bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aurora Kinases as Anticancer Drug Targets
Authors: Gautschi Oliver , Heighway Jim , Mack Philip C. , Purnell Phillip R. , Lara Primo N. , Gandara David R. 
Published: March 2008

Abstract
The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.
The Epothilones: Translating from the Laboratory to the Clinic
Authors: Lee James J. , Swain Sandra M. 
Published: March 2008

Abstract
The epothilones are macrolide compounds that have been shown to stabilize microtubules. The epothilones are strong promoters of tubulin polymerization in vitro and have significant antitumor activity against human cancer cells that are taxane resistant, express the multidrug resistance gene MDR-1 (ABCB1), and have acquired tubulin mutations. Several epothilones have been evaluated in clinical trials in a variety of tumor types. Ixabepilone (aza-epothilone B) has significant antitumor activity in breast cancer resistant to an anthracycline and a taxane, and has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic or locally advanced breast cancer. There have been sustained efforts to develop pharmacodynamic markers to monitor the pharmacologic effect of the epothilones on tumors and normal tissues. The development of predictive markers for epothilone chemotherapy is highly desired to provide more tailored therapy for patients with cancer.
Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade
Authors: Orlowski Robert Z. , Kuhn Deborah J. 
Published: March 2008

Abstract
The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
Newer Cytotoxic Agents: Attacking Cancer Broadly
Authors: Teicher Beverly A. 
Published: March 2008

Abstract
The plasticity and instability of the cancer genome is impressive and is characterized by gene amplifications and deletions, rearrangements, and many silent and active mutations. Although targeted therapeutics have had effect in some diseases, there remains a large role for new cytotoxic agents that have the potential to be broadly active across multiple cancers. Platinum-based regimens are the basis for treatment of several common tumors. Satraplatin and picoplatin are newer platinum complexes that form bulkier lesions in DNA than their forerunners. Microtubules are a key target for anticancer agents. Vinca alkaloid and similar compounds fragment these critical structures, whereas taxanes stabilize them. Vinflunine is a new fluorinated Vinca alkaloid derivative with vascular disrupting effects, as well as antitumor effects. Epothilones are a new class of microtubule stabilizers. Mitosis has been targeted directly and indirectly by many anticancer agents. The aurora kinases are new targets in this class. Inhibitors of aurora kinases are likely to be cytotoxic. Finally, protein regulation is essential for cellular integrity. With the approval of bortezomib (Velcade, PS-341), the proteosome, a master protein regulator, has been validated as an anticancer target. The five articles in this issue of CCR Focus present the current status of these next generation cytotoxic agents.
Expression of the Bric-a-Brac Tramtrack Broad Complex Protein NAC-1 in Cervical Carcinomas Seems to Correlate with Poorer Prognosis
Authors: Yeasmin Shamima , Nakayama Kentaro , Ishibashi Masako , Katagiri Atsuko , Iida Kouji , Purwana Indri Nuryani , Nakayama Naomi , Miyazaki Kohji 
Published: March 2008

Abstract
Purpose: Recent studies have suggested a novel oncogenic role of a bric-a-brac tramtrack broad complex (also known as POZ) domain gene, NAC-1, in ovarian carcinomas. The aim of this study was to clarify the functional role of NAC-1 in human cervical carcinomas.
Experimental Design: NAC-1 expression in cervical cancer was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. NAC-1 gene knockdown using small interfering RNA and a NAC-1 gene transfection system were used to asses NAC-1 function in cervical cancer in vivo.
Results: Immunohistochemical and gene expression analysis revealed that NAC-1 is significantly overexpressed in cervical adenocarcinomas and adenosquamous carcinomas compared with squamous cell carcinomas. Patients with squamous cell carcinomas positive for NAC-1 expression who received radiotherapy had significantly shorter overall survival than peers whose tumors did not express NAC-1, and multivariate analysis showed that NAC-1 expression was an independent prognostic factor for overall survival after radiotherapy. Overexpressions of the NAC-1 gene stimulated cell proliferation in cervical carcinoma cells of the TCS, CaSki, and HeLa P3 lines, which do not have endogenous NAC-1 expression. NAC-1 gene knockdown inhibited cell growth and induced apoptosis in HeLa, HeLa TG, and ME180 cells, all of which overexpressed NAC-1.
Conclusions: Our findings suggest that NAC-1 may play an important role in cervical carcinomas; moreover, these findings provide a rationale for future development of NAC-1–based therapy for cervical carcinomas that overexpress this candidate oncogene.
Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model
Authors: Sapra Puja , Zhao Hong , Mehlig Mary , Malaby Jennifer , Kraft Patricia , Longley Clifford , Greenberger Lee M. , Horak Ivan D. 
Published: March 2008

