bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3806: Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF)
Authors: Belkacemi Louiza , Rivera Armando , Yang Lu , Bose Rathindra N. , Zhang Shaun X. 
Published: July 2016

Abstract
Pigment Epithelial Derived Factor (PEDF) is a secreted glycoprotein that exhibits several biological activities, most notably as a potent anti-angiogenic agent as well as a neurotrophic factor. As such, this molecule has potential application as therapeutics for cancer and a variety of neurological diseases. However, prior art methods directed towards enhancing and stabilizing PEDF expression in vivo have met with little success. Therefore, methods that could lead to the stable expression of PEDF in vivo are still needed. We have recently shown that PEDF protein is overexpressed in tumor cells treated with platinum based drugs; phosphaplatins that are platinum-(II) and platinum-(IV) complexes coordinated to a pyrophosphate moiety. The objective of this study is to extend our previous findings by measuring PEDF expression in both malignant cells and normal neuronal tissues after treating them with these compounds. We also investigated the impact of PEDF upregulation on important biological processes such as apoptosis, proliferation and invasion of tumor cells. Our data showed that there was a significant upregulation (over 4-fold) of PEDF in brain of mice treated with phosphoplatins when compared to the control animals. The compounds were found to stimulate PEDF expression in cultured neuronal cells when assessed in vitro (P&lt;0.05 vs. untreated control groups). In tumor cells, phosphoplatins upregulated PEDF expression in a dose-dependent manner in various tumor cell lines. In one particular mouse breast tumor cell line (4T1), the data showed that phosphaplatin doses in the range of 25 to 100 μM stimulated the expression of PEDF at 12 and 24 hrs, which declined thereafter. Remarkably, a subsequent treatment of the tumor cells with phosphaplatins at 24 hrs prevented the decline of PEDF expression, suggesting a direct correlation between phosphaplatins and PEDF overexpression. The upregulation of PEDF in the tumor cells was paralleled by increased apoptosis and decreased cell proliferation and invasion. In summary, phosphaplatins mediated overexpression of PEDF in vivo suggests a potential neuroprotective effect of these compounds. While in tumors, phosphaplatins may exhibit antitumor activity via multiple effects, including anti-angiogenesis, enhanced apoptosis, and decreased proliferation and invasion, predominately through stimulating overexpression of PEDF.
Citation Format: Louiza Belkacemi, Armando Rivera, Lu Yang, Rathindra N. Bose, Shaun X. Zhang. Phosphaplatins are potent inducers of pigment epithelial- derived factor (PEDF). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3806.
Abstract 3808: Novel compound conferring selectivity for cancer cells
Authors: Jaunky Dilan B. , Forgione Pat , Piekny Alisa 
Published: July 2016

