bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined IFN-γ and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells
Authors: Cetinkaya Cihan , Hultquist Anne , Su Yingtao , Wu Siqin , Bahram Fuad , Påhlman Sven , Guzhova Irina , Larsson Lars-Gunnar 
Published: October 2007

Abstract
The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-γ synergistically potentiates retinoic acid (RA)–induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN-γ down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN-γ treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-γ and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma. [Mol Cancer Ther 2007;6(10):2634–41]
Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway
Authors: Lee Seung Ho , Son Seung Mo , Son Dong Ju , Kim Sun Mi , Kim Tack Joong , Song Sukgil , Moon Dong Cheul , Lee Hyo Won , Ryu Jae Chun , Yoon Do-Young , Hong Jin Tae 
Published: October 2007

AbstractMolecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1–100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G2-M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-κB (NF-κB) via IκB degradation through IκB kinase (IKKα and IKKβ) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKKα and β did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced β-tubulin polymerization and the formation of p50/β-tubulin complex. However, β-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKKα and β. Moreover, epothilone B and D increased the expressions of NF-κB–dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B–induced cell death and NF-κB activation. These findings suggest that the activation of NF-κB/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization–independent manner. [Mol Cancer Ther 2007;6(10):2786–97]
Treatment of colon cancer cells using the cytosine deaminase/5-fluorocytosine suicide system induces apoptosis, modulation of the proteome, and Hsp90β phosphorylation
Authors: Negroni Luc , Samson Michel , Guigonis Jean-Marie , Rossi Bernard , Pierrefite-Carle Valérie , Baudoin Christian 
Published: October 2007

AbstractThe bacterial cytosine deaminase (CD) gene, associated with the 5-fluorocytosine (5FC) prodrug, is one of the most widely used suicide systems in gene therapy. Introduction of the CD gene within a tumor induces, after 5FC treatment of the animal, a local production of 5-fluorouracil resulting in intratumor chemotherapy. Destruction of the gene-modified tumor is then followed by the triggering of an antitumor immune reaction resulting in the regression of distant wild-type metastasis. The global effects of 5FC on colorectal adenocarcinoma cells expressing the CD gene were analyzed using the proteomic method. Application of 5FC induced apoptosis and 19 proteins showed a significant change in 5FC-treated cells compared with control cells. The up-regulated and down-regulated proteins include cytoskeletal proteins, chaperones, and proteins involved in protein synthesis, the antioxidative network, and detoxification. Most of these proteins are involved in resistance to anticancer drugs and resistance to apoptosis. In addition, we show that the heat shock protein Hsp90β is phosphorylated on serine 254 upon 5FC treatment. Our results suggest that activation of Hsp90β by phosphorylation might contribute to tumor regression and tumor immunogenicity. Our findings bring new insights into the mechanism of the anticancer effects induced by CD/5FC treatment. [Mol Cancer Ther 2007;6(10):2747–56]
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6-Methylguanine-DNA-methyltransferase promoter demethylation is involved in basic fibroblast growth factor–induced resistance against temozolomide in human melanoma cells
Authors: Fontijn Dennis , Adema Auke D. , Bhakat Kishor K. , Pinedo Herbert M. , Peters Godefridus J. , Boven Epie 
Published: October 2007

Abstract
Basic fibroblast growth factor (bFGF) is a multifunctional protein and one of the most important growth factors in cutaneous melanoma development and progression. We hypothesized that high bFGF expression might be responsible for chemoresistance in advanced melanoma. M14 human melanoma cells expressing low levels of bFGF were successfully transfected with vectors encoding either the 18 kDa or all isoform proteins of bFGF. M14 cells and bFGF-overexpressing clones had a similar growth rate in vitro. Overexpression of 18 kDa or all isoform proteins of bFGF resulted in, respectively, 2.9- and 6.9-fold resistance against temozolomide. O6-Alkylguanine-DNA-alkyltransferase (AGT) protein levels were highly elevated. Specific inhibition of AGT with O6-benzylguanine completely reversed the resistance in the 18 kDa clone, and partially in the clone overexpressing all isoforms. A methylation-specific PCR showed that at least in the 18 kDa overexpressing clone, increased AGT expression was the result of demethylation of the O6-methylguanine-DNA-methyltransferase promoter. In parental M14 cells, the demethylating agent 5-azacytidine generated AGT expression resulting in temozolomide resistance. Overexpression of all isoform proteins of bFGF, but not the 18 kDa isoform alone, resulted in 2.9-fold resistance against cisplatin, which could not be reversed by O6-benzylguanine. The expression levels of the mismatch repair proteins MSH2, MSH6, and MLH1 were not decreased, which likely excludes a defective mismatch repair system as a cause for cisplatin resistance. There were no changes in sensitivity to docetaxel and doxorubicin. In conclusion, bFGF overexpression can result in resistance against temozolomide mediated by demethylation of the O6-methylguanine-DNA-methyltransferase promoter. [Mol Cancer Ther 2007;6(10):2807–15]
Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines
Authors: Emlet David R. , Brown Kathryn A. , Kociban Deborah L. , Pollice Agnese A. , Smith Charles A. , Ong Ben Brian L. , Shackney Stanley E. 
Published: October 2007

