated that this compound could induce HER-2 degradation in the breast cancer cell line BT-474 in vitro at concentrations between 100-300 nM. The compound showed an ideal pharmacological kinetic feature of less exposure and fast clearance in rat retina after intravenous administration, thus reducing the possibility of ocular toxicity as demonstrated by some other earlier HSP90 inhibitors. The compound also caused tumor growth inhibition in the xenograft tumor models, correlating with its target inhibition activity in these tumors. These data supports further development of this compound as a cancer therapeutic agent.
Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1729. doi:10.1158/1538-7445.AM2015-1729
Abstract 1746: Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment
Authors: Zhang Wei , Zhai Ling , Lu Wenyan , Wang Yimin , Gupta Vandana V. , Padmalayam Indira , Bostwick Robert J. , White Lucile , Larry Ross , Maddry Joseph , Ananthan Sam , Suto Mark , Xu Bo , Li Rongbao , Li Yonghe 
Published: August 2015

Abstract
Historically, drugs used in the treatment of certain cancers may cause damage to healthy cells while affecting cancer cells. Therefore, finding compounds that are specific toward cancer cells only is still a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis which can cause cell death by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cell survival. Therefore, targeting KIFC1 may give some insight into how a novel therapy can selectively target only cancer cells. Here, we report that KIFC1 up-regulation is a frequent event in human breast cancer and that KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. We also found that depletion of KIFC1 in breast cancer cells induced cell death. From a high throughput screen of 30,000 compounds, we identified a small molecule KIFC1 inhibitor, SRH06, which has an enzymatic IC50 value of 6.5 μM versus KIFC1 and binds directly to KIFC1 without interacting with the microtubule. Results from our computer modeling studies suggested that SRH06 binds to a novel allosteric site on KIFC1 that appears suitable for the development of selective KIFC1 inhibitors. Importantly, SRH06 prevented bipolar clustering of extra-centrosomes in breast cancer cells and significantly reduced colony formation and cell viability, but was less toxic to normal LL47 fibroblasts. Therefore, SRH06 provides a very valuable tool to study the biological function of KIFC1 and serves as a potential lead for the development of a novel therapeutic agent for the treatment of breast cancer.
Citation Format: Wei Zhang, Ling Zhai, Wenyan Lu, Yimin Wang, Vandana V. Gupta, Indira Padmalayam, Robert J. Bostwick, Lucile White, Ross Larry, Joseph Maddry, Sam Ananthan, Mark Suto, Bo Xu, Rongbao Li, Yonghe Li. Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2015-1746
Abstract 1750: Preclinical efficacy of Hsp90 inhibition by using PF-04942847 in osteosarcoma
Authors: Baud'Huin Marc , Ory Benjamin , Verrecchia Franck , Heymann Dominique , Redini Francoise , Lamoureux Francois 
Published: August 2015

Abstract
This work was supported by foundation ARC and INSERM, France.
Introduction and Objective: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among new therapeutic approaches, Heat shock protein (HSP) 90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival. In this study, we assessed the in vitro and in vivo antitumor properties of a novel synthetic HSP90 inhibitor, PF-04942847 both in vitro and in vivo in osteosarcoma.
Methods: The effects of the HSP90 inhibitor were evaluated in vitro on U2OS, SaOS2, MNNG/HOS, KHOS, MG63, G292, CAL72, SJSA1 and 143B cell growth and apoptosis. The signaling pathways were analyzed by western blotting. The consequence of HSP90 therapy in vivo was evaluated in athymic mice bearing MNNG/HOS xenografts. The effect of PF-04942847 on osteoclastogenesis was assessed in vitro on purified human CD14+ monocytes.
Results: In our panel of osteosarcoma cell lines, PF-04942847 inhibited cell growth in a dose-dependent manner (IC50 ± 50nM) and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of Akt, Erk, MYC, c-MET, STAT-3, and modulation of HSP expression. When administered orally 3 times/week (25mg/kg) to mice bearing osteosarcoma tumors, PF-04942847 significantly inhibited tumor growth by 40% and prolonged survival compared to controls. Moreover, in contrast to 17-AAG, the novel PF-04942847 compound inhibits osteoclast differentiation in vitro.
Conclusions: Targeting HSP90 using PF-04942847 inhibited osteosarcoma tumor growth in vitro and in vivo and appears to inhibit osteoclastogenesis. All these data provides a strong rationale for clinical evaluation of PF-04942847 in osteosarcoma.
Citation Format: Marc Baud'Huin, Benjamin Ory, Franck Verrecchia, Dominique Heymann, Francoise Redini, Francois Lamoureux. Preclinical efficacy of Hsp90 inhibition by using PF-04942847 in osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2015-1750
Abstract 1751: Y15 and Pyridoxal 5′ Phosphate enhances the cytotoxic profile of Cisplatin and Paclitaxel in platinum resistant ovarian cancer cells
Authors: Reboe Monique P. , Waite Terry-ann , Levy Arkene S. , Dhandayuthapani Sivanesan , Rathinavelu Appu 
Published: August 2015

