bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment
Authors: Ragusa Marco , Majorana Alessandra , Statello Luisa , Maugeri Marco , Salito Loredana , Barbagallo Davide , Guglielmino Maria Rosa , Duro Laura R. , Angelica Rosario , Caltabiano Rosario , Biondi Antonio , Di Vita Maria , Privitera Giuseppe , Scalia Marina , Cappellani Alessandro , Vasquez Enrico , Lanzafame Salvatore , Basile Francesco , Di Pietro Cinzia , Purrello Michele
Published: April 2023

Abstract
The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras–mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response. Mol Cancer Ther; 9(12); 3396–409. © 2010 AACR.
Data from Real-time Fluorescent Resonance Energy Transfer Analysis to Monitor Drug Resistance in Chronic Myelogenous Leukemia
Authors: Tunceroglu Ahmet , Matsuda Michiyuki , Birge Raymond B.
Published: April 2023

Abstract
Despite the initial effectiveness of oncogene-directed cancer therapeutics, acquired drug resistance remains the ultimate “Achilles' heel” for long-term durable remission in cancer patients. Acquisition of drug resistance is not more evident elsewhere than in the use of tyrosine kinase inhibitors, imatinib and dasatinib, for patients with chronic myelogenous leukemia. Hence, even though imatinib initially produces remission in the chronic phase, ultimately these therapeutics fail via the emergence of drug resistance, in which chronic myelogenous leukemia could inevitably progress to a terminal blast phase culminating in fatal outcome. Technically, it is challenging to predict the onset of drug resistance in a small number of oncogene-transformed cells, making the decision of when and how to employ second-generation tyrosine kinase inhibitors, or employ novel compounds that would be of benefit in treating drug-resistant Bcr-Abl mutants mainly retrospective. Here, we characterize a rapid and sensitive real-time fluorescent resonance energy transfer–based assay that is able to detect the in vivo activity of Bcr-Abl and its inhibition by small molecule compounds. Due to its real-time and in vivo nature, such an approach has the potential to monitor a drug-resistant phenotype, as well as to identify pharmaceutical agents that inhibit drug-resistant Bcr-Abl oncoproteins in vivo. Mol Cancer Ther; 9(11); 3065–73. ©2010 AACR.
Data from Inhibition of S-adenosylmethionine decarboxylase by inhibitor SAM486A connects polyamine metabolism with p53-Mdm2-Akt/protein kinase B regulation and apoptosis in neuroblastoma
Authors: Koomoa Dana-Lynn T. , Borsics Tamas , Feith David J. , Coleman Craig C. , Wallick Christopher J. , Gamper Ivonne , Pegg Anthony E. , Bachmann André S.
Published: April 2023

Abstract
S-adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme of polyamine (PA) biosynthesis, and both AdoMetDC and PA levels are often up-regulated in cancer cells. The second-generation inhibitor SAM486A inhibits AdoMetDC enzyme activity and has been evaluated in phase II clinical cancer trials. However, little is known about the mechanism of action and potential use of this therapeutic drug in the treatment of the pediatric cancer neuroblastoma (NB). Here, we show that p53 wild-type NB cells are highly sensitive to SAM486A treatment. Most notably, SAM486A treatment resulted in the rapid accumulation of proapoptotic proteins p53 and Mdm2. Concomitant with the increase of proteins at endogenous levels, the in vivo phosphorylation of p53 at residues Ser46/Ser392 and Mdm2 at residue Ser166 was observed. Moreover, the antiapoptotic protein Akt/protein kinase B was down-regulated and also dephosphorylated at residue Ser473 in a dose- and time-dependent manner and NB cells entered apoptotic cell death. The results presented in this study highlight the importance of PA homeostasis and provide a direct link between PA metabolism and apoptotic cell signaling pathways in p53 wild-type NB cells. PA inhibitors such as SAM486A may be effective alternative agents for the treatment of NBs with or without MYCN amplification. [Mol Cancer Ther 2009;8(7):2067–75]
Data from Oligodeoxyribozymes That Cleave β-Catenin Messenger RNA Inhibit Growth of Colon Cancer Cells via Reduction of β-Catenin Response Transcription
Authors: Choi Bo-Ra , Gwak Jungsug , Kwon Hyun-Mi , Oh Sangtaek , Kim Kwang Pyo , Choi Woo-Hyung , Cho Yo-Han , Kim Dong-Eun
Published: April 2023

