bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Prostate-derived factor—a novel inhibitor of drug-induced cell death in colon cancer cells
Authors: Proutski Irina , Stevenson Leanne , Allen Wendy L. , McCulla Andrea , Boyer John , McLean Estelle G. , Longley Daniel B. , Johnston Patrick G.
Published: April 2023

Abstract
We investigated the role of the divergent transforming growth factor-β superfamily member, prostate-derived factor (PDF), in regulating response to chemotherapies used in the treatment of colorectal cancer. A clear p53-dependent expression pattern of PDF was shown in a panel of colorectal cancer cell lines following acute exposure to oxaliplatin, 5-fluorouracil, and SN38. PDF gene silencing before chemotherapy treatment significantly sensitized cells expressing wild-type p53, but not p53-null or p53-mutant cells, to drug-induced apoptosis. Similarly, knockdown of PDF expression sensitized HCT116 drug-resistant daughter cell lines to their respective chemotherapies. Inducible PDF expression and treatment with recombinant PDF both significantly attenuated drug-induced apoptosis. Further analysis revealed that PDF activated the Akt but not the extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, cotreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin abrogated PDF-mediated resistance to chemotherapy-induced apoptosis. Together, these data suggest that PDF may be a novel inhibitor of drug-induced cell death in colorectal cancer cells and that the mature secreted form of the protein activates the phosphatidylinositol 3-kinase/Akt pathway as an acute mechanism of chemoresistance. [Mol Cancer Ther 2009;8(9):2566–74]
Data from SCH 2047069, a Novel Oral Kinesin Spindle Protein Inhibitor, Shows Single-Agent Antitumor Activity and Enhances the Efficacy of Chemotherapeutics
Authors: Basso Andrea D. , Liu Ming , Dai Chaoyang , Gray Kimberly , Nale Lissette , Tevar Seema , Lee Suining , Liang Lianzhu , Ponery Abdul , Yaremko Bohdan , Smith Elizabeth , Tang Huadong , Sheth Payal R. , Siddiqui M. Arshad , Hicklin Daniel J. , Kirschmeier Paul
Published: April 2023

Abstract
Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine. Mol Cancer Ther; 9(11); 2993–3002. ©2010 AACR.
Data from The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells
Authors: Joshi Sanket , Perera Swetha , Gilbert Jayne , Smith Charlotte M. , Mariana Anna , Gordon Christopher P. , Sakoff Jennette A. , McCluskey Adam , Robinson Phillip J. , Braithwaite Antony W. , Chircop Megan
Published: April 2023

Abstract
The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer. Mol Cancer Ther; 9(7); 1995–2006. ©2010 AACR.
Data from Activity of dasatinib against L576P KIT mutant melanoma: Molecular, cellular, and clinical correlates
Authors: Woodman Scott E. , Trent Jonathan C. , Stemke-Hale Katherine , Lazar Alexander J. , Pricl Sabrina , Pavan Giovanni M. , Fermeglia Maurizio , Gopal Y.N. Vashisht , Yang Dan , Podoloff Donald A. , Ivan Doina , Kim Kevin B. , Papadopoulos Nicholas , Hwu Patrick , Mills Gordon B. , Davies Michael A.
Published: April 2023

Abstract
Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma (∼30-40%). In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = −2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas. [Mol Cancer Ther 2009;8(8):2079–85]
Data from Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
Authors: Cui Jian , Wang Qingyang , Wang Jing , Lv Ming , Zhu Ning , Li Yan , Feng Jiannan , Shen Beifen , Zhang Jiyan
Published: April 2023

Abstract
Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in T-ALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity. [Mol Cancer Ther 2009;8(12):3214–22]
Data from γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors
Authors: Kannappan Ramaswamy , Ravindran Jayaraj , Prasad Sahdeo , Sung Bokyung , Yadav Vivek R. , Reuter Simone , Chaturvedi Madan M. , Aggarwal Bharat B.
Published: April 2023

