bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage
Authors: Sturgeon Christopher M. , Knight Zachary A. , Shokat Kevan M. , Roberge Michel 
Published: April 2006

Abstract
In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms and of checkpoints that delay cell cycle progression to allow more time for DNA repair. Inhibiting both responses with drugs might cause cancer cells to undergo cell division in the presence of lethal amounts of unrepaired DNA. However, we show that interfering with DNA repair via inhibition of DNA-dependent protein kinase (DNA-PK) reduces the ability of checkpoint inhibitors to abrogate G2 arrest and their radiosensitizing activity. Cells exposed to the DNA-PK inhibitor AMA37, DNA-PK-deficient cells, and nonhomologous end joining–deficient cells all enter prolonged G2 arrest after exposure to ionizing radiation doses as low as 2 Gy. The checkpoint kinase Chk2 becomes rapidly and transiently overactivated, whereas Chk1 shows sustained overactivation that parallels the prolonged accumulation of cells in G2. Therefore, in irradiated cells, DNA repair inhibition elicits abnormally strong checkpoint signaling that causes essentially irreversible G2 arrest and strongly reduces the ability of checkpoint kinase inhibitors to overcome G2 arrest and radiosensitize cells. Variable levels of proteins controlling DNA repair have been documented in cancer cells. Therefore, these results have relevance to the development of DNA-PK inhibitors and G2 checkpoint inhibitors as experimental therapeutic approaches to enhance the selective killing of tumor cells by radiotherapy or DNA-damaging chemotherapeutic agents. [Mol Cancer Ther 2006;5(4):885–92]
Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors
Authors: Guo Jun , Marcotte Patrick A. , McCall J. Owen , Dai Yujia , Pease Lori J. , Michaelides Michael R. , Davidsen Steven K. , Glaser Keith B. 
Published: April 2006

Abstract
The properties of several multitargeted receptor tyrosine kinase inhibitors have been studied for their inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling. A structurally novel, multitargeted tyrosine kinase inhibitor (ABT-869), imatinib (STI571), and four compounds currently in clinical development (AG013736, BAY 43-9006, CHIR258, and SU11248) were tested for inhibition of CSF-1R signaling in both the enzymatic and cellular assays. ABT-869 showed potent CSF-1R inhibition in both the enzyme and cell-based assays (IC50s &lt; 20 nmol/L). In contrast to a previous report, we have found that imatinib has activity against human CSF-1R in both assays at submicromolar concentrations. In enzyme assays, we have found that the inhibition of CSF-1R by both ABT-869 and imatinib are competitive with ATP, with Ki values of 3 and 120 nmol/L, respectively. SU11248 is a potent inhibitor of CSF-1R in the enzyme assay (IC50 = 7 nmol/L) and inhibits receptor phosphorylation in the cellular assay (IC50 = 61 nmol/L). AG013736 was also a potent inhibitor of CSF-1R in both assays (enzyme, IC50 = 16 nmol/L; cellular, IC50 = 21 nmol/L), whereas BAY 43-9006 is less potent in the enzyme assay (IC50 = 107 nmol/L) than in the cellular system (IC50 = 20 nmol/L). In contrast, we found that CHIR258 had less activity in the cellular assay (IC50 = 535 nmol/L) relative to its enzymatic potency (IC50 = 26 nmol/L). These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ. [Mol Cancer Ther 2006;5(4):1007–13]
Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells
Authors: Sikora Ewa , Bielak-Żmijewska Anna , Magalska Adriana , Piwocka Katarzyna , Mosieniak Grazyna , Kalinowska Magdalena , Widlak Piotr , Cymerman Iwona A. , Bujnicki Janusz M. 
Published: April 2006