Abstract
Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that responsiveness to trastuzumab and AG1478 (an anti-EGFR agent), varied directly with levels of HER2 expression. HER2 and EGFR up-regulate vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis and participates in autocrine growth-stimulatory pathways that might be active in vitro. Here, we show that trastuzumab, erlotinib, and bevacizumab, individually and in combination, inhibit cell proliferation in a panel of unrelated human breast cancer cell lines, in proportion to their levels of HER2 expression. The combination of all three drugs provided a greater suppression of growth than any single drug or two-drug combination in the high HER2–expressing cell lines (P &lt; 0.001). Combination index analysis suggested that the effects of these drugs in combination were additive. The pretreatment net level of VEGF production in each cell line was correlated with the level of HER2 expression (r = 0.883, P = 0.016). Trastuzumab and erlotinib each reduced total net VEGF production in all cell lines. Multiparameter flow cytometry studies indicated that erlotinib alone and the triple drug combination produced a prolonged but reversible blockade of cells in G1, but did not increase apoptosis substantially. These studies suggest that the effects of two and three-drug combinations of trastuzumab, erlotinib, and bevacizumab might offer potential therapeutic advantages in HER2-overexpressing breast cancers, although these effects are of low magnitude, and are likely to be transient. [Mol Cancer Ther 2007;6(10):2664–74]
p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells
Authors: Roy Srirupa , Kaur Manjinder , Agarwal Chapla , Tecklenburg Marianne , Sclafani Robert A. , Agarwal Rajesh 
Published: October 2007

Abstract
Recent studies have shown that silibinin induces p21/Cip1 and p27/Kip1 and G1 arrest in different prostate cancer cells irrespective of p53 status; however, biological significance and mechanism of such induction have not been studied. Here, using two different prostate cancer cell lines DU145 and 22Rv1, representing androgen-independent and androgen-dependent stages of malignancy, first we investigated the importance of p21 and p27 induction in silibinin-mediated G1 arrest. Silencing p21 and p27 individually by RNA interference showed marked reversal in G1 arrest; however, their simultaneous ablation showed additional reversal of G1 arrest in 22Rv1 but not DU145 cells. These results suggest that whereas relative importance of these molecules might be cell line specific, their induction by silibinin is essential for its G1 arrest effect. Next, studies were done to examine mechanisms of their induction where cycloheximide-chase experiments showed that silibinin increases p21 and p27 protein half-life. This effect was accompanied by strong reduction in Skp2 level and its binding with p21 and p27 together with strong decrease in phosphorylated Thr187 p27 without considerable change in proteasomal activity, suggesting a posttranslational mechanism. Skp2 role was further elucidated using Skp2-small interfering RNA–transfected cells, where decreased G1 arrest and attenuated Cip/Kip induction were observed with silibinin treatment. Further, silibinin caused a marked increase in p21 and p27 mRNA levels together with an increase in their promoter activity, also indicating a transcriptional mechanism. Together, our results for the first time identify a central role of p21 and p27 induction and their regulatory mechanism in silibinin-mediated cell cycle arrest. [Mol Cancer Ther 2007;6(10):2696–707]
IB05204, a dichloropyridodithienotriazine, inhibits angiogenesis in vitro and in vivo
Authors: Martínez-Poveda Beatriz , Muñoz-Chápuli Ramón , Rodríguez-Nieto Salvador , Quintela José M. , Fernández Antonio , Medina Miguel-Ángel , Quesada Ana R. 
Published: October 2007