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G1 cell cycle arrest revealed that γ-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that γ-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that γ-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by γ-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by γ-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by γ-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that γ-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins. Mol Cancer Ther; 9(8); 2196–207. ©2010 AACR.
Data from PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation
Authors: Chang Marisa , Kanwar Nisha , Feng Eric , Siu Allan , Liu Xiujie , Ma Dawei , Jongstra Jan
Published: April 2023

Abstract
Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC50s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3Tyr705). Treatment of DU-145 cells with M-110 or with a structurally unrelated PIM inhibitor, SGI-1776, significantly reduces pSTAT3Tyr705 expression without affecting the expression of STAT3. Furthermore, treatment of DU-145 cells with M-110 attenuates the interleukin-6–induced increase in pSTAT3Tyr705. To determine which of the three PIM kinases is most likely to inhibit expression of pSTAT3Tyr705, we used PIM-1–, PIM-2–, or PIM-3–specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3Tyr705. These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3Tyr705. Mol Cancer Ther; 9(9); 2478–87. ©2010 AACR.
Data from Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800
Authors: Massey Andrew J. , Schoepfer Joseph , Brough Paul A. , Brueggen Josef , Chène Patrick , Drysdale Martin J. , Pfaar Ulrike , Radimerski Thomas , Ruetz Stephan , Schweitzer Alain , Wood Mike , Garcia-Echeverria Carlos , Jensen Michael Rugaard
Published: April 2023

Abstract
Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH2-terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-RafV600E, Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development. Mol Cancer Ther; 9(4); 906–19. ©2010 AACR.
Data from Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells
Authors: Moiseeva Elena P. , Almeida Gabriela M. , Jones George D.D. , Manson Margaret M.
Published: April 2023

Abstract
Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of curcumin, 3,3′-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, or indole-3-carbinol (I3C) in breast cancer MDA-MB-231 cells, exposed in long-term culture to low concentrations, achievable in vivo. Curcumin and EGCG increased cell doubling time. Curcumin, EGCG, and I3C inhibited clonogenic growth by 55% to 60% and induced 1.5- to 2-fold higher levels of the basal caspase-3/7 activity. No changes in expression of cell cycle–related proteins or survivin were found; however, I3C reduced epidermal growth factor receptor expression, contributing to apoptosis. Because some phytochemicals are shown to inhibit DNA and histone modification, modulation of expression by the agents in a set of genes (cadherin-11, p21Cip1, urokinase-type plasminogen activator, and interleukin-6) was compared with changes induced by inhibitors of DNA methylation or histone deacetylation. The phytochemicals modified protein and/or RNA expression of these genes, with EGCG eliciting the least and DIM the most changes in gene expression. DIM and curcumin decreased cadherin-11 and increased urokinase-type plasminogen activator levels correlated with increased cell motility. Curcumin, DIM, EGCG, and genistein reduced cell sensitivity to radiation-induced DNA damage without affecting DNA repair. This model has revealed that apoptosis and not arrest is likely to be responsible for growth inhibition. It also implicated new molecular targets and activities of the agents under conditions relevant to human exposure. [Mol Cancer Ther 2007;6(11):3071–9]
Data from The Quassinoid Derivative NBT-272 Targets Both the AKT and ERK Signaling Pathways in Embryonal Tumors
Authors: Castelletti Deborah , Fiaschetti Giulio , Di Dato Valeria , Ziegler Urs , Kumps Candy , De Preter Katleen , Zollo Massimo , Speleman Frank , Shalaby Tarek , De Martino Daniela , Berg Thorsten , Eggert Angelika , Arcaro Alexandre , Grotzer Michael A.
Published: April 2023

Abstract
The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G1/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET. Mol Cancer Ther; 9(12); 3145–57. ©2010 AACR.
Data from Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo
Authors: Kortenhorst Madeleine S.Q. , Isharwal Sumit , van Diest Paul J. , Chowdhury Wasim H. , Marlow Cameron , Carducci Michael A. , Rodriguez Ronald , Veltri Robert W.
Published: April 2023