Abstract
There is a need to develop novel compounds that can effectively treat a broad range of cancers on their own, or in combination with approved therapies. As personalized medicine is developed, combinatorial approaches will become more common making it crucial to increase the repertoire of available drugs. In the past, drugs often were developed to target a biologically-relevant molecule, but structural limitations, stability and solubility issues, or lack of selectivity have hindered the clinical use of many of these drugs. Our approach was to first find a ‘high-quality’ compound that is selective for cancer cells, then characterize its mechanism of action and identify its target. High throughput screening (HTS) helped to rapidly identify a subset of compounds with selective toxicity toward MCF-7 (breast cancer) cells. Some of these compounds were further tested for their efficacy in HeLa (cervical cancer) cells, and we found one that selectively causes mitotic arrest at 250 nM in comparison to non-cancerous HFF-1 (foreskin fibroblast) cells. At 200 nM, this compound synergizes with drugs known to affect microtubule dynamics and cause mitotic arrest including Nocodazole and Paclitaxel (currently in use as an anti-cancer drug), causing them to be more effective at lower concentrations. Excitingly, this compound also provides a shielding effect for HFF-1 cells treated with Paclitaxel. To learn the mechanism of action for this compound, we performed immunofluorescence microscopy on HeLa and HFF-1 cells treated with a range of concentrations. We found that the mitotic spindle is improperly organized in HeLa cells at 250 nM, but not in HFF-1 cells. Interestingly, microtubules are completely gone in mitotic HeLa cells and are reduced in mitotic HFF-1 cells treated with &gt;500 nM. Given that this compound synergizes with drugs that directly bind to tubulin subunits to modify their dynamics of assembly and disassembly, and differently affects cancerous vs. healthy cells, we hypothesize that it has a unique mechanism of action and may affect microtubule nucleation. We are continuing to characterize the compound, and will identify its molecular target. In addition, we are generating further iterations to explore the Structure-Activity Relationship, and optimize its efficacy. Our in vitro data shows that our approach has the potential to identify novel compounds with the potential for therapeutic use.
Citation Format: Dilan B. Jaunky, Pat Forgione, Alisa Piekny. Novel compound conferring selectivity for cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3808.
Abstract 3813: Potent compounds targeting the human MutT homolog 1 (hMTH1) activity and their cytotoxicity evaluation
Authors: Zhou Wenjuan , Ma Liying , Hu Biao , Li Lingyu , Wang Bo , Liu Hong-Min , Zhao Wen 
Published: July 2016

Abstract
Recently, it has been reported that MTH1, a sanitizing protein for the oxidized dNTP pool, plays an important role in cancer-associated damage in the dNTP pool and is required for survival in cancer cells. To study the antitumor mechanism of MTH1 and screen effective anti-cancer drugs, the current study was designed to set up an in vitro expressing and activity evaluation system for MTH1, which will be used for MTH1 specific inhibitor screening. Briefly, the acquired recombinant vector pET-28b-MTH1 was transfected into E.Coli BL21(DE3). The MTH1 protein expression was induced by IPTG and purified by Ni2+ affinity chromatography. Through converting dGTP to dGMP and pyrophosphate by MTH1, the latter of which can then be hydrolyzed to inorganic pyrophosphate by inorganic pyrophosphatase, the MTH1 activity is evaluated through measuring the amount of inorganic pyrophosphate after reacting with malachite green and ammonium molybdate at 630nm. Using this method, we have successfully generated a reliable in vitro evaluation system for MTH1 activity. Furthermore, five brand new series of hybrids with total more than one hundred compounds were virtually designed and synthesized. Their potential MTH1 inhibitory effects were screened based on our system. We found that some of them exhibited moderate to excellent inhibitory activity toward MTH1 with nanomole IC50 values, which also showed significant cytotoxicity on several gastric cancer cell lines by MTT assay (with IC50 below 10μM). On the other hand, our studies in human gastric cancer patients also indicated that MTH1 expression levels were significantly enhanced in these patients’ cancer tissues, compared to the para-cancer ones. Our findings suggest that MTH1 may be a potential therapeutic target in gastric cancer. Compounds specifically designed to target MTH1 activity may represent a novel and useful strategy for anti-gastric cancer drug discovery.
*Corresponding author: Wen Zhao, Ph.D, Tel.: 01186-15003898187. Email: zhaowen100@139.com
Funding Sources.
This work was supported by National Natural Science Foundation of China (Project No. 81430085, No. 21372206 and No. 81172937 for H.-M.L.; Project No. 81270270 and No. 81470524 for W.Z.); Ph.D Educational Award from Ministry of Education (No. 20134101130001, for H.-M.L. and No. 20134101110013, for W.Z.); The 2013 Scientific Innovation Talent Award from Department of Education of Henan Province (No. 13HASTIT029, for W.Z.).
Citation Format: Wenjuan Zhou, Liying Ma, Biao Hu, Lingyu Li, Bo Wang, Hong-Min Liu, Wen Zhao. Potent compounds targeting the human MutT homolog 1 (hMTH1) activity and their cytotoxicity evaluation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3813.
Abstract 3823: Staphylococcal nuclease and tudor domain containing 1 (SND1) in development and progression of hepatocellular carcinoma
Authors: Jariwala Nidhi , Rajasekaran Devaraja , Gredler Rachel , Akiel Maaged , Robertson Chadia , Fisher Paul , Sanyal Arun , Sarkar Devanand 
Published: July 2016