Abstract
Abnormal regulation of Wnt/β-catenin signaling followed by increased levels of the β-catenin protein have been identified in enhanced cellular proliferation and development of colon polyps and cancers. To inhibit β-catenin gene expression in colon cancer cells, RNA-cleaving oligodeoxyribozyme (DNAzyme) was employed to destroy the β-catenin mRNA. We designed a strategy to identify the cleavage sites in β-catenin RNA with a pool of random sequences from a DNAzyme library and identified four potential DNAzyme-working sites. DNAzymes were constructed for the selected target sites and were tested for the ability to cleave β-catenin RNA. When introduced into the cells, the selected DNAzymes decreased the expression of β-catenin significantly as well as its downstream gene, cyclin D1. Additionally, we designed short hairpin RNA that targets the same cleavage site for the selected DNAzyme. The designed short hairpin RNA also inhibited β-catenin gene expression in colon cancer cells. Our studies show that RNA-cleaving DNAzymes and RNA interference targeted to β-catenin significantly reduced β-catenin–dependent gene expression, resulting in inhibition of colon cancer cell growth. These results indicate that the functional antisense oligonucleotides directed against β-catenin might have potential as a therapeutic intervention to treat colon cancer. Mol Cancer Ther; 9(6); 1894–902. ©2010 AACR.
Data from Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy
Authors: Kim Young H. , Choi Beom K. , Oh Ho S. , Kang Woo J. , Mittler Robert S. , Kwon Byoung S.
Published: April 2023

Abstract
Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8+ T cells, the 4-1BB–dependent expansion and differentiation of which into IFN-γ–producing CD11c+CD8+ T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced ∼60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8+ T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs. [Mol Cancer Ther 2009;8(2):469–78
Data from Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors
Authors: Weisberg Ellen , Choi Hwan Geun , Barrett Rosemary , Zhou Wenjun , Zhang Jianming , Ray Arghya , Nelson Erik A. , Jiang Jingrui , Moreno Daisy , Stone Richard , Galinsky Ilene , Fox Edward , Adamia Sophia , Kung Andrew L. , Gray Nathanael S. , Griffin James D.
Published: April 2023

Abstract
For a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine kinase, mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, however, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit can arise from the combination of two structurally diverse inhibitors that target—but bind differently to—the same protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need for identification and development of novel FLT3 inhibitors that have the ability to positively combine with PKC412 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of drug resistance and consequently prolong disease remission. Here, we report the effects of the novel type II ATP-competitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point mutants via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown in vivo to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice harboring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, HG-7-85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant PKC412-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients. Mol Cancer Ther; 9(9); 2468–77. ©2010 AACR.
Data from Endocytosis of PEGylated Agents Enhances Cancer Imaging and Anticancer Efficacy
Authors: Chuang Kuo-Hsiang , Wang Hsin-Ell , Chen Fang-Ming , Tzou Shey-Cherng , Cheng Chiu-Min , Chang Ya-Chen , Tseng Wei-Lung , Shiea Jentaie , Lin Shiu-Ru , Wang Jaw-Yuan , Chen Bing-Mae , Roffler Steve R. , Cheng Tian-Lu
Published: April 2023