Abstract
Histone deacetylase inhibitors such as valproic acid (VPA) are promising anticancer agents that change the acetylation status of histones and loosen the chromatin structure. We assessed nuclear structure changes induced by VPA in prostate cancer LNCaP, CWR22R, DU145, and PC3 cell lines and xenografts and their potential use as a biomarker of treatment. In vitro tissue microarrays consisted of prostate cancer cell lines treated for 3, 7, or 14 days with 0, 0.6, or 1.2 mmol/L VPA. In vivo tissue microarrays consisted of cores from prostate cancer xenografts from nude mice treated for 30 days with 0.2% or 0.4% VPA in drinking water. Digital images of at least 200 Feulgen DNA-stained nuclei were captured using the Nikon CoolScope and nuclear alterations were measured. With a set of seven most frequently significant nuclear alterations (determined by univariate logistic regression analysis), control and VPA treatment nuclei were compared in vitro and in vivo. Depending on the cell line, area under the curve-receiver operating characteristics ranged between 0.6 and 0.9 and were dose- and time-dependent both in vitro and in vivo. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). In vitro and in vivo VPA treatment of prostate cancer cell lines results in significant dose- and time-dependent changes in nuclear structure. Further, VPA induces nuclear structural changes in normal liver and kidney tissue, which likely reflects a natural physiologic response. Therefore, nuclear structural alterations may serve as a biomarker for histone deacetylase inhibitor treatment. [Mol Cancer Ther 2009;8(4):802–8]
Data from MicroRNA expression profiles for the NCI-60 cancer cell panel
Authors: Blower Paul E. , Verducci Joseph S. , Lin Shili , Zhou Jin , Chung Ji-Hyun , Dai Zunyan , Liu Chang-Gong , Reinhold William , Lorenzi Philip L. , Kaldjian Eric P. , Croce Carlo M. , Weinstein John N. , Sadee Wolfgang
Published: April 2023

Abstract
Advances in the understanding of cancer cell biology and response to drug treatment have benefited from new molecular technologies and methods for integrating information from multiple sources. The NCI-60, a panel of 60 diverse human cancer cell lines, has been used by the National Cancer Institute to screen >100,000 chemical compounds and natural product extracts for anticancer activity. The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. Recently, microRNAs have been shown to target particular sets of mRNAs, thereby preventing translation or accelerating mRNA turnover. To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis. Cell line groupings based on microRNA expression were generally consistent with tissue type and with cell line clustering based on mRNA expression. However, mRNA expression seemed to be somewhat more informative for discriminating among tissue types than was microRNA expression. In addition, we found that there does not seem to be a significant correlation between microRNA expression patterns and those of known target transcripts. Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance. [Mol Cancer Ther 2007;6(5):1483–91]
Data from Silencing of Integrated Human Papillomavirus-16 Oncogenes by Small Interfering RNA–Mediated Heterochromatization
Authors: Palanichamy Jayanth Kumar , Mehndiratta Mohit , Bhagat Mohita , Ramalingam Pradeep , Das Brati , Das Prerna , Sinha Subrata , Chattopadhyay Parthaprasad
Published: April 2023

Abstract
Double-stranded RNAs or small interfering RNAs (siRNA) targeting the promoters of genes are known to cause gene knockdown by a process known as transcriptional gene silencing (TGS). We screened multiple siRNAs homologous to one of the NF-1 binding sites in the human papillomavirus-16 (HPV-16) enhancer and identified one siRNA which causes specific TGS of the HPV-16 oncogenes E6 and E7 when transfected into two HPV-16–positive cell lines siHa and CaSki. This phenomenon was specific to the HPV-16 enhancer with no effect on the HPV-18 enhancer. TGS was associated with heterochromatization of the targeted region of the enhancer but no DNA methylation was noted during the time period studied. The choice of target in the enhancer was important as siRNAs differing by one or two bases showed no suppression of downstream gene expression. A low copy number enhancer-associated transcript was detected in the cell lines studied and its level decreased significantly after treatment with the siRNA that caused TGS. This supports the RNA:RNA model described previously for TGS. This siRNA which causes simultaneous silencing of E6 as well as E7 oncogenes by an epigenetic mechanism might be useful as a therapeutic modality for HPV-16–positive cervical and other epithelial cancers. Mol Cancer Ther; 9(7); 2114–22. ©2010 AACR.
Data from IFNγ Restores Breast Cancer Sensitivity to Fulvestrant by Regulating STAT1, IFN Regulatory Factor 1, NF-κB, BCL2 Family Members, and Signaling to Caspase-Dependent Apoptosis
Authors: Ning Yanxia , Riggins Rebecca B. , Mulla Jennifer E. , Chung Haniee , Zwart Alan , Clarke Robert
Published: April 2023