Abstract
Staphylococcal nuclease and tudor domain containing 1 (SND1) is identified as an oncogene in hepatocellular carcinoma (HCC) and overexpression of SND1 has been correlated with HCC progression. Here, we present effect of liver specific overexpression of human SND1 in a novel transgenic mouse model. We observe greater tumor load and tumor volume in transgenic mice than wildtype mice, when subjected to chemical carcinogenesis. Approximately 30% of transgenic animals manifest spontaneous tumorigenesis with age. Liver specific expression of cancer stem cell markers such as EpCAM and CD133 as well as inflammatory markers was found to be higher in transgenic mice. SND1 overexpressing hepatocytes show increased activation of insulin and NFκB signaling pathways compared to wildtype hepatocytes. However, no significant differences in liver weight or liver function was noted among transgenic and wildtype animals. Overall, our findings confirm that overexpression of SND1 in vivo plays a vital role in development and progression of HCC. Thus, molecular targeting of SND1 seems to be potential therapeutic intervention for HCC management in patients.
Citation Format: Nidhi Jariwala, Devaraja Rajasekaran, Rachel Gredler, Maaged Akiel, Chadia Robertson, Paul Fisher, Arun Sanyal, Devanand Sarkar. Staphylococcal nuclease and tudor domain containing 1 (SND1) in development and progression of hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3823.
Abstract 3829: Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment
Authors: Bryant Kirsten L. , Hayes Tikvah K. , Zeitouni Daniel , George Samuel D. , Kher Swapnil , Samatar Ahmed A. , Wood Kris C. , Kimmelman Alec C. , Der Channing J. 
Published: July 2016

Abstract
Pancreatic cancer is the 4th leading cause of cancer deaths in the US and the 5-year survival rate is a dismal 6%. The KRAS oncogene is mutated in ∼95% of pancreatic ductal adenocarcinoma (PDAC) and targeting KRAS is one of four key priorities for pancreatic cancer research, as outlined by the NCI. We hypothesize that inhibition of K-Ras effector signaling is the most promising approach to achieve this goal, and that concurrent inhibition of mutant KRAS-mediated metabolic reprogramming, in particular upregulated autophagy, is needed to disrupt resistance mechanisms that render PDAC cells unaffected by inhibition of either pathway alone. Our preliminary data show that PDAC cells increase levels of autophagic signaling upon KRAS silencing as a compensatory mechanism for the cell to maintain anabolic processes, particularly due to the loss of upregulated glycolytic signaling and macropincytotic scavenging. Furthermore, we show that ERK inhibitor treatment, just like KRAS silencing, increases autophagic flux in PDAC cells. Additionally, we have demonstrated in vitro that chloroquine (CQ), an inhibitor of autophagy, synergistically enhances the anti-proliferative capacity of two different ERK inhibitors, one of which is under clinical evaluation. Finally, we show that signaling pathways that promote resistance to ERK inhibitor treatment alone are incapable of promoting resistance to the combination treatment with CQ. Overall, our studies support the further clinical evaluation of duel ERK and autophagy inhibition as a treatment for PDAC.
Citation Format: Kirsten L. Bryant, Tikvah K. Hayes, Daniel Zeitouni, Samuel D. George, Swapnil Kher, Ahmed A. Samatar, Kris C. Wood, Alec C. Kimmelman, Channing J. Der. Preclinical development of a combination inhibitor strategy to block K-Ras effector signaling and autophagy for pancreatic cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3829.
Abstract 3831: Oncogenic BRAF and concomitant RAS or PTEN/PI3K mutations determine together the response to RAS/RAF/PI3K signaling network inhibition
Authors: Garay Tamas M. , Molnar Eszter , Rittler Dominika , Berger Walter , Döme Balazs , Timar Jozsef , Hegedus Balazs 
Published: July 2016