Abstract
Curcumin is a natural pigment that has been shown to induce cell death in many cancer cells; however, the death mode depends on the cell type and curcumin concentration. Here we show that, in Jurkat cells, 50 μmol/L curcumin severely lowers cell survival and induces initial stage of chromatin condensation. It also induces caspase-3, which is sufficient to cleave DNA fragmentation factor 45 [DFF45/inhibitor of caspase-activated DNase (ICAD)], the inhibitor of DFF40/CAD endonuclease. However, the release of DFF40/CAD from its inhibitor does not lead to oligonucleosomal DNA degradation in curcumin-treated cells. Moreover, curcumin treatment protects cells from UVC-induced oligonucleosomal DNA degradation. In biochemical experiments using recombinant DFF activated with caspase-3, we show that curcumin inhibits plasmid DNA and chromatin degradation although it does not prevent activation of DFF40/CAD endonuclease after its release from the inhibitor. Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction. Instead, molecular modeling indicates that the inhibitory effect of curcumin on DFF40/CAD activity results from curcumin binding to the active center of DFF40/CAD endonuclease. [Mol Cancer Ther 2006;5(4):927–34]
Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft
Authors: Shukla Sanjeev , Gupta Sanjay 
Published: April 2006

Abstract
Apigenin (4′,5,7-trihydroxyflavone) is a promising chemopreventive agent abundantly present in fruits and vegetables that has been shown to promote cell cycle arrest and apoptosis in various malignant cell lines. To determine whether pharmacologic intervention with apigenin has a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice, we examined cell cycle regulatory molecules as precise molecular targets of apigenin action. Apigenin feeding by gavage to these mice at doses of 20 and 50 μg/mouse/d in 0.2 mL of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 resulted in significant decreases in tumor volume and mass of androgen-sensitive 22Rv1 and androgen-insensitive PC-3-implanted cells. Oral intake of apigenin resulted in dose-dependent (a) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (b) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (c) decrease in retinoblastoma phosphorylation at serine 780; (d) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (e) decrease in the binding of cyclin E toward cdk2 in both types of tumors. In addition, apigenin feeding resulted in stabilization of p53 by phosphorylation at serine 15 in 22Rv1 tumors, which seems to exhibit p53-dependent growth inhibitory responses. Apigenin intake by these mice also resulted in induction of apoptosis, which positively correlated with serum and tumor apigenin levels. Taken together, this is the first systematic in vivo study showing the involvement of cell cycle regulatory proteins as potential molecular targets of apigenin. [Mol Cancer Ther 2006;5(4):843–52]
Potent antitumor activity of 10-methoxy-9-nitrocamptothecin
Authors: Luo Peihua , He Qiaojun , He Xungui , Hu Yongzhou , Lu Wei , Cheng Yiyu , Yang Bo 
Published: April 2006

AbstractThe present data showed that 10-methoxy-9-nitrocamptothecin (MONCPT), a family of camptothecin analogues, possessed high antitumor activity in vitro and in vivo. Cytotoxicity assays showed that MONCPT was a potential and highly efficient antitumor compound with IC50 values of 0.1 to 500 nmol/L in nine tumor cell lines. The high cytotoxic potency of MONCPT was paralleled with its ability to increase the cellular accumulation of DNA damage. DNA relaxation assay also showed that MONCPT exerted high potency as a topoisomerase I inhibitor. Moreover, administration of MONCPT (5–20 mg/kg) for 15 to 17 days significantly inhibited tumor growth in human androgen–independent prostate tumor (PC3) and human non–small cell lung tumor (A549) xenografts; the inhibition rates ranged from 29.6% to 98%. The cytotoxic effect of 1,000 nmol/L of MONCPT in PC3 cells was associated with causing an arrest in G0-G1 phase, whereas that of 10 and 100 nmol/L MONCPT was relative to a persistent block in G2-M phase. Furthermore, down-regulation of CDK2, CDK4, and cyclin D1 was observed in PC3 cells treated with 1,000 nmol/L of MONCPT, whereas overexpression of CDK7, CDK1, and cyclin B1 was seen in PC3 cells treated with 10 and 100 nmol/L of MONCPT. These results suggested that cell cycle regulation might contribute to the anticancer properties of MONCPT and strongly support the further anticancer development of MONCPT. [Mol Cancer Ther 2006;5(4):962–8]
Construction of a novel DNA decoy that inhibits the oncogenic β-catenin/T-cell factor pathway
Authors: Seki Yosuke , Yamamoto Hirofumi , Yee Ngan Chew , Yasui Masayoshi , Tomita Naruya , Kitani Kotaro , Takemasa Ichiro , Ikeda Masataka , Sekimoto Mitsugu , Matsuura Nariaki , Albanese Chris , Kaneda Yasufumi , Pestell Richard G. , Monden Morito 
Published: April 2006