AbstractPurpose: Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker.Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivo–selected CPT-11–refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography.Results: In vitro, EZN-2208 was 10- to 245-fold more potent than CPT-11 in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for &gt;16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P &lt; 0.01). Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as second-round therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11.Conclusions: Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11 treatment.
Understanding the Biology of Bone Metastases: Key to the Effective Treatment of Prostate Cancer
Authors: Logothetis Christopher J. , Navone Nora M. , Lin Sue-Hwa 
Published: March 2008

Abstract
Advanced prostate cancer is dominated by bone-forming osseous metastases. Understanding the biology behind this striking clinical manifestation is the key to its effective treatment. A clinical trial using a bone-targeting radiopharmaceutical agent, strontium 89, combined with chemotherapy showed increased survival time among patients with progression of prostate cancer in bone, suggesting that therapeutic strategies focused on treating the tumor in bone are effective. We and others thus hypothesize that interactions between prostate cancer cells and the bone microenvironment play a role in the progression of prostate cancer in bone. Clinical trials and basic science investigations aiming to understand such interactions have been carried out in parallel. In the laboratory studies, human bone marrow specimens have been collected for identification of proteins involved in the bidirectional interactions between prostate cancer cells and bone. In addition, specimens from bone biopsies of the cancer lesions have been used to generate xenografts in animals to establish animal models for testing therapeutic strategies. Clinical trials using agents to inhibit the stromal-prostate cancer interactions (e.g., docetaxel/imatinib or thalidomide) have been done. Analyses of the specimens from these trials provided support of our hypothesis and future development of diagnosis and therapy strategies.
Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in ApcMin/+ mice
Authors: Alferez Denis , Wilkinson Robert W. , Watkins Jim , Poulsom Richard , Mandir Nikki , Wedge Stephen R. , Pyrah Ian T. , Smith Neil R. , Jackson Lynsay , Ryan Anderson J. , Goodlad Robert A. 
Published: March 2008

Abstract
Both the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) pathways are associated with intestinal cancer, and therapeutic approaches targeting either EGF receptor (EGFR) or VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced colorectal cancer. The ApcMin/+ mouse is a well-characterized in vivo model of intestinal tumorigenesis, and animals with this genetic mutation develop macroscopically detectable adenomas from ∼6 weeks of age. Previous work in the ApcMin/+ mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using ZD6474 (Vandetanib, ZACTIMA), a selective inhibitor of VEGFR and EGFR tyrosine kinases. To assess the effects of ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old ApcMin/+ mice for 28 days. ZD6474 markedly reduced both the number and the size of polyps when administered at either an early or a later stage of polyp development. This reduction in both adenoma number and size resulted in a total reduction in tumor burden in the small intestine of nearly 75% in both studies (P &lt; 0.01). The current data build on the concept that EGFR-dependent tumor cell proliferation and VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer. [Mol Cancer Ther 2008;7(3):590–8]
Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment
Authors: Burden Roberta E. , Snoddy Philip , Buick Richard J. , Johnston James A. , Walker Brian , Scott Christopher J. 
Published: March 2008

AbstractHuman cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L–like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L–like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L–like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L–like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis. [Mol Cancer Ther 2008;7(3):538–47]
Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase
Authors: Okabe Takafumi , Okamoto Isamu , Tsukioka Sayaka , Uchida Junji , Iwasa Tsutomu , Yoshida Takeshi , Hatashita Erina , Yamada Yuki , Satoh Taroh , Tamura Kenji , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: March 2008

AbstractSomatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors. [Mol Cancer Ther 2008;7(3):599–606]
Preclinical modeling of cytosine arabinoside response inMll-Enltranslocator mouse leukemias
Authors: Cano Florencia , Pannel Richard , Follows George A. , Rabbitts Terence H. 
Published: March 2008

AbstractMouse models of human cancer are a potential preclinical setting for drug testing and for development of methods for delivery of macromolecular drugs to tumors. We have assessed a mouse model of leukemia caused by Mll-Enl protein fusion as a preclinical situation in which myeloid-lineage leukemia results from de novo occurrence of chromosomal translocations between Mll and Enl genes. Here, we show that the mouse leukemias respond to cytosine arabinoside, a frontline treatment for human leukemia. The observations show that the myeloid cells are susceptible to the drug and the mice undergo a remission that comprises a reduction of the myeloid population of cells and recovery of the lymphoid population. This translocator model should therefore prove useful for future drug assessments against the recurrent mixed-lineage leukemia–associated translocations. [Mol Cancer Ther 2008;7(3):730–5]
Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo
Authors: Maksimovic-Ivanic Danijela , Mijatovic Sanja , Harhaji Ljubica , Miljkovic Djordje , Dabideen Darrin , Fan Cheng Kai , Mangano Katia , Malaponte Graziella , Al-Abed Yousef , Libra Massimo , Garotta Gianni , Nicoletti Ferdinando , Stosic-Grujicic Stanislava 
Published: March 2008

Abstract
Preclinical studies have shown that nitric oxide (NO)–donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting. [Mol Cancer Ther 2008;7(3):510–20]
Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1α controls sensitivity to econazole
Authors: Yu Yongmao , Niapour Maryam , Zhang Yicheng , Berger Stuart A. 
Published: March 2008

Abstract
Econazole is an azole antifungal with anticancer activity that blocks Ca2+ influx and stimulates endoplasmic reticulum (ER) Ca2+ release through the generation of mitochondrial reactive oxygen species (ROS), resulting in sustained depletion of ER Ca2+ stores, protein synthesis inhibition, and cell death. c-Myc, a commonly activated oncogene, also promotes apoptosis in response to growth factor withdrawal and a variety of chemotherapeutic agents. We have investigated the role of c-myc in regulating sensitivity to econazole. Here, we show that c-myc-negative cells are profoundly resistant to econazole. c-Myc-negative rat fibroblasts failed to generate mitochondrial ROS in response to econazole and consequently failed to deplete the ER of Ca2+. HL60 cells knocked down for c-myc expression also displayed decreased ROS generation and decreased econazole sensitivity. Addition of H2O2 restored sensitivity to econazole in both c-myc-negative rat fibroblasts and c-myc knocked-down HL60 cells, supporting a role for ROS in cell death induction. c-Myc-negative cells and HL60 cells knocked down for c-myc have reduced mitochondrial content compared with c-myc-positive cells. The hypoxia sensor, hypoxia-inducible factor-1α (HIF-1α), interacts antagonistically with c-myc and also regulates mitochondrial biogenesis. Knockdown of HIF-1α in c-myc-negative cells increased mitochondrial content restored ROS generation in response to econazole and increased sensitivity to the drug. Taken together, these results show that c-myc and HIF-1α regulate sensitivity to econazole by modulating the ability of the drug to generate mitochondrial ROS. [Mol Cancer Ther 2008;7(3):483–91]
A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities
Authors: Handeli Shlomo , Simon Julian A. 
Published: March 2008

Abstract
Activation of the Wnt/β-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based β-catenin/Tcf–responsive reporter. We identified FH535, a compound that suppresses both Wnt/β-catenin and peroxisome proliferator–activated receptor (PPAR) signaling. FH535 antagonizes both PPARγ and PPARδ ligand–dependent activation and shows structural similarity to GW9662, a known PPARγ antagonist. The effect of FH535 on β-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARδ gene, as well as by the PPARγ agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators β-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of β-catenin recruitment, in comparison with GW9662, is linked to FH535′s unique capability to inhibit the Wnt/β-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521–9]