Abstract
Background: BRAF is key component in the growth factor signaling cascade that is often impaired in tumors. Although oncogenic BRAF mutation is considered to be the driver mutation in a variety of malignancies, the response to RAS/RAF/PI3K signaling network inhibition is not uniform among BRAF mutant tumors. Accordingly, we investigated the in vitro effect of RAS/RAF/PI3K signaling network inhibitors (panRAF, mutant BRAF specific, MEK and PI3K/mTOR inhibitors) in relation with BRAF concomitant RAS or PTEN/PI3K mutations in a panel of human cancer cell lines.
Methods: Altogether 12 human cancer cell lines were investigated in vitro to assess the effect of inhibitors acting at the different levels of the RAS/RAF signaling network. The seven melanoma, two colon, two lung and one breast cancer cell lines were divided into 3 groups according to their mutational status: BRAF-mutant with no PTEN/PI3K/RAS mutations (A375, WM35, SK-MEL-28, CRL5885), BRAF + PTEN-PI3K (A2058, WM239, HT29, SW1417) and BRAF + RAS double mutant (WM3629, WM3670, MDA-MB-231, CRL5922). Effect of inhibitors on proliferation, clonogenic potential and migration were investigated SRB and clonogenic assays and videomicroscopy measurements, respectively. Both single agent and combination treatments were applied.
Results: In single agent treatments panRAF and PI3K/mTOR inhibitors did not show mutation dependent differences in proliferation, however, mutant-BRAF and MEK specific inhibitors were more effective in cells without concomitant PTEN/PI3K or RAS mutations. Interestingly, not only the combination of BRAF and MEK inhibitors but the combination of PI3K/mTOR and MEK inhibition showed additive inhibitory effect on proliferation in all subgroups. Importantly, a distinct pattern emerged for the mutational subgroup specific migration inhibitory effects in comparison to the inhibition of proliferation.
Conclusion: BRAF mutant cells carrying various concomitant PTEN/PI3K/RAS alterations display distinct response to RAS/RAF/PI3K network inhibition in terms of proliferation as well as migration. Our data suggests that combination treatments acting concurrently on different targets of the RAS/RAF/PI3K network can be more effective as single therapies.
Citation Format: Tamas M. Garay, Eszter Molnar, Dominika Rittler, Walter Berger, Balazs Döme, Jozsef Timar, Balazs Hegedus. Oncogenic BRAF and concomitant RAS or PTEN/PI3K mutations determine together the response to RAS/RAF/PI3K signaling network inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3831.
Abstract 3833: Restoration of wildtype structure and function of mutant p53 by thiosemicarbozones using a novel zinc metallochaperone based mechanism
Authors: Yu Xin , Blanden Adam R. , Tsang Ashley T. , Zaman Saif , Gelleran John , Augeri David , Kimball S. David , Loh Stewart N. , Carpizo Darren R. 
Published: July 2016

Abstract
NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure and function to the most common p53 missense mutant (p53-R175H). We identified that ZMC1 functions as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding of p53 protein, and increasing cellular reactive oxygen species to transactivate the newly conformed p53-R175H (via post-translational modifications). ZMC1 was identified from an in silico screen of the NCI anti-cancer drug screen along with two other thiosemicarbazones (TSCs), NSC319725 and NSC328784. We investigated these TSCs to determine if they could reactivate mutant p53 using a zinc metallochaperone mechanism. We found that indeed these compounds could reactivate mutant p53 by functioning as zinc metallochaperones. In distinction, Triapine the only TSC in clinical development, does not function as a zinc metallochaperone and is not a mutant p53 reactivator.
Citation Format: Xin Yu, Adam R. Blanden, Ashley T. Tsang, Saif Zaman, John Gelleran, David Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo. Restoration of wildtype structure and function of mutant p53 by thiosemicarbozones using a novel zinc metallochaperone based mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3833.
Abstract 3841: Curcumin enhances the efficacy of docetaxel- induced apoptosis of prostate cancer cell
Authors: Banerjee Saswati , Singh Santosh K. , Lillard James W. , Singh Rajesh 
Published: July 2016