Abstract
In the course of a blind screening program for inhibitors of angiogenesis, IB05204 (4,8-dichloro-12-phenylpyrido[5′,6′:4″,5″;3′,2′:4,5]dithieno[3″,2″−d′:3,2−d]-1,2,3-ditriazine) was selected for its ability to inhibit endothelial tubule-like network formation on Matrigel. IB05204 inhibits the in vivo angiogenesis in the chorioallantoic membrane (CAM) and the mouse Matrigel plug assays. Antiangiogenic activity seems to be highly dependent on the chloro substituents because their removal results in a complete loss of the in vitro inhibitory activity of endothelial differentiation and in vivo antiangiogenic activity in CAM assay. Although IB05204 inhibits the growth of endothelial and tumor cells in culture, its antiangiogenic activity seems to be mainly dependent on the prevention of endothelial capillary-like tube formation and inhibition of endothelial migration because these effects are recorded at lower concentrations. IB05204 treatment inhibits matrix metalloproteinase-2 (MMP-2) production in endothelial and tumor cells, down-regulates endothelial cyclooxygenase-2 expression, and represses phosphorylation of endothelial Akt in response to serum stimulation, suggesting that IB05204 interferes with molecular mechanisms of cell migration and survival. IB05204 induces apoptosis in endothelial cells through cytochrome c release and caspase activation. Data here shown altogether indicate that IB05204 is a compound that interferes with several key steps of angiogenesis, making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies. [Mol Cancer Ther 2007;6(10):2675–85]
Anti-CD166 single chain antibody-mediated intracellular delivery of liposomal drugs to prostate cancer cells
Authors: Roth Audrey , Drummond Daryl C. , Conrad Fraser , Hayes Mark E. , Kirpotin Dmitri B. , Benz Christopher C. , Marks James D. , Liu Bin 
Published: October 2007

AbstractTargeted delivery of small-molecule drugs has the potential to enhance selective killing of tumor cells. We have identified previously an internalizing single chain [single chain variable fragment (scFv)] antibody that targets prostate cancer cells and identified the target antigen as CD166. We report here the development of immunoliposomes using this anti-CD166 scFv (H3). We studied the effects of a panel of intracellularly delivered, anti-CD166 immunoliposomal small-molecule drugs on prostate cancer cells. Immunoliposomal formulations of topotecan, vinorelbine, and doxorubicin each showed efficient and targeted uptake by three prostate cancer cell lines (Du-145, PC3, and LNCaP). H3-immunoliposomal topotecan was the most effective in cytotoxicity assays on all three tumor cell lines, showing improved cytotoxic activity compared with nontargeted liposomal topotecan. Other drugs such as liposomal doxorubicin were highly effective against LNCaP but not PC3 or Du-145 cells, despite efficient intracellular delivery. Post-internalization events thus modulate the overall efficacy of intracellulary delivered liposomal drugs, contributing in some cases to the lower than expected activity in a cell line–dependent manner. Further studies on intracellular tracking of endocytosed liposomal drugs will help identify and overcome the barriers limiting the potency of liposomal drugs. [Mol Cancer Ther 2007;6(10):2737–46]
Thioredoxin-like domains required for glucose regulatory protein 58–mediated reductive activation of mitomycin C leading to DNA cross-linking
Authors: Adikesavan Anbu Karani , Jaiswal Anil K. 
Published: October 2007

Abstract
Glucose regulatory protein (GRP58) is known to mediate mitomycin C (MMC)–induced DNA cross-linking. However, the mechanism remains elusive. We hypothesized that thioredoxin-like domains, one at NH2 terminus and another at COOH terminus, are required for GRP58-mediated MMC reductive activation leading to DNA cross-linking. Site-directed mutagenesis mutated cysteines in thioredoxin domains to serines. Wild-type (WT) and mutant GRP58 were cloned in pcDNA to produce GRP58 V5-tagged WT and mutant proteins on transfection in mammalian cells. Human colon carcinoma (HCT116) cells transiently expressing and Chinese hamster ovary cells stably expressing WT and mutant GRP58 were analyzed for MMC-induced DNA cross-linking. WT GRP58 was highly efficient in MMC-induced DNA cross-linking. However, both NH2- and COOH-terminal thioredoxin mutants showed significant reduction in MMC-induced DNA cross-linking. The coexpression of GRP58 with thioredoxin reductase 1 and/or treatment of cells with NADPH increased MMC-induced DNA cross-linking from the WT GRP58. In similar experiments, siRNA inhibition of thioredoxin reductase 1 led to decreased MMC-induced DNA cross-linking. Further experiments revealed that mutations in thioredoxin domains led to significant decrease in metabolic reductive activation of MMC. These results led to conclusion that GRP58, through its two thioredoxin-like domains, functions as a reductase leading to bioreductive drug MMC activation and DNA cross-linking. [Mol Cancer Ther 2007;6(10):2719–27]
Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity
Authors: Hahm Eun-Ryeong , Singh Shivendra V. 
Published: October 2007