Abstract
PEGylated nanoparticles and macromolecules are increasingly used in cancer imaging and anticancer treatment. The role of receptor-mediated endocytosis in the efficacy of these agents, however, has not been clearly defined. Here, we developed a matched pair of endocytic and nonendocytic receptors to directly and unambiguously assess this issue. The ligand-binding domains of the low-density lipoprotein receptor (LDLR) or a truncated LDLR lacking the NPXY endocytosis motif (ΔLDLR) were replaced with an anti–polyethylene glycol antibody (αPEG) to form endocytic αPEG-LDLR and nonendocytic αPEG-ΔLDLR receptors. The receptors were stably expressed at similar levels on the surface of HCC36 cells. HCC36/αPEG-LDLR cells, but not HCC36/αPEG-ΔLDLR cells, rapidly endocytosed PEG-quantum dots and PEG-liposomal doxorubicin (Lipo-Dox) in vitro and in vivo. Lipo-Dox was significantly more cytotoxic to HCC36/αPEG-LDLR cells than to HCC36/αPEG-ΔLDLR cells. HCC36/αPEG-LDLR tumors also accumulated significantly more PEGylated near-IR probes (PEG-NIR797) and PEG-liposomal-111In than HCC36/αPEG-ΔLDLR tumors in vivo. Furthermore, Lipo-Dox more significantly suppressed the growth of established HCC36/αPEG-LDLR tumors as compared with HCC36/αPEG-ΔLDLR tumors. Our data show that endocytosis of PEGylated probes and drugs enhances both cancer imaging and anticancer efficacy, indicating that endocytic receptors are superior targets for the design of cancer imaging probes and immunoliposomal drugs. Mol Cancer Ther; 9(6); 1903–12. ©2010 AACR.
Data from Drug ratio–dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo
Authors: Tardi Paul G. , Dos Santos Nancy , Harasym Troy O. , Johnstone Sharon A. , Zisman Natalia , Tsang Alan W. , Bermudes David G. , Mayer Lawrence D.
Published: April 2023

Abstract
Irinotecan and cisplatin are two established anticancer drugs, which together constitute an effective combination for treating small-cell lung cancer. We investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vivo administration. Irinotecan and cisplatin combinations were evaluated systematically for drug ratio–dependent synergy in vitro using a panel of 20 tumor cell lines. In vitro screening informatics on drug ratio–dependent cytotoxicity identified a consistently antagonistic region between irinotecan/cisplatin molar ratios of 1:2 to 4:1, which was bordered by two synergistic regions. Liposomal co-formulations of these two agents were developed that exhibited plasma drug half-lives of ∼6 hours and maintained a fixed drug ratio for more than 24 hours. Drug ratio–dependent antitumor activity was shown in vivo for these liposome formulations, and irinotecan/cisplatin ratios between 5:1 and 10:1 were identified as therapeutically optimal. The relationship between irinotecan/cisplatin ratio and in vivo efficacy was consistent with in vitro drug ratio dependency results. Superior antitumor activity was observed for the liposome-encapsulated 7:1 molar ratio of irinotecan/cisplatin (designated CPX-571) compared with the free-drug cocktail in all models tested. Further efficacy studies in a range of human tumor xenografts, including an irinotecan-resistant model, showed that both liposomal agents contributed to the overall efficacy in a manner consistent with in vivo synergy. These results show the ability of drug delivery technology to enhance the therapeutic activity of irinotecan/cisplatin combination treatment by maintaining synergistic ratios in vivo. CPX-571, a fixed-ratio formulation of irinotecan and cisplatin, is a promising candidate for clinical development. [Mol Cancer Ther 2009;8(8):2266–75]
Data from Drugs aimed at targeting characteristic karyotypic phenotypes of cancer cells
Authors: Wallqvist Anders , Huang Ruili , Covell David G. , Roschke Anna V. , Gelhaus Kristen S. , Kirsch Ilan R.
Published: April 2023

