bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase inhibition enhances the response to anticancer drug treatment in human breast cancer cells
Authors: Cerone Maria Antonietta , Londoño-Vallejo J. Arturo , Autexier Chantal 
Published: August 2006

Abstract
Breast cancer is the most common malignancy among women. Current therapies for breast tumors are based on the use of chemotherapeutic drugs that are quite toxic for the patients and often result in resistance. Telomerase is up-regulated in 95% of breast carcinomas but not in adjacent normal tissues. Therefore, it represents a very promising target for anticancer therapies. Unfortunately, the antiproliferative effects of telomerase inhibition require extensive telomere shortening before they are fully present. Combining telomerase inhibition with common chemotherapeutic drugs can be used to reduce this lag phase and induce tumor cell death more effectively. Few studies have analyzed the effects of telomerase inhibition in combination with anticancer drugs in breast cancer cells. In this study, we inhibited telomerase activity in two breast cancer cell lines using a dominant-negative human telomerase reverse transcriptase and analyzed cell viability after treatment with different anticancer compounds. We found that dominant-negative human telomerase reverse transcriptase efficiently inhibits telomerase activity and causes telomere shortening over time. Moreover, cells in which telomerase was suppressed were more sensitive to anticancer agents independently of their mechanism of action and this sensitization was dependent on the presence of shorter telomeres. Altogether, our data show that blocking telomere length maintenance in combination with anticancer drugs can be used as an effective way to induce death of breast cancer cells. [Mol Cancer Ther 2006;5(7):1669–75]
CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo
Authors: Cao Z. Alexander , Bass Kathryn E. , Balasubramanian Sriram , Liu Liang , Schultz Brian , Verner Erik , Dai YuQin , Molina Rafael A. , Davis Jack R. , Misialek Shawn , Sendzik Martin , Orr Christine J. , Leung Ling , Callan Ondine , Young Peter , Dalrymple Stacie A. , Buggy Joseph J. 
Published: August 2006

Abstract
CRA-026440 is a novel, broad-spectrum, hydroxamic acid–based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of α-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity. [Mol Cancer Ther 2006;5(7):1693–701]
Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in anin vitrobladder cancer carcinogenesis model
Authors: Jin Yusheng , Iwata Kenneth K. , Belldegrun Arie , Figlin Robert , Pantuck Allan , Zhang Zuo-Feng , Lieberman Ronald , Rao Jianyu 
Published: August 2006

AbstractAlteration of actin remodeling is a marker of malignant-associated field defect and a potential surrogate biomarker for chemoprevention trials. We tested erlotinib, a specific tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), on actin remodeling in a bladder carcinogenic model consisting of untransformed HUC-PC cells and transformed MC-T11 cells, both derived from the same normal human urothelial clone immortalized by SV40. Erlotinib had a selective growth inhibitory and actin remodeling effect on MC-T11 cells over HUC-PC cells, as examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and immunofluorescence labeling with laser scan cytometer analysis, respectively. The IC50 of untransformed HUC-PC cells was significantly higher than that of transformed MC-T11 cells (P &lt; 0.05, t test). The actin remodeling effect was more prominent at lower dosage levels (1/8-1/4 of IC50), which was accompanied by an increased cell adhesion and decreased motility. At higher dosage levels (1/2 of IC50), erlotinib induced a decreased adhesion and anoikis (detachment-associated apoptosis). The transformed MC-T11, but not HUC-PC, showed a weak constitutive EGFR phosphorylation activity, which was inhibited by erlotinib in a dose-response manner. However, on epidermal growth factor stimulation, both cell lines showed a similar dose-response inhibitory effect on phosphorylated EGFR and mitogen-activated protein kinase (MAPK; P44/P42) activities, and MAPK inhibitor PD98059 showed no specific effect on erlotinib-induced actin remodeling, suggesting that pathways other than MAPK (P44/P42) may be responsible for erlotinib-induced actin remodeling. The findings provide evidence to support erlotinib-based bladder cancer chemoprevention and using actin remodeling as a marker for erlotinib-based intervention trials. [Mol Cancer Ther 2006;5(7):1754–63]
Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL
Authors: Cheng Jinrong , Hylander Bonnie L. , Baer Maria R. , Chen Xing , Repasky Elizabeth A. 
Published: August 2006