Abstract
The oncogenic β-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumor cells. We first established the TCF-activated model using nontumor human embryonic kidney 293 (HEK293) cells by introducing a β-catenin cDNA. Based on a consensus TCF-binding sequence in the cyclin D1 and c-myc promoters, several double-stranded oligodeoxynucleotides were designed and tested for their ability to inhibit TCF activity in the HEK293 model. Among them, the 18-mer oligodeoxynucleotide stably formed double-stranded DNA and efficiently inhibited TCF activity. FITC-labeled oligodeoxynucleotide was efficiently incorporated into the nucleus at 6 hours and remained within cells for up to 72 to 96 hours. When compared with scrambled oligodeoxynucleotide, we found that the 18-mer TCF decoy significantly inhibited TCF activity and promoter activities of the downstream target genes, such as cyclin D1, c-myc, and matrix metalloproteinase 7 in HCT116 colon cancer cells. Reverse transcription-PCR assays indicated that mRNA expression of these genes decreased with treatment of the TCF decoy. Proliferation assay showed that the TCF decoy significantly inhibited growth of HCT116 tumor cells, but not of nontumor HEK293 cells. Our data provide evidence that the TCF decoy reduced both TCF activity and transcriptional activation of downstream target genes. Thus, this TCF decoy is potentially an efficient and nontoxic molecular targeting therapy for controlling malignant properties of cancer cells. [Mol Cancer Ther 2006;5(4):985–94]
Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth
Authors: Gable Karissa L. , Maddux Betty A. , Penaranda Cristina , Zavodovskaya Marianna , Campbell Michael J. , Lobo Margaret , Robinson Louise , Schow Steven , Kerner John A. , Goldfine Ira D. , Youngren Jack F. 
Published: April 2006

AbstractIn breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti–breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 μmol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 &lt;1 μmol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 μmol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 μmol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 μmol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers. [Mol Cancer Ther 2006;5(4):1079–86]
Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
Authors: Albert Daniel H. , Tapang Paul , Magoc Terrance J. , Pease Lori J. , Reuter David R. , Wei Ru-Qi , Li Junling , Guo Jun , Bousquet Peter F. , Ghoreishi-Haack Nayereh S. , Wang Baole , Bukofzer Gail T. , Wang Yi-Chun , Stavropoulos Jason A. , Hartandi Kresna , Niquette Amanda L. , Soni Nirupama , Johnson Eric F. , McCall J. Owen , Bouska Jennifer J. , Luo Yanping , Donawho Cherrie K. , Dai Yujia , Marcotte Patrick A. , Glaser Keith B. , Michaelides Michael R. , Davidsen Steven K. 
Published: April 2006

Abstract
ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s &gt; 1 μmol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-β, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, &gt;1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (&gt;50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5–5 mg/kg, twice daily) and is also effective (&gt;50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 μg/mL, ≥7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer. [Mol Cancer Ther 2006;5(4):995–1006]
The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor–related apoptosis-inducing ligand
Authors: Horinaka Mano , Yoshida Tatsushi , Shiraishi Takumi , Nakata Susumu , Wakada Miki , Sakai Toshiyuki 
Published: April 2006

Abstract
Dietary flavonoid apigenin is expected to have preventive and therapeutic potential against malignant tumors. In this report, we show for the first time that apigenin markedly induces the expression of death receptor 5 (DR5) and synergistically acts with exogenous soluble recombinant human tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to induce apoptosis in malignant tumor cells. TRAIL is a promising candidate for cancer therapeutics due to its ability to selectively induce apoptosis in cancer cells. The combined use of apigenin and TRAIL at suboptimal concentrations induces Bcl-2-interacting domain cleavage and the activation of caspases-8, -10, -9, and -3. Furthermore, human recombinant DR5/Fc chimera protein and caspase inhibitors dramatically inhibit apoptosis induced by the combination of apigenin and TRAIL. On the other hand, apigenin-mediated induction of DR5 expression is not observed in normal human peripheral blood mononuclear cells. Moreover, apigenin does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis. These results suggest that this combined treatment with apigenin and TRAIL might be promising as a new therapy against malignant tumors. [Mol Cancer Ther 2006;5(4):945–51]
Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract
Authors: Tang Li , Zhang Yuesheng , Jobson Hillary E. , Li Jun , Stephenson Katherine K. , Wade Kristina L. , Fahey Jed W. 
Published: April 2006