Abstract
The karyotypic features of cancer cells have not been a particular focus of anticancer drug targeting either as guidance for treatment or as specific drug targets themselves. Cancer cell lines typically have considerable, characteristic, and variable chromosomal aberrations. Here, we consider small-molecule screening data across the National Cancer Institute's 60 tumor cell line drug screening panel (NCI-60) analyzed for specific association with karyotypic variables (numerical and structural complexity and heterogeneity) determined for these same cell lines. This analysis is carried out with the aid of a self-organizing map allowing for a simultaneous assessment of all screened compounds, revealing an association between karyotypic variables and a unique part of the cytotoxic response space. Thirteen groups of compounds based on related specific chemical structural motifs are identified as possible leads for anticancer drug discovery. These compounds form distinct groups of molecules associated with relatively unexplored regions of the NCI-60 self-organizing map where anticancer agents currently standard in the clinic are not present. We suggest that compounds identified in this study may represent new classes of potential anticancer agents.
Data from Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma
Authors: Hegde Ganapati V. , Munger Corey M. , Emanuel Katy , Joshi Avadhut D. , Greiner Timothy C. , Weisenburger Dennis D. , Vose Julie M. , Joshi Shantaram S.
Published: April 2023

Abstract
Mantle cell lymphoma (MCL) has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival of only 3 to 4 years. Therefore, a better understanding of the underlying mechanisms that regulate MCL proliferation/survival is needed to develop an effective therapy. Because sonic hedgehog (Shh)-GLI signaling has been shown to be important in the proliferation and survival of several cancers, and no such information is available for MCL, this study was undertaken. Our results show that the molecules associated with Shh-GLI signaling, such as PTCH and SMO receptors, and GLI1 and GLI2 target transcription factors were expressed in the human MCL cell lines and primary MCL cells from patients. Perturbation of this signaling in the presence of exogenous Shh/cyclopamine significantly (P < 0.001) influenced the proliferation of JVM2 MCL cells. Furthermore, down-regulation of GLI transcription factors using antisense oligonucleotides not only resulted in significantly (P < 0.001) decreased proliferation of the MCL cells but also significantly (P < 0.05) increased their susceptibility to chemotherapeutic drug, doxorubicin. Also, down-regulation of GLI decreased cyclin D1 and BCL2 transcript levels, which suggests that these key molecules might be regulated by GLI in MCL. Thus, our results indicate a significant role for Shh-GLI signaling in the proliferation of MCL, and molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL. [Mol Cancer Ther 2008;7(6):1450–60]
Data from GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers
Authors: Sabbatini Peter , Korenchuk Susan , Rowand Jason L. , Groy Arthur , Liu Qi , Leperi Dominic , Atkins Charity , Dumble Melissa , Yang Jingsong , Anderson Kelly , Kruger Ryan G. , Gontarek Richard R. , Maksimchuk Kenneth R. , Suravajjala Sapna , Lapierre Russell R. , Shotwell J. Brad , Wilson Joseph W. , Chamberlain Stanley D. , Rabindran Sridhar K. , Kumar Rakesh
Published: April 2023

Abstract
The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC50s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non–small cell lung cancers. GSK1838705A inhibits ALK, with an IC50 of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers. [Mol Cancer Ther 2009;8(10):2811–20]
Data from Histone Deacetylase Inhibition Attenuates Cell Growth with Associated Telomerase Inhibition in High-Grade Childhood Brain Tumor Cells
Authors: Rahman Ruman , Osteso-Ibanez Teresa , Hirst Robert A. , Levesley Jane , Kilday John-Paul , Quinn Siobhan , Peet Andrew , O'Callaghan Chris , Coyle Beth , Grundy Richard G.
Published: April 2023