Abstract
Targeting death receptors with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has the remarkable potential to selectively kill malignant cells whereas normal cells are largely unaffected by this treatment. However, some tumor cells, including leukemia cells, exhibit resistance to this molecule. To investigate the basis for resistance of leukemia cells to the zinc-bound form of Apo2 ligand (Apo2L)/TRAIL, which is currently being evaluated in clinical trial, we isolated several resistant HL60 clones from parental HL60 cells by selection using the recombinant Apo2L/TRAIL. Differing resistance mechanisms were identified and characterized in these Apo2L/TRAIL-resistant clones. In one case, the level of the cell-surface death receptor DR4, but not DR5, was significantly decreased. However, these cells did undergo apoptosis in response to another form of recombinant TRAIL, histidine-tagged TRAIL, suggesting differing contributions of DR4 and DR5 in the response to these two forms of TRAIL. In the case of other clones, expression of procaspase-8 protein was lost and this was associated with a novel Leu22→Phe22 point mutation in CASP-8 gene. These results show that cells within a given tumor can have widely distinct mechanisms underlying resistance to Apo2L/TRAIL. [Mol Cancer Ther 2006;5(7):1844–53]
Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases
Authors: Troiani Teresa , Lockerbie Owen , Morrow Mark , Ciardiello Fortunato , Eckhardt S. Gail 
Published: August 2006

Abstract
To date, clinical studies combining the new generation of targeted therapies and chemotherapy have had mixed results. Preclinical studies can be used to identify potential antagonism/synergy between certain agents, with the potential to predict the most efficacious combinations for further investigation in the clinical setting. In this study, we investigated the sequence-dependent interactions of ZD6474 with oxaliplatin in two human colon cell lines in vitro. We evaluated the in vitro antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and RET tyrosine kinase activity, and oxaliplatin using three combination schedules: ZD6474 before oxaliplatin, oxaliplatin before ZD6474, and concurrent exposure. Cell proliferation studies showed that treatment with oxaliplatin followed by ZD6474 was highly synergistic, whereas the reverse sequence was clearly antagonistic as was concurrent exposure. Oxaliplatin induced a G2-M arrest, which was antagonized if the cells were previously or concurrently treated with ZD6474. ZD6474 enhanced oxaliplatin-induced apoptosis but only when added after oxaliplatin. The sequence-dependent antitumor effects appeared, in part, to be based on modulation of compensatory prosurvival pathways. Thus, expression of total and active phosphorylated EGFR, as well as AKT and extracellular signal-regulated kinase, was markedly increased by oxaliplatin. This increase was blocked by subsequent treatment with ZD6474. Furthermore, the synergistic sequence resulted in reduced expression of insulin-like growth factor-I receptor and a marked reduction in secretion of vascular endothelial growth factor protein. ZD6474 in combination with oxaliplatin has synergistic antiproliferative properties in human colorectal cancer cell lines in vitro when oxaliplatin is administered before ZD6474. [Mol Cancer Ther 2006;5(7):1883–94]
Inorganic selenium sensitizes prostate cancer cells to TRAIL-induced apoptosis through superoxide/p53/Bax-mediated activation of mitochondrial pathway
Authors: Hu Hongbo , Jiang Cheng , Schuster Todd , Li Guang-Xun , Daniel Peter T. , Lü Junxuan 
Published: August 2006

AbstractTumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in prostate cancer cells through DR4 and DR5 death receptors, but not in normal prostate cells, which do not express these receptors. Therefore, TRAIL has excellent potential to be a selective prostate cancer therapeutic agent with minimal toxic side effects. However, prostate cancer cells, as many other cancer types, develop resistance to TRAIL, and the underlying molecular mechanisms require further investigation. We hypothesize that selenium may sensitize TRAIL-resistant cells to undergo caspase-mediated apoptosis and increase therapeutic efficacy. Here, we report that TRAIL signaling in LNCaP prostate cancer cells stalled at downstream of caspase-8 and BID cleavage, as indicated by the lack of Bax translocation into mitochondria, and no subsequent activation of the caspase-9 cascade. Selenite induced a rapid generation of superoxide and p53 Ser15 phosphorylation and increased Bax abundance and translocation into the mitochondria. Selenite and TRAIL combined treatment led to synergistic increases of Bax abundance and translocation into mitochondria, loss of mitochondrial membrane potential, cytochrome c release, and cleavage activation of caspase-9 and caspase-3. Inactivating p53 with a dominant-negative mutant abolished apoptosis without affecting superoxide generation, whereas a superoxide dismutase mimetic agent blocked p53 activation, Bax translocation to mitochondria, cytochrome c release, and apoptosis induced by selenite/TRAIL. In support of Bax as a crucial target for cross-talk between selenite and TRAIL pathways, introduction of Bax into p53 mutant DU145 cells enabled selenite to sensitize these cells for TRAIL-induced apoptosis. Taken together, the results indicate that selenite induces a rapid superoxide burst and p53 activation, leading to Bax up-regulation and translocation into mitochondria, which restores the cross-talk with stalled TRAIL signaling for a synergistic caspase-9/3 cascade-mediated apoptosis execution. [Mol Cancer Ther 2006;5(7):1873–82]
Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells
Authors: Ding Wei-Qun , Liu Bolin , Vaught Joshua L. , Palmiter Richard D. , Lind Stuart E. 
Published: August 2006

AbstractClioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-κB activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways. [Mol Cancer Ther 2006;5(7):1864–72]
Silymarin inhibits UV radiation-induced immunosuppression through augmentation of interleukin-12 in mice
Authors: Meeran Syed M. , Katiyar Suchitra , Elmets Craig A. , Katiyar Santosh K. 
Published: August 2006