Abstract
Antiestrogens are effective therapies for the management of many estrogen receptor-α (ER)–positive breast cancers. Nonetheless, both de novo and acquired resistance occur and remain major problems in the clinical setting. IFNγ is an inflammatory cytokine that induces the expression and function of IFN regulatory factor 1 (IRF1), a tumor suppressor gene that can increase antiestrogen responsiveness. We show that IFNγ, but not IFNα, IFNβ, or fulvestrant (ICI; ICI 182,780; Faslodex), induces IRF1 expression in antiestrogen-resistant MCF7/LCC9 and LY2 cells. Moreover, IFNγ restores the responsiveness of these cells to fulvestrant. Increased IRF1 activation suppresses NF-κB p65 (RELA) activity, inhibits the expression of prosurvival (BCL2, BCL-W), and induces the expression of proapoptotic members (BAK, mitochondrial BAX) of the BCL2 family. This molecular signaling is associated with the activation of signal transducer and activator of transcription 1 and leads to increased mitochondrial membrane permeability; activation of caspase-7 (CASP7), CASP8, and CASP9; and induction of apoptosis but not autophagy. Whereas antiestrogen-resistant cells are capable of inducing autophagy through IFN-mediated signaling, their ability to do so through antiestrogen-regulated signaling is lost. The abilities of IFNγ to activate CASP8, induce apoptosis, and restore antiestrogen sensitivity are prevented by siRNA targeting IRF1, whereas transient overexpression of IRF1 mimics the effects of IFNγ treatment. These observations support the exploration of clinical trials combining antiestrogens and compounds that can induce IRF1, such as IFNγ, for the treatment of some ER-positive breast cancers. Mol Cancer Ther; 9(5); 1274–85. ©2010 AACR.
Data from Reprogramming Murine Telomerase Rapidly Inhibits the Growth of Mouse Cancer Cells In vitro and In vivo
Authors: Xu Tong , Xu Yucheng , Liao Chun-Peng , Lau Roy , Goldkorn Amir
Published: April 2023

Abstract
Telomerase plays a critical role in cancer, prompting the pursuit of various telomerase-based therapeutic strategies. One such strategy, telomerase interference, exploits the high telomerase activity in cancer cells and reprograms telomerase to encode “toxic” telomeres. To date, telomerase interference has been tested in human cancer cells xenografted into mice, an approach that does not recapitulate spontaneous malignancy and offers few insights about host toxicities, because human telomerase is targeted in a mouse host. To address these limitations, we designed and validated two new gene constructs specifically targeting mouse telomerase: mutant template mouse telomerase RNA (MT-mTer) and small interfering RNA against wild-type mouse telomerase RNA (α-mTer-siRNA). Using lentiviral delivery in mouse prostate cancer cells, we achieved α-mTer-siRNA–mediated knockdown of wild-type mTer (80% depletion) and concurrent overexpression of MT-mTer (50-fold). We showed that the two constructs effectively synergize to reprogram murine telomerase to add mutant instead of wild-type telomeric repeats, resulting in rapid telomeric uncapping (5-fold increase in DNA damage foci). This, in turn, led to rapid and significant apoptosis (>90% of cells) and growth inhibition in vitro (90% reduction in viable cell mass) and in vivo (75% reduction in tumor allograft wet weight). In summary, we have shown that mouse cancer cells are vulnerable to direct telomerase interference using novel murine telomerase-targeting constructs; this approach can now be used to study the true therapeutic potential of telomerase interference in mouse spontaneous cancer models. Mol Cancer Ther; 9(2); 438–49
Data from Response prediction to a multitargeted kinase inhibitor in cancer cell lines and xenograft tumors using high-content tyrosine peptide arrays with a kinetic readout
Authors: Versele Matthias , Talloen Willem , Rockx Cindy , Geerts Tamara , Janssen Boud , Lavrijssen Tom , King Peter , Göhlmann Hinrich W.H. , Page Martin , Perera Tim
Published: April 2023

