bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug ratio–dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo
Authors: Tardi Paul G. , Dos Santos Nancy , Harasym Troy O. , Johnstone Sharon A. , Zisman Natalia , Tsang Alan W. , Bermudes David G. , Mayer Lawrence D. 
Published: August 2009

Abstract
Irinotecan and cisplatin are two established anticancer drugs, which together constitute an effective combination for treating small-cell lung cancer. We investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vivo administration. Irinotecan and cisplatin combinations were evaluated systematically for drug ratio–dependent synergy in vitro using a panel of 20 tumor cell lines. In vitro screening informatics on drug ratio–dependent cytotoxicity identified a consistently antagonistic region between irinotecan/cisplatin molar ratios of 1:2 to 4:1, which was bordered by two synergistic regions. Liposomal co-formulations of these two agents were developed that exhibited plasma drug half-lives of ∼6 hours and maintained a fixed drug ratio for more than 24 hours. Drug ratio–dependent antitumor activity was shown in vivo for these liposome formulations, and irinotecan/cisplatin ratios between 5:1 and 10:1 were identified as therapeutically optimal. The relationship between irinotecan/cisplatin ratio and in vivo efficacy was consistent with in vitro drug ratio dependency results. Superior antitumor activity was observed for the liposome-encapsulated 7:1 molar ratio of irinotecan/cisplatin (designated CPX-571) compared with the free-drug cocktail in all models tested. Further efficacy studies in a range of human tumor xenografts, including an irinotecan-resistant model, showed that both liposomal agents contributed to the overall efficacy in a manner consistent with in vivo synergy. These results show the ability of drug delivery technology to enhance the therapeutic activity of irinotecan/cisplatin combination treatment by maintaining synergistic ratios in vivo. CPX-571, a fixed-ratio formulation of irinotecan and cisplatin, is a promising candidate for clinical development. [Mol Cancer Ther 2009;8(8):2266–75]
Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model
Authors: Slack-Davis Jill K. , Hershey E. Daniel , Theodorescu Dan , Frierson Henry F. , Parsons J. Thomas 
Published: August 2009

Abstract
Increasing evidence indicates that adhesion signaling plays an important role in the tumor microenvironment, contributing to cancer progression, invasion, and metastasis. Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that regulates adhesion-dependent cell signaling and has been implicated in mediating steps in cancer progression and metastasis in many human cancers, including prostate. We have investigated the role of FAK in the appearance of adenocarcinoma (atypical epithelial hyperplasia of T antigen) and neuroendocrine carcinomas in the transgenic adenocarcinoma of mouse prostate (TRAMP) model using either Cre-mediated recombination to genetically ablate FAK expression or pharmacologic inhibition of FAK activity with the small-molecule inhibitor, PF-562,271. We provide evidence that loss of FAK or its inhibition with PF-562,271 does not alter the progression to adenocarcinoma. However, continued FAK expression (and activity) is essential for the androgen-independent formation of neuroendocrine carcinoma. These data indicate that integrin signaling through FAK is an important component of cancer progression in the TRAMP model and suggest that treatment modalities targeting FAK may be an appropriate strategy for patients with castrate-resistant cancer. [Mol Cancer Ther 2009;8(8):2470–77]
Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1
Authors: Koeberle Andreas , Northoff Hinnak , Werz Oliver 
Published: August 2009

AbstractProstaglandin E2 (PGE2) plays a crucial role in the apparent link between tumor growth and chronic inflammation. Cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1, which are overexpressed in many cancers, are functionally coupled and thus produce massive PGE2 in various tumors. Curcumin, a polyphenolic β-diketone from tumeric with anti-carcinogenic and anti-inflammatory activities, was shown to suppress PGE2 formation and to block the expression of COX-2 and of microsomal PGE2 synthase-1. Here, we identified microsomal PGE2 synthase-1 as a molecular target of curcumin and we show that inhibition of microsomal PGE2 synthase-1 activity is the predominant mechanism of curcumin to suppress PGE2 biosynthesis. Curcumin reversibly inhibited the conversion of PGH2 to PGE2 by microsomal PGE2 synthase-1 in microsomes of interleukin-1β–stimulated A549 lung carcinoma cells with an IC50 of 0.2 to 0.3 μmol/L. Closely related polyphenols (e.g., resveratrol, coniferyl alcohol, eugenol, rosmarinic acid) failed in this respect, and isolated ovine COX-1 and human recombinant COX-2 were not inhibited by curcumin up to 30 μmol/L. In lipopolysaccharide-stimulated human whole blood, curcumin inhibited COX-2–derived PGE2 formation from endogenous or from exogenous arachidonic acid, whereas the concomitant formation of COX-2–mediated 6-keto PGF1α and COX-1–derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was suppressed only at significant higher concentrations. Based on the key function of PGE2 in inflammation and carcinogenesis, inhibition of microsomal PGE2 synthase-1 by curcumin provides a molecular basis for its anticarcinogenic and anti-inflammatory activities. [Mol Cancer Ther 2009;8(8):2348–55]
An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance
Authors: Mitra Doyel , Brumlik Michael J. , Okamgba Stella U. , Zhu Yun , Duplessis Tamika T. , Parvani Jenny G. , Lesko Samuel M. , Brogi Edi , Jones Frank E. 
Published: August 2009