Abstract
Aberrant epigenetic regulation of gene expression contributes to tumor initiation and progression. Studies from a plethora of hematologic and solid tumors support the use of histone deacetylase inhibitors (HDACi) as potent anticancer agents. However, the mechanism of HDACi action with respect to the temporal order of induced cellular events is unclear. The present study investigates the anticancer effects of the HDACi trichostatin A in high-grade childhood brain tumor cells. Acute exposure to trichostatin A resulted in marked inhibition of cell proliferation, an increase in the proportion of G2-M cells, activation of H2A.X, and subsequent induction of apoptosis in the majority of cell lines. These phenotypic effects were associated with abrogation of telomerase activity and human telomerase reverse transcriptase downregulation in the majority of cell lines. In contrast, no cytotoxicity was observed in primary ependymal cells with respect to cilia function. Thus, inhibition of histone deacetylases leads to antiproliferative and proapoptotic effects in childhood brain tumor cells, likely to involve altered chromatin regulation at the human telomerase reverse transcriptase promoter. Mol Cancer Ther; 9(9); 2568–81. ©2010 AACR.
Data from Nuclear factor κB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos
Authors: Daroczi Borbala , Kari Gabor , Ren Qing , Dicker Adam P. , Rodeck Ulrich
Published: April 2023

Abstract
Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor κB (NF-κB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-κB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-κB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional IκB kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-κB activation may be useful in alleviating radiation toxicity in patients. [Mol Cancer Ther 2009;8(9):2625–34]
Data from Systematic Interpretation of Comutated Genes in Large-Scale Cancer Mutation Profiles
Authors: Gu Yunyan , Yang Da , Zou Jinfeng , Ma Wencai , Wu Ruihong , Zhao Wenyuan , Zhang Yuannv , Xiao Hui , Gong Xue , Zhang Min , Zhu Jing , Guo Zheng
Published: April 2023

Abstract
By high-throughput screens of somatic mutations of genes in cancer genomes, hundreds of cancer genes are being rapidly identified, providing us abundant information for systematically deciphering the genetic changes underlying cancer mechanism. However, the functional collaboration of mutated genes is often neglected in current studies. Here, using four genome-wide somatic mutation data sets and pathways defined in various databases, we showed that gene pairs significantly comutated in cancer samples tend to distribute between pathways rather than within pathways. At the basic functional level of motifs in the human protein-protein interaction network, we also found that comutated gene pairs were overrepresented between motifs but extremely depleted within motifs. Specifically, we showed that based on Gene Ontology that describes gene functions at various specific levels, we could tackle the pathway definition problem to some degree and study the functional collaboration of gene mutations in cancer genomes more efficiently. Then, by defining pairs of pathways frequently linked by comutated gene pairs as the between-pathway models, we showed they are also likely to be codisrupted by mutations of the interpathway hubs of the coupled pathways, suggesting new hints for understanding the heterogeneous mechanisms of cancers. Finally, we showed some between-pathway models consisting of important pathways such as cell cycle checkpoint and cell proliferation were codisrupted in most cancer samples under this study, suggesting that their codisruptions might be functionally essential in inducing these cancers. All together, our results would provide a channel to detangle the complex collaboration of the molecular processes underlying cancer mechanism. Mol Cancer Ther; 9(8); 2186–95. ©2010 AACR.
Data from Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets
Authors: Yang Peiying , Menter David G. , Cartwright Carrie , Chan Diana , Dixon Susan , Suraokar Milind , Mendoza Gabriela , Llansa Norma , Newman Robert A.
Published: April 2023

Abstract
Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase α3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of α3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of α3 to α1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the α3 expression relative to α1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of α3 was decreased by knocking down the expression of α3 isoform with α3 siRNA or increasing expression of the α1 isoform through transient transfection of α1 cDNA to the cells. Our data suggest that the relative lack of α3 (relative to α1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of α3 with the limited expression of α1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin. [Mol Cancer Ther 2009;8(8):2319–28]
Data from Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance
Authors: Humeniuk Rita , Menon Lata G. , Mishra Prasun J. , Gorlick Richard , Sowers Rebecca , Rode Wojciech , Pizzorno Giuseppe , Cheng Yung-Chi , Kemeny Nancy , Bertino Joseph R. , Banerjee Debabrata
Published: April 2023