Abstract
Multitargeted kinase inhibitors have shown clinical efficacy in a range of cancer types. However, two major problems associated with these drugs are the low fraction of patients for which these treatments provide initial clinical benefit and the occurrence of resistance during prolonged therapy. Several types of predictive biomarkers have been suggested, such as expression level and phosphorylation status of the major targeted kinase(s), mutational status of the kinases involved and of key components of the downstream signaling cascades, and gene expression signatures. In this work, we describe the development of a response prediction platform that does not require prior knowledge of the relevant kinases targeted by the inhibitor; instead, a phosphotyrosine peptide profile using peptide arrays with a kinetic readout is derived in lysates in the presence and absence of a kinase inhibitor. We show in a range of cell lines and in xenograft tumors that this approach allows for the stratification of responders and nonresponders to a multitargeted kinase inhibitor. [Mol Cancer Ther 2009;8(7):1846–55]
Data from Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin
Authors: Newbold Andrea , Lindemann Ralph K. , Cluse Leonie A. , Whitecross Kate F. , Dear Anthony E. , Johnstone Ricky W.
Published: April 2023

Abstract
Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Eμ-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-XL inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-XL, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-XL was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities. [Mol Cancer Ther 2008;7(5):1066–79]
Data from Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer
Authors: Bisht Savita , Mizuma Masamichi , Feldmann Georg , Ottenhof Niki A. , Hong Seung-Mo , Pramanik Dipankar , Chenna Venugopal , Karikari Collins , Sharma Rajni , Goggins Michael G. , Rudek Michelle A. , Ravi Rajani , Maitra Amarnath , Maitra Anirban
Published: April 2023

Abstract
Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-κB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy. Mol Cancer Ther; 9(8); 2255–64. ©2010 AACR.
Data from Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis
Authors: Shah Girish V. , Muralidharan Anbalagan , Thomas Shibu , Gokulgandhi Mitan , Mudit Mudit , Khanfar Mohammad , El Sayed Khalid
Published: April 2023

Abstract
Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer, and activated CT-CTR autocrine axis plays a pivotal role in tumorigenicity and metastatic potential of multiple prostate cancer cell lines. Recent studies suggest that CT promotes prostate cancer metastasis by reducing cell-cell adhesion through the disassembly of tight and adherens junctions and activation of β-catenin signaling. We attempted to identify a class of molecules that enhances cell-cell adhesion of prostate cells and reverses the disruptive actions of CT on tight and adherens junctions. Screening several compounds led to the emergence of phenyl-methylene hydantoin (PMH) as a lead candidate that can augment cell-cell adhesion and abolish disruptive actions of CT on junctional complexes. PMH reduced invasiveness of PC-3M cells and abolished proinvasive actions of CT. Importantly, PMH did not display significant cytotoxicity on PC-3M cells at the tested doses. I.p. administered PMH and its S-ethyl derivative remarkably decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs of nude mice. PMH treatment also reduced the growth of spontaneous tumors in LPB-Tag mice to a significant extent without any obvious cytotoxic effects. By virtue of its ability to stabilize cell junctions, PMH could reverse the effect of CT on junctional disruption and metastasis, which strengthens the possibility of using PMH as a potential drug candidate for CT-positive androgen-independent prostate cancers. [Mol Cancer Ther 2009;8(3):509–20]
Data from A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor–dependent tumor growth in vivo
Authors: Ji Qun-sheng , Mulvihill Mark J. , Rosenfeld-Franklin Maryland , Cooke Andrew , Feng Lixin , Mak Gilda , O'Connor Matthew , Yao Yan , Pirritt Caroline , Buck Elizabeth , Eyzaguirre Alexandra , Arnold Lee D. , Gibson Neil W. , Pachter Jonathan A.
Published: April 2023