Abstract
The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in &lt;6 months (1–3). The reason for the clinical failure of trastuzumab in this setting remains unclear. Here we show that local lymph node–positive disease progression in 89% of breast cancer patients with HER2-positive tumors involves the HER2 oncogenic variant HER2Δ16. We further show that ectopic expression of HER2Δ16, but not wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase. Cotargeting of HER2Δ16 and Src kinase with the single-agent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Δ16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Δ16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Δ16 and Src signaling. Our results suggest that HER2Δ16 expression is an important genetic event driving trastuzumab-refractory breast cancer. We propose that successful targeted therapeutics for intervention of aggressive HER2-positive breast cancers will require a strategy to suppress HER2Δ16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Δ16 and Src tyrosine kinase pathways. [Mol Cancer Ther 2009;8(8):2152–62]
Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance
Authors: Perez Edith A. 
Published: August 2009

AbstractMicrotubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents. [Mol Cancer Ther 2009;8(8):2086–95]
BAX/BAK–Independent Mitoptosis during Cell Death Induced by Proteasome Inhibition?
Authors: Lomonosova Elena , Ryerse Jan , Chinnadurai G. 
Published: August 2009

Abstract
Proteasome inhibitors induce rapid death of cancer cells. We show that in epithelial cancer cells, such death is associated with dramatic and simultaneous up-regulation of several BH3-only proteins, including BIK, BIM, MCL-1S, NOXA, and PUMA, as well as p53. Elevated levels of these proteins seem to be the result of direct inhibition of their proteasomal degradation, induction of transcription, and active translation. Subsequent cell death is independent of BAX, and probably BAK, and proceeds through the intrinsic mitochondrial apoptosis pathway. We identify the cascade of molecular events responsible for cell death induced by a prototypical proteasome inhibitor, MG132, starting with rapid accumulation of BH3-only proteins in the mitochondria, proceeding through mitochondrial membrane permeabilization and subsequent loss of ΔΨm, and leading to irreversible changes of mitochondrial ultrastructure, degradation of mitochondrial network, and detrimental impairment of crucial mitochondrial functions. Our results also establish a rationale for the broader use of proteasome inhibitors to kill apoptosis-resistant tumor cells that lack functional BAX/BAK proteins. (Mol Cancer Res 2009;7(8):1268–84)
MDM2 Controls the Timely Expression of Cyclin A to Regulate the Cell Cycle
Authors: Frum Rebecca , Ramamoorthy Mahesh , Mohanraj Lathika , Deb Sumitra , Deb Swati Palit 
Published: August 2009

Abstract
Overexpression of MDM2 has been related to oncogenesis. In this communication, we present evidence to show that MDM2 controls the cell cycle–dependent expression of cyclin A by using a pathway that ensures its timely expression. MDM2 does not inhibit cyclin D or E expression. Silencing of endogenous MDM2 expression elevates cyclin A expression. The p53-binding domain of MDM2 harbors a SWIB region homologous to a conserved domain of a chromosome remodeling factor BRG1-associated protein. The SWIB domain of MDM2 inhibits cyclin A expression in a p53- and BRG1-dependent fashion, suggesting that MDM2 interferes with p53 binding of the BRG1 complex freeing it to repress cyclin A expression. Silencing of cyclin-dependent kinase (cdk) inhibitor p16 prevents MDM2-mediated inhibition of cyclin A expression, implicating its role in the process. MDM2-mediated repression of cyclin A expression induces G1-S arrest, which can be rescued by ectopic expression of cyclin A. Cancer cells lacking p53, p16, or BRG1 escape MDM2-mediated repression of cyclin A expression and growth arrest. Our data propose a novel mechanism by which MDM2 controls the cell cycle in normal cells and how cancer cells may escape this important safety barrier. (Mol Cancer Res 2009;7(8):1253–67)
Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3
Authors: Arulanandam Rozanne , Vultur Adina , Cao Jun , Carefoot Esther , Elliott Bruce E. , Truesdell Peter F. , Larue Lionel , Feracci Hélène , Raptis Leda 
Published: August 2009

Abstract
Signal transducer and activator of transcription-3 (Stat3) is activated by a number of receptor and nonreceptor tyrosine kinases, whereas a constitutively active form of Stat3 alone is sufficient to induce neoplastic transformation. In the present report, we show that Stat3 can also be activated through homophilic interactions by the epithelial (E)-cadherin. Indeed, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of this cadherin, we clearly show that cadherin engagement can activate Stat3, even in the absence of direct cell-to-cell contact. Most importantly, our results also reveal for the first time an unexpected and dramatic surge in total Rac1 and Cdc42 protein levels triggered by cadherin engagement and an increase in Rac1 and Cdc42 activity, which is responsible for the Stat3 stimulation observed. Inhibition of cadherin interactions using a peptide, a soluble cadherin fragment, or genetic ablation induced apoptosis, points to a significant role of this pathway in cell survival signaling, a finding that could also have important therapeutic implications. (Mol Cancer Res 2009;7(8):1310–27)
Small Interfering RNA–Directed Knockdown of Uracil DNA Glycosylase Induces Apoptosis and Sensitizes Human Prostate Cancer Cells to Genotoxic Stress
Authors: Pulukuri Sai Murali Krishna , Knost James A. , Estes Norman , Rao Jasti S. 
Published: August 2009

Abstract
Uracil DNA glycosylase (UNG) is the primary enzyme responsible for removing uracil residues from DNA. Although a substantial body of evidence suggests that DNA damage plays a role in cancer cell apoptosis, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in cell survival. To test the hypothesis that the repair of DNA damage associated with uracil misincorporation is critical for cancer cell survival, we used small interfering RNA (siRNA) to target the human UNG gene. In a dose-dependent and time-dependent manner, siRNA specifically inhibited UNG expression and modified the expression of several genes at both mRNA and protein levels. In LNCaP cells, p53, p21, and Bax protein levels increased, whereas Bcl2 levels decreased. In DU145 cells, p21 levels were elevated, although mutant p53 and Bax levels remained unchanged. In PC3 cells, UNG inhibition resulted in elevated p21 and Bax levels. In all three cell lines, UNG inhibition reduced cell proliferation, induced apoptosis, and increased cellular sensitivity to genotoxic stress. Furthermore, an in vitro cleavage experiment using uracil-containing double-stranded DNA as a template has shown that siRNA-mediated knockdown of UNG expression significantly reduced the uracil-excising activity of UNG in human prostate cancer cells, which was associated with DNA damage analyzed by comet assay. Taken together, these findings indicate that RNA interference–directed targeting of UNG is a convenient, novel tool for studying the biological role of UNG and raises the potential of its application for prostate cancer therapy. (Mol Cancer Res 2009;7(8):1285–93)
FOXO Transcription Factors Enforce Cell Cycle Checkpoints and Promote Survival of Hematopoietic Cells after DNA Damage
Authors: Lei Hong , Quelle Frederick W. 
Published: August 2009

Abstract
The PI3K/AKT signaling pathway contributes to cell cycle progression of cytokine-dependent hematopoietic cells under normal conditions, and it is absolutely required to override DNA damage–induced cell cycle arrest checkpoints in these cells. Phosphatidylinositol-3-kinase (PI3K)/AKT activity also correlates with Cdk2 activity in hematopoietic cells, suggesting that Cdk2 activation may be a relevant end point for this signaling pathway. However, mediators downstream of AKT in this pathway have not been defined. The forkhead transcription factor O (FOXO) family are negatively regulated by AKT-dependent phosphorylation and are known regulators of genes affecting cell cycle progression. We show that enhanced FOXO activity replicates the effect of PI3K inhibitors in enforcing G1 and G2 phase arrest after DNA damage. Conversely, knockdown of endogenous FOXO proteins increased Cdk2 activity and overrode DNA damage checkpoints in cells lacking PI3K activity. Moreover, loss of FOXO activity caused an increase in sensitivity to cisplatin-induced cell death, which was associated with failure to arrest cell cycle progression in the face of DNA damage caused by this chemotherapeutic agent. These cell cycle arrests were dependent on p27 expression when mediated by FOXO3a alone, but also involve p27-independent mechanisms when promoted by endogenous FOXO proteins. Together, these observations show that FOXO proteins enforce DNA damage–induced cell cycle arrest in hematopoietic cells. Inhibition of FOXO activity by cytokine-induced PI3K/AKT signaling is sufficient to override these DNA damage–induced cell cycle checkpoints, but may negatively impact hematopoietic cell viability. (