Abstract
Overexpression of the Tyrosine Kinase, Focal Adhesion Kinase (FAK) has been implicated in the development of resistance to front line agents, cisplatin and paclitaxel, in the treatment of ovarian cancer. Moreover vitamins such as Pyridoxal 5′ phosphate (PLP) has been shown to induce cytotoxicity in cancers. Therefore, the aim of this study was to assess the cytotoxic efficacy of FAK inhibition using 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) and PLP combined with cisplatin and paclitaxel. Platinum resistant OVCAR-3 cells were treated with varying concentrations of Y15 (10μM, 15 μM, 30 μM, 100 μM), and PLP (0.25mM, 1mM, 2Mm). Cells were also treated with Y15 + PLP, Y15 + Cisplatin + Paclitaxel, PLP + cisplatin + paclitaxel and Cisplatin + paclitaxel for 24 hrs in triplicate and control cells with 2N HCl or media only. The cytotoxic profile of each treatment was assessed using the automated trypan blue assay and DNA fragmentation assay was performed to evaluate the mechanism of cell death. Dose dependent and statistically significant cytotoxicities were seen with Y15 and PLP compared to the controls with IC 50 values 80 μM (p &lt;0.05) and 2 mM (p&lt;0.05) respectively. The use of Y15 in combination with PLP showed enhanced cytotoxic efficacy in OVCAR-3 cell (p&lt;0.0001). Similarly, Y15 significantly increased percentage cell death when combined with cisplatin + paclitaxel (62%, p&lt;0.0001) in comparison to cisplatin + paclitaxel (35%). The use of PLP with cisplatin + paclitaxel also showed a greater cytotoxic profile of 55% (p&lt;0.002). Cell death by apoptosis was not confirmed by DNA fragments in Y15 and PLP positive treatment groups.
Y15 and PLP significantly enhances the cytotoxic profile of cisplatin, paclitaxel in resistant OVCAR-3 cells suggesting that targeting FAK activity through the inhibition of Y397 site and the use of PLP augments resistance to paclitaxel and cisplatin. However further studies are needed to determine the mechanistic pathway of Y15 and Pyridoxal 5′Phosphate induce cytotoxicity.
Citation Format: Monique P. Reboe, Terry-ann Waite, Arkene S. Levy, Sivanesan Dhandayuthapani, Appu Rathinavelu. Y15 and Pyridoxal 5′ Phosphate enhances the cytotoxic profile of Cisplatin and Paclitaxel in platinum resistant ovarian cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1751. doi:10.1158/1538-7445.AM2015-1751
Abstract 1754: BPR2P001S0, a Coumarin derivative, induced cell cycle arrest in A549 through inhibiting PDPK1 activity
Authors: Lin Pi-Han , Jao Tzu-Ming , Hung Yu-Lin , Hsieh Hsing-Pang , Yang Ya-Chien , Chang Sui-Yuan 
Published: August 2015