Abstract
Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non–small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC50 of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II–driven human tumor model. [Mol Cancer Ther 2007;6(8):2158–67]
Data from ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
Authors: Mitchell Dianne , Pobre Eileen G. , Mulivor Aaron W. , Grinberg Asya V. , Castonguay Roselyne , Monnell Travis E. , Solban Nicolas , Ucran Jeffrey A. , Pearsall R. Scott , Underwood Kathryn W. , Seehra Jasbir , Kumar Ravindra
Published: April 2023

Abstract
Activin receptor–like kinase-1 (ALK1) is a type I, endothelial cell–specific member of the transforming growth factor-β superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-β–related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor–, fibroblast growth factor–, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization. Mol Cancer Ther; 9(2); 379–
Data from Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors
Authors: Helguera Gustavo , Rodríguez José A. , Penichet Manuel L.
Published: April 2023

Abstract
We have previously generated antihuman HER2/neu–humanized IgG3 fused to interleukin-2 (IL-2), IL-12, or granulocyte macrophage colony-stimulating factor (GM-CSF) [monofunctional fusion proteins (mono-AbFP)] or fused to IL-2 and IL-12 or IL-12 and GM-CSF [bifunctional fusion proteins (bi-AbFP)]. These AbFPs retained cytokine and antigen-binding activities. We have now further characterized the AbFPs and determined the heparin-binding activity of the fused cytokines, their ability to trigger IFN-γ secretion and natural killer (NK) activation, and their direct antitumor efficacy. Flow cytometry revealed heparin-binding activity in the AbFPs containing IL-12 and IL-2, although this activity seems to be decreased in the bi-AbFPs. However, both bi-AbFPs retained the capacity to stimulate IL-12-dependent IFN-γ secretion in the NK cell line KY-1, and IL-12/IL-2 bi-AbFP induced NK activity in splenocytes. The antitumor effectiveness of bi-AbFPs and mono-AbFP combinations was studied in mice challenged i.p. with three different human HER2/neu murine syngeneic models (D2F2/E2, CT26-HER2/neu, and MC38-HER2/neu). Although a significant variability in the profile of antitumor response was observed in the different tumor models, the combination of IL-12 and GM-CSF mono-AbFPs protected 100% of D2F2/E2-challenged and 75% of CT26-HER2/neu–challenged mice. In contrast, bi-AbFPs protected less than the combination of mono-AbFPs and, in some models, even less than mono-AbFPs alone. However, in all cases, most of long-term survivors showed protection after s.c. rechallenge with the tumors and later with the parental tumors not expressing HER2/neu. These results show that, although the pattern of protection is tumor model dependent, treatments with AbFPs can effectively generate high levels of protection against peritoneal tumors expressing HER2/neu, which may be relevant in patients with primary or metastatic peritoneal carcinomatosis that may be observed in ovarian, colon, stomach, bladder, lung, and breast cancers. [Mol Cancer Ther 2006;5(4):1029–40]
Rodzina i konstrukcje tożsamości młodzieży w warunkach pogranicza
Authors: Szczurek-Boruta Alina
Published: April 2023

Ramą teoretyczną prowadzonych rozważań jest konstruktywizm oraz koncepcja wielopłaszczyznowej i ustawicznie kreującej się tożsamości Jerzego Nikitorowicza. Autorka przyjmuje, że tożsamość jednostki jest społecznie konstruowana. Za ważne czynniki, w kluczowy sposób uwikłane w proces formowania się tożsamości, uznaje podmiotowe cechy jednostki, które rozpatruje w szerszym kontekście doświadczeń społecznych gromadzonych i (re)konstruowanych w trakcie socjalizacji pierwotnej i socjalizacji wtórnej.
Podstawą podjętych rozważań są wyniki wielozmiennowych badań ilościowych i jakościowych prowadzonych od ponad trzydziestu lat na pograniczu polsko-czeskim na Śląsku Cieszyńskim. Przedstawione w tym artykule analizy dotyczą znaczenia rodziny (cieszyńskiej – funkcjonującej w polskiej części Śląska Cieszyńskiego oraz zaolziańskiej – funkcjonującej w czeskiej części Śląska Cieszyńskiego) w konstruowaniu tożsamości jednostki. W ich kontekście należy stwierdzić, że w procesie socjalizacji pierwotnej jednostka kształtuje rdzeń tożsamości, względnie stałą jej część. Rdzeń pozwala zachować ciągłość i stanowi konstruktywną odpowiedź na wieloznaczność świata. Jednostka rekonstruuje swoją tożsamość, opierając się na dostępnych źródłach kulturowych, dokładając je do rdzenia tożsamości.
Mercury-resistant biofilm-forming bacteria and local plants in phytoremediation of small-scale gold mine tailings in Lombok Island, Indonesia
Authors: Nurfitriani Siska , Arisoesilaningsih Endang , Nuraini Yulia
Published: April 2023