Abstract
5-Fluorouracil (5-FU) continues to be widely used for treatment of gastrointestinal cancers. Because many tumors show primary or acquired resistance, it is important to understand the molecular basis underlying the mechanism of resistance to 5-FU. In addition to its effect on thymidylate synthase inhibition and DNA synthesis, 5-FU may also influence RNA metabolism. Our previous studies revealed that colorectal cancer cells resistant to bolus 5-FU (HCT-8/4hFU) showed significantly decreased incorporation of the drug into RNA. Resistance to bolus 5-FU was associated with lower expression of UMP kinase (UMPK), an enzyme that plays an important role in the activation of 5-FU to 5-FUTP and its incorporation into RNA. Activities of other 5-FU–metabolizing enzymes (e.g., thymidine kinase, uridine phosphorylase, thymidine phosphorylase, and orotate phosphoribosyltransferase) remained unchanged between sensitive and resistant cell lines. Herein, we show that UMPK down-regulation in 5-FU–sensitive cells (HCT-8/P) induces resistance to bolus 5-FU treatment. Moreover, HCT-8/4hFU cells are even more cross-resistant to treatment with 5-fluorouridine, consistent with the current understanding of 5-fluorouridine as a RNA-directed drug. Importantly, colorectal cancer hepatic metastases isolated from patients clinically resistant to weekly bolus 5-FU/leucovorin treatment exhibited decreased mRNA expression of UMPK but not thymidylate synthase or dihydropyrimidine dehydrogenase compared with tumor samples of patients not previously exposed to 5-FU. Our findings provide new insights into the mechanisms of acquired resistance to 5-FU in colorectal cancer and implicate UMPK as an important mechanism of clinical resistance to pulse 5-FU treatment in some patients.[Mol Cancer Ther 2009;8(4):OF1–8]
Data from Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen
Authors: Ariazi Eric A. , Leitão Andrei , Oprea Tudor I. , Chen Bin , Louis Teresa , Bertucci Anne Marie , Sharma Catherine G.N. , Gill Shaun D. , Kim Helen R. , Shupp Heather A. , Pyle Jennifer R. , Madrack Alexis , Donato Anne L. , Cheng Dong , Paige James R. , Jordan V. Craig
Published: April 2023

Abstract
Aromatase inhibitors (AI) are being evaluated as long-term adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor α (ERα) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the non-aromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane down-regulated ERα protein levels at high concentrations in a cell type–specific manner similarly as 17β-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17β-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERα. Molecular modeling also indicated that 17-hydroexemestane interacted with ERα and AR through selective recognition motifs employed by 17β-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs. [Mol Cancer Ther 2007;6(11):2817–27]
Data from Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor
Authors: Moretti Luigi , Kim Kwang Woon , Jung Dae Kwang , Willey Christopher D. , Lu Bo
Published: April 2023

Abstract
Despite recent advances in the management of breast and lung cancer, novel treatment strategies are still needed to further improve patient outcome. The targeting of cell death pathways has therefore been proposed to enhance therapeutic ratio in cancer. In this study, we examined the in vitro and in vivo effects of Z-VAD, a broad-spectrum caspase inhibitor, on breast and lung cancer in association with radiation. Using clonogenic assays, we observed that Z-VAD markedly radiosensitized breast and lung cancer cells, with a radiation dose enhancement ratio of 1.31 (P < 0.003). For both models, the enhanced tumor cytotoxicity was associated with induction of autophagy. Furthermore, we found that administration of Z-VAD with radiation in both breast and lung cancer xenograft produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo and thus represents an attractive anticancer therapeutic strategy. In conclusion, this preclinical study supports the therapeutic potential of Z-VAD as a radiosensitizer in breast and lung cancer. This study also suggests caspase inhibition as a promising strategy to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are needed to determine the potential of this combination therapy in cancer patients. [Mol Cancer Ther 2009;8(5):OF1–10]
Data from Improved grading and survival prediction of human astrocytic brain tumors by artificial neural network analysis of gene expression microarray data
Authors: Petalidis Lawrence P. , Oulas Anastasis , Backlund Magnus , Wayland Matthew T. , Liu Lu , Plant Karen , Happerfield Lisa , Freeman Tom C. , Poirazi Panayiota , Collins V. Peter
Published: April 2023