AbstractWe have shown previously that silymarin, a plant flavonoid, inhibits UVB-induced photocarcinogenesis in mice. As UVB-induced immunosuppression has been implicated in the development of skin cancer, we investigated whether silymarin can modulate the effects of UVB radiation on the immune system. Treatment of C3H/HeN mice with topically applied silymarin (0.5 or 1.0 mg/cm2) or silibinin, a major component of silymarin, markedly inhibited UVB (180 mJ/cm2)–induced suppression of contact hypersensitivity response in a local model of immunosuppression and had a moderate inhibitory effect in a systemic model of contact hypersensitivity. Silymarin reduced the UVB-induced enhancement of the levels of the immunosuppressive cytokine, interleukin (IL)-10, in the skin and draining lymph nodes and enhanced the levels of the immunostimulatory cytokine, IL-12. Intraperitoneal injection of mice treated with silymarin with an endotoxin-free neutralizing anti-IL-12 antibody abrogated the protective effects of the silymarin against UVB-induced suppression of the contact hypersensitivity response. Furthermore, the treatment of silymarin did not prevent UVB-induced suppression of the contact hypersensitivity response in IL-12 knockout mice but prevented it in their wild-type mice. Moreover, i.p. injection of IL-12 to silymarin-treated or non-silymarin-treated IL-12 knockout mice resulted in an enhanced response to contact hypersensitivity compared with the response in mice that were exposed to either UVB alone or silymarin plus UVB. These data indicate for the first time that silymarin has the ability to protect mice from UVB-induced immunosuppression and that this protective effect is mediated, at least in part, through IL-12. [Mol Cancer Ther 2006;5(7):1660–8]
5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo
Authors: Dehn Donna L. , Siegel David , Zafar Khan Shoeb , Reigan Philip , Swann Elizabeth , Moody Christopher J. , Ross David 
Published: August 2006

Abstract
The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1, would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2 contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochemical staining of human pancreatic tumor cells. ES936 treatment inhibited NQO1 activity by &gt;98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells with an IC50 of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936, contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide generation. [Mol Cancer Ther 2006;5(7):1702–9]
Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle
Authors: Zhang Qiang , Yang Ximing J. , Kundu Shilajit D. , Pins Michael , Javonovic Borko , Meyer Robert , Kim Seong-Jin , Greenberg Norman M. , Kuzel Timothy , Meagher Richard , Guo Yinglu , Lee Chung 
Published: August 2006

AbstractTransforming growth factor-β (TGF-β) is a potent immunosuppressant. Overproduction of TGF-β by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-β-insensitive CD8+ T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8+ T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8+ T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-β by introducing a dominant-negative TGF-β type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 × 105) into the flank of male BALB/c-Rag1−/− mice, tumor-reactive, TGF-β-insensitive CD8+ T cells (1.5 × 107) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8+ T cells or green fluorescent protein-empty vector–transfected tumor-reactive CD8+ T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-β-insensitive CD8+ T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P &lt; 0.05). Tumors in animals of the former group showed a massive infiltration of CD8+ T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology. [Mol Cancer Ther 2006;5(7):1733-43]
Discovery and characterization of inhibitors of human palmitoyl acyltransferases
Authors: Ducker Charles E. , Griffel Lindsay K. , Smith Ryan A. , Keller Staci N. , Zhuang Yan , Xia Zuping , Diller John D. , Smith Charles D. 
Published: August 2006

Abstract
The covalent attachment of palmitate to specific proteins by the action of palmitoyl acyltransferases (PAT) plays critical roles in the biological activities of several oncoproteins. Two PAT activities are expressed by human cells: type 1 PATs that modify the farnesyl-dependent palmitoylation motif found in H- and N-Ras, and type 2 PATs that modify the myristoyl-dependent palmitoylation motif found in the Src family of tyrosine kinases. We have previously shown that the type 1 PAT HIP14 causes cellular transformation. In the current study, we show that mRNA encoding HIP14 is up-regulated in a number of types of human tumors. To assess the potential of HIP14 and other PATs as targets for new anticancer drugs, we developed three cell-based assays suitable for high-throughput screening to identify inhibitors of these enzymes. Using these screens, five chemotypes, with activity toward either type 1 or type 2 PAT activity, were identified. The activity of the hits were confirmed using assays that quantify the in vitro inhibition of PAT activity, as well as a cell-based assay that determines the abilities of the compounds to prevent the localization of palmitoylated green fluorescent proteins to the plasma membrane. Representative compounds from each chemotype showed broad antiproliferative activity toward a panel of human tumor cell lines and inhibited the growth of tumors in vivo. Together, these data show that PATs, and HIP14 in particular, are interesting new targets for anticancer compounds, and that small molecules with such activity can be identified by high-throughput screening. [Mol Cancer Ther 2006;5(7):1647–59]