Small-scale gold mining is one of the sectors that contribute to the world's largest mercury contamination through the tailings it produces. Many efforts have been made to reduce mercury concentrations from tailings, one of which is by utilizing a combination of plants and bacteria. This study aims to analyze the combination of mercury-resistant biofilm-forming bacteria and local plants in the phytoremediation of small-scale gold mine tailings. This study used ten plant species divided into three groups and three biofilm-forming mercury-resistant bacteria (Bacillus toyonensis, Burkholderia cepacia, and Microbacterium chocolatum). Parameters observed included plant biomass, total chlorophyll, plant mercury content and media. The results showed that adding bacteria to each plant in the treatment had a different effect. Some plants with the addition of biofilm-forming bacteria had a higher wet weight than others. However, the addition of bacteria was not effective in increasing plant dry weight. The combination of biofilm-forming bacteria in the first and second plant groups reduced tailings mercury concentrations better than without the addition of bacteria. The combination of plants and bacteria in the third group gave higher media and plant mercury concentrations. This study shows that the addition of biofilm-forming bacteria can lead to increased remediation by plants. The second plant group treatment with a combination of P. indica, P. conjugatum, and S. sesban plants was the most effective in reducing tailings mercury content.
Physico-Chemical Comparison of Four Commercially Available Mineral Trioxide Aggregates
Authors: Montero-Aguilar Mauricio , Vega-Baudrit José Roberto , Pereira-Reyes Reinaldo , Pozos-Guillén Amaury , Ulate-Rodríguez Esteban , Chavarría-Bolaños Daniel
Published: April 2023

To compare the physicochemical composition of 4 MTAs commercially available in Latin America. ProRoot MTA (Dentsply, USA), MTA Angelus (Angelus, Brazil), MTA Flow (Ultradent, USA), and MTA Viarden (Viarden, Mexico) were physically and chemically compared. Scanning electron microscopy (SEM) images were obtained from the MTA powder and the prepared presentations. Energy Dispersive X-Ray Spectroscopy (EDS) analyses were performed by triplicate, to calculate the mass proportion of calcium (Ca), silicon (Si), the Ca/Si proportion among the 4 brands. Thermogravimetric analyses (TGA) were conducted (50ºC-1000ºC), and mass loss and inflection points were calculated for each material. Statistical differences for Ca and Si content were determined by ANOVA (p<0.05). SEM images showed evident differences in the appearance of both the powder and the prepared MTAs among brands. Angelus MTA showed cubic prisms not observed in the other 3 brands. ProRoot MTA and MTA Flow showed similar homogeneous structures. MTA Viarden was the less homogeneous, with random structures (>15um). When comparing the mass proportions of Ca and Si between the 4 powder samples, MTA Viarden showed a significantly lower proportions of both elements when compared with the other brands (p<0.005). TGA analysis showed a similar behavior for ProRoot MTA, MTA Angelus and MTA Flow, with less than 2% mass loss when the 1000C temperature was reached. MTA Viarden showed a mass loss of 9,94% before the 700C, indicating the presence of different content sensible to temperature degradation. The analyzed MTAs demonstrated to vary significantly in their chemical composition and physical characteristics. Clinicians must be aware of the differences between different brands of a same material, and future research should focus on the clinical implications of these differences.