Abstract
Histopathologic grading of astrocytic tumors based on current WHO criteria offers a valuable but simplified representation of oncologic reality and is often insufficient to predict clinical outcome. In this study, we report a new astrocytic tumor microarray gene expression data set (n = 65). We have used a simple artificial neural network algorithm to address grading of human astrocytic tumors, derive specific transcriptional signatures from histopathologic subtypes of astrocytic tumors, and asses whether these molecular signatures define survival prognostic subclasses. Fifty-nine classifier genes were identified and found to fall within three distinct functional classes, that is, angiogenesis, cell differentiation, and lower-grade astrocytic tumor discrimination. These gene classes were found to characterize three molecular tumor subtypes denoted ANGIO, INTER, and LOWER. Grading of samples using these subtypes agreed with prior histopathologic grading for both our data set (96.15%) and an independent data set. Six tumors were particularly challenging to diagnose histopathologically. We present an artificial neural network grading for these samples and offer an evidence-based interpretation of grading results using clinical metadata to substantiate findings. The prognostic value of the three identified tumor subtypes was found to outperform histopathologic grading as well as tumor subtypes reported in other studies, indicating a high survival prognostic potential for the 59 gene classifiers. Finally, 11 gene classifiers that differentiate between primary and secondary glioblastomas were also identified. [Mol Cancer Ther 2008;7(5):1013–24]
Data from ZD6474, a Multitargeted Inhibitor for Receptor Tyrosine Kinases, Suppresses Growth of Gliomas Expressing an Epidermal Growth Factor Receptor Mutant, EGFRvIII, in the Brain
Authors: Yiin Jia-Jean , Hu Bo , Schornack Paul A. , Sengar Raghvendra S. , Liu Kun-wei , Feng Haizhong , Lieberman Frank S. , Chiou Shih-Hwa , Sarkaria Jann N. , Wiener Erik C. , Ma Hsin-I , Cheng Shi-Yuan
Published: April 2023

Abstract
Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-XL expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII. Mol Cancer Ther; 9(4); 929–41. ©2010 AACR.
Data from Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia
Authors: Hu Shuiying , Niu Hongmei , Minkin Patton , Orwick Shelley , Shimada Akira , Inaba Hiroto , Dahl Gary V.H. , Rubnitz Jeffrey , Baker Sharyn D.
Published: April 2023

Abstract
We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 μmol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 μmol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by ≥50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML. [Mol Cancer Ther 2008;7(5):1110–20]
Data from Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis
Authors: Chen Ying , Hao Hua , He Songqing , Cai Lei , Li Yongsheng , Hu Shunze , Ye Duyun , Hoidal John , Wu Ping , Chen Xiaoping
Published: April 2023

Abstract
Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A4 (LXA4) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164–74. ©2010 AACR.
Data from Cisplatin Treatment Induces a Transient Increase in Tumorigenic Potential Associated with High Interleukin-6 Expression in Head and Neck Squamous Cell Carcinoma
Authors: Poth Kim J. , Guminski Alexander D. , Thomas Gethin P. , Leo Paul J. , Jabbar Ibtissam A. , Saunders Nicholas A.
Published: April 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of ∼50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited >99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6–positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment. Mol Cancer Ther; 9(8); 2430–9. ©2010 AACR.
Data from AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
Authors: Zabludoff Sonya D. , Deng Chun , Grondine Michael R. , Sheehy Adam M. , Ashwell Susan , Caleb Benjamin L. , Green Stephen , Haye Heather R. , Horn Candice L. , Janetka James W. , Liu Dongfang , Mouchet Elizabeth , Ready Shannon , Rosenthal Judith L. , Queva Christophe , Schwartz Gary K. , Taylor Karen J. , Tse Archie N. , Walker Graeme E. , White Anne M.
Published: April 2023

Abstract
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955–66]