Abstract
Lung cancer is one of the most common causes of cancer deaths in the world, and the emergence of resistant lung cancer cells can lead to treatment failure. The development of new drugs to treat lung cancer, especially those resistant lung cancer cells, is urgent. Previously we identified that coumarin could inhibit replication of human lung cancer A549 cells. The efficacy of 284 coumarin derivatives on human lung cancer A549 cells was examined, and BPR2P001S0 was the most potent compound. BPR2P001S0 exhibited growth inhibition and apoptotic activity on A549 cells with an IC50 of 10 nM. A similar level of inhibitory effects was also observed in cisplatin-resistant A549 cells (IC50 = 12.5 nM). The ability of colony formation and migration capability of A549 cells decreased significantly in the presence of BPR2P001S0. In cell cycle analysis, BPR2P001S0 induced cell cycle arrest at the G0/G1 phase through down-regulation of cyclin D1 and Cdk4 protein expression. The expression of cyclinD1/Cdk4 regulatory protein, Akt, was also decreased. Subsequently, we found that the expression level of Ser241 phosphorated PDPK1 protein, an Akt activator in Akt pathway, was also reduced. By molecular docking analysis, we found that the reduced PDPK1 phosphorylation is likely resulted from the allosteric effect of interactions between BPRHIV001 and PDPK1. In conclusion, our results suggest that the anti-tumor activity of BPR2P001S0 is likely resulting from its ability to interfere with PDPK1 autophosphorylation at Ser241, which leads to reduced Akt protein and subsequent cyclin D1 degradation.
Citation Format: Pi-Han Lin, Tzu-Ming Jao, Yu-Lin Hung, Hsing-Pang Hsieh, Ya-Chien Yang, Sui-Yuan Chang. BPR2P001S0, a Coumarin derivative, induced cell cycle arrest in A549 through inhibiting PDPK1 activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1754. doi:10.1158/1538-7445.AM2015-1754
Abstract 176: MicroRNA-122 is a potential regulator of DNA methylation partly by affecting the global level profile of 5hmC
Authors: Tsou Ann-Ping , Wang Kuan-Hua , Huang Hsi-Yuan , Chen Li-Jung , Liu Tze-Tze 
Published: August 2015

Abstract
MicroRNA-122 is a liver specific microRNA. Previously, we demonstrated that Mir122a-/- mice developed steatohepatitis, fibrosis and HCC which recapitulates the multistep hepatocarcinogenesis found in human. In addition, we detected a global change of gene expression involving upregulation of 606 genes and downregulation of 280 genes. Among the genes highly differentially expressed in Mir122a-/- livers are several classic imprinted genes H19/Igf2, Meg3, Mirg, Gdf10 and Rian. Imprinting of both H19/Igf2 and Mirg loci is controlled by CTCF, which is a direct target of miR-122. These earlier findings imply that miR-122 may have a role in epigenetic regulation.
Recently, the active demethylation pathway involving 5-hydroxymethylcytosine (5hmC) and TET (tet methylcytosine dioxygenase) enzymes are found to regulate the genome epigenetically. 5hmC epigenetic mark was found to associate with human cancer development with frequent downregulation in cancers, including HCC.
We detected a progressive loss of 5hmC in liver, the tumor-adjacent tissues and liver tumors of Mir122a-/- mice similar to that of human HCC. Loss of 5hmC is accompanied with downregulation of DNA dioxygenase (Tet1 and Tet3), and upregulation of DNA deaminases (Apobec1 and Apobec3) as well as DNA glycosyalse (Smug1) in Mir122a-/- tumors.
A genome-wide profiling of 5hmC was performed to delineate the dynamic changes of DNA methylation. The 5hmC-containing genomic DNA fragments were collected and sequenced. Our preliminary results showed that Mir122a-/- livers appear to have significantly fewer 5hmC peaks and covered smaller portion of the genome than that of WT. Even fewer 5hmC peaks covering small portion of the genome were detected for the Mir122a-/- liver tumor samples. The number of identified 5hmC peaks follows the order of WT &gt; Mir122a-/- (2-month) &gt; tumor-adjacent liver tissue &gt; tumor of Mir122a-/-, a trend that is in agreement with quantification of 5hmC by both IHC and DNA dot blotting.
The preliminary finding that aberrant DNA demethylation was initiated in young Mir122a-/- mice suggests that active demethylation is likely an early event of hepatocarcinogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Ann-Ping Tsou, Kuan-Hua Wang, Hsi-Yuan Huang, Li-Jung Chen, Tze-Tze Liu. MicroRNA-122 is a potential regulator of DNA methylation partly by affecting the global level profile of 5hmC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 176. doi:10.1158/1538-7445.AM2015-176