Abstract
Despite the different prostate cancer (PCa) treatment therapies it continues to be one of the leading causes of death in men. Docetaxel is a well-established chemotherapeutic agent used to target metastatic PCa, however long-term treatment with docetaxel results in drug resistant and toxicity in PCa cells. Combining agents is common to improve outcomes, but the combination should not significantly increase toxicity. Curcumin is a non-toxic natural compound with multifaceted chemo preventive potential. In current study we evaluated whether curcumin can reinforce the effect of docetaxel on PCa cell lines (RWPE-1, C4-2b, DU145 and PC3). PCa cell lines were treated with curcumin or docetaxel alone or in combination followed by cell viability (MTT assay) and apoptosis assay (TUNEL assay and flow-cytometric analysis of annexin V/propidium iodide-stained cells). The expressions of pro- and anti-apoptotic markers were quantitated with real-time PCR and western blot assay. Our results indicate that curcumin combined with docetaxel led to lower cell viability than treatment with docetaxel or curcumin alone. Annexin V staining followed by flow cytometric analysis demonstrated that curcumin treatment enhanced the docetaxel-induced apoptosis of PCa cells, which was further confirmed by TUNEL assay. The down-regulation of the anti-apoptotic proteins (Bcl2, Mcl-1) and upregulation of pro-apoptotic proteins (Bax, Bid etc.) further confirm that we can considerably reduce docetaxel dose using synergistic combination therapy with curcumin. Thus, our results strongly suggest that we can reduce dose levels of docetaxel and compensate it with non-toxic curcumin and it could be a potential therapeutic contender in enhancing the efficacy of docetaxel in PCa treatment.
Citation Format: Saswati Banerjee, Santosh K. Singh, James W. Lillard, Rajesh Singh. Curcumin enhances the efficacy of docetaxel- induced apoptosis of prostate cancer cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3841.
Abstract 3849: The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells
Authors: Strekalova Elena , Malin Dmitry , Cryns Vincent 
Published: July 2016

Abstract
Most metastatic tumors, such as triple negative breast cancer (TNBC) respond poorly to conventional chemotherapy. We have previously demonstrated that targeting TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) might be an effective pathway against metastatic TNBC. However, many TNBCs are resistant to TRAIL receptor agonists. Here we demonstrate that diabetes drug metformin, previously linked to preventing and treating several types of cancer, enhances sensitivity of TNBC cells to recombinant TRAIL and TRAIL-R2 agonistic humanized monoclonal antibody (lexatumumab)-induced apoptosis. We have demonstrated that combination of metformin with lexatumumab or TRAIL augments response to TRAIL therapy and reduce cancer cell viability via induction of apoptosis and inhibiting long-term survival of three different metastatic TNBC cell lines. Intriguingly, metformin treatment also sensitized transformed MCF10A-RasV12 cells, but not untransformed MCF10A-Vector cells, to TRAIL agonist therapy. This effect was associated with reduction of X-linked Inhibitor of Apoptosis Protein (XIAP) levels after metformin treatment. Similar to metformin treatment, inhibition of XIAP by small interfering RNA sensitized breast cancer cells to TRAIL-induced apoptosis. Moreover, metformin treatment in combination with TRAIL more efficiently inhibited primary tumor growth and lung metastases in orthotopic model of TNBC. Overall, our results demonstrate that metformin treatment in combination with targeting TRAIL receptors may be a good strategy to augment the antitumor effects of TRAIL receptors agonistic therapy and provide the foundation for a clinical trial combining dietary metfomin and TRAIL agonists.
Citation Format: Elena Strekalova, Dmitry Malin, Vincent Cryns. The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3849.