Abstract
The present study was undertaken to gain insights into the mechanism of cell cycle arrest caused by honokiol, a constituent of oriental herb Magnolia officinalis. The honokiol treatment decreased the viability of PC-3 and LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which correlated with G0-G1 phase cell cycle arrest. The honokiol-mediated cell cycle arrest was associated with a decrease in protein levels of cyclin D1, cyclin-dependent kinase 4 (Cdk4), Cdk6, and/or cyclin E and suppression of complex formation between cyclin D1 and Cdk4 as revealed by immunoprecipitation using anti–cyclin D1 antibody followed by immunoblotting for Cdk4 protein. The honokiol-treated PC-3 and LNCaP cells exhibited a marked decrease in the levels of total and phosphorylated retinoblastoma protein (Rb), which correlated with the suppression of transcriptional activity of E2F1. Exposure of PC-3 and LNCaP cells to honokiol resulted in the induction of p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP). However, small interfering RNA (siRNA)–mediated knockdown of either p21 (PC-3 and LNCaP) or p53 (LNCaP) protein failed to confer any protection against honokiol-induced cell cycle arrest. The honokiol treatment caused the generation of reactive oxygen species (ROS), and the cell cycle arrest caused by honokiol was partially but significantly attenuated in the presence of antioxidant N-acetylcysteine. In conclusion, the present study reveals that the honokiol-mediated G0-G1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein level/phosphorylation of Rb leading to inhibition of transcriptional activity of E2F1. [Mol Cancer Ther 2007;6(10):2686–95]
Molecular Biology of Bone Metastasis
Authors: Kingsley Lauren A. , Fournier Pierrick G.J. , Chirgwin John M. , Guise Theresa A. 
Published: October 2007

AbstractMetastasis is a final stage of tumor progression. Breast and prostate cancer cells preferentially metastasize to bone, wherein they cause incurable osteolytic and osteoblastic lesions. The bone matrix is rich in factors, such as transforming growth factor-β and insulin-like growth factors, which are released into the tumor microenvironment by osteolysis. These factors stimulate the growth of tumor cells and alter their phenotype, thus promoting a vicious cycle of metastasis and bone pathology. Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth. These elements of the microenvironment are potential targets for chemotherapeutic intervention to halt tumor growth and suppress bone metastasis. [Mol Cancer Ther 2007;6(10):2609–17]
Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity
Authors: Lin Chentao , Wei Wei , Zhang Jinchun , Liu Shilian , Liu Yanxin , Zheng Dexian 
Published: October 2007

AbstractFormyl peptide receptor-like 1 (FPRL1), which is a G protein–coupled receptor of chemoattractant subfamily, plays an important role in the regulation of host defense against pathogenic infection and the chemotactic and activating effects of Aβ42 on mononuclear phagocytes as well as in the elimination of damaged or pathogen-infected cells. In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor κB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death. Together, these data provide novel evidence for the physiologic role of FPRL1 and TRAIL in tumor immune surveillance and innate immunity, and implicate a novel strategy for cancer therapy by triggering the endogenous TRAIL expression via stimulation of G protein–coupled receptor FPRL1. [Mol Cancer Ther 2007;6(10):2618–25]
DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145
Authors: Kiakos Konstantinos , Sato Atsushi , Asao Tetsuji , McHugh Peter J. , Lee Moses , Hartley John A. 
Published: October 2007

AbstractAS-I-145 is a novel achiral seco-amino-cyclopropylbenz[e]indolone (seco-amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents lacking the characteristic chiral center of the natural agents. The sequence specificity of this compound was assessed by a Taq polymerase stop assay, identifying the sites of covalent modification on plasmid DNA. The adenine-N3 adducts were confirmed at AT-rich sequences using a thermally induced strand cleavage assay. These studies reveal that this compound retains the inherent sequence selectivity of the related natural compounds. The AS-I-145 sensitivity of yeast mutants deficient in excision and post-replication repair (PRR) pathways was assessed. The sensitivity profile suggests that the sequence-specific adenine-N3 adducts are substrates for nucleotide excision repair (NER) but not base excision repair (BER). Single-strand ligation PCR was employed to follow the induction and repair of the lesions at nucleotide resolution in yeast cells. Sequence specificity was preserved in intact cells, and adduct elimination occurred in a transcription-coupled manner and was dependent on a functional NER pathway and Rad18. The involvement of NER as the predominant excision pathway was confirmed in mammalian DNA repair mutant cells. AS-I-145 showed good in vivo antitumor activity in the National Cancer Institute standard hollow fiber assay and was active against the human breast MDA-MD-435 xenograft when administered i.v. or p.o. Its novel structure and in vivo activity renders AS-I-145 a new paradigm in the design of novel achiral analogues of CC-1065 and the duocarmycins. [Mol Cancer Ther 2007;6(10):2708–18]