Abstract
We have previously shown that broccoli sprouts are a rich source of chemopreventive isothiocyanates, which potently induce carcinogen-detoxifying enzymes and inhibit the development of mammary and skin tumors in rodents. However, the principal isothiocyanate present in broccoli sprout extracts, sulforaphane, not only induces carcinogen-detoxifying enzymes but also activates apoptosis and blocks cell cycle progression. In this article, we show that an aqueous extract of broccoli sprouts potently inhibits the growth of human bladder carcinoma cells in culture and that this inhibition is almost exclusively due to the isothiocyanates. Isothiocyanates are present in broccoli sprouts as their glucosinolate precursors and blocking their conversion to isothiocyanates abolishes the antiproliferative activity of the extract. Moreover, the potency of isothiocyanates in the extract in inhibiting cancer cell growth was almost identical to that of synthetic sulforaphane, as judged by their IC50 values (6.6 versus 6.8 μmol/L), suggesting that other isothiocyanates in the extract may be biologically similar to sulforaphane and that nonisothiocyanate substances in the extract may not interfere with the antiproliferative activity of the isothiocyanates. Further study showed that the isothiocyanate extract of broccoli sprouts activated the mitochondria-mediated apoptosis pathway and halted cells in S and M phases. Cell cycle arrest was associated with down-regulation of Cdc25C and disruption of mitotic spindles. These data show that broccoli sprout isothiocyanate extract is a highly promising substance for cancer prevention/treatment and that its antiproliferative activity is exclusively derived from isothiocyanates. [Mol Cancer Ther 2006;5(4):935–44]
Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neuexpressing tumors
Authors: Helguera Gustavo , Rodríguez José A. , Penichet Manuel L. 
Published: April 2006

AbstractWe 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]
Integrin-linked kinase functions as a downstream mediator of endothelin-1 to promote invasive behavior in ovarian carcinoma
Authors: Rosanò Laura , Spinella Francesca , Di Castro Valeriana , Dedhar Shoukat , Nicotra Maria Rita , Natali Pier Giorgio , Bagnato Anna 
Published: April 2006

Abstract
The endothelin-1 (ET-1) axis represents a novel target in several malignancies, including ovarian carcinoma. Upon being activated, the endothelin A receptor (ETAR) mediates multiple tumor-promoting activities, including mitogenesis, escape from apoptosis, angiogenesis, metastasis-related protease activation, epithelial-mesenchymal transition, and invasion. Integrin-linked kinase (ILK) is a multidomain focal adhesion protein that conveys intracellular signaling elicited by β1-integrin and growth factor receptors. In this study, we investigate whether the signaling triggered by ETAR leading to an aggressive phenotype is mediated by an ILK-dependent mechanism. In HEY and OVCA 433 ovarian carcinoma cell lines, activation of ETAR by ET-1 enhances the expression of α2β1 and α3β1 integrins. ILK activity increases as ovarian cancer cells adhere to type I collagen through β1 integrin signaling, and do so to a greater extent on ET-1 stimulation. ET-1 increases ILK mRNA and protein expression and activity in a time- and concentration-dependent manner. An ILK small-molecule inhibitor (KP-392) or transfection with a dominant-negative ILK mutant effectively blocks the phosphorylation of downstream signals, Akt and glycogen synthase kinase-3β. The blockade of ET-1/ETAR-induced ILK activity results in an inhibition of matrix metalloproteinase activation as well as of cell motility and invasiveness in a phosphoinositide 3 kinase–dependent manner. In ovarian carcinoma xenografts, ABT-627, a specific ETAR antagonist, suppresses ILK expression, Akt and glycogen synthase kinase-3β phosphorylation, and tumor growth. These data show that ILK functions as a downstream mediator of the ET-1/ETAR axis to potentiate aggressive cellular behavior. Thus, the ILK-related signaling cascade can be efficiently targeted by pharmacologic blockade of ETAR. [Mol Cancer Ther 2006;5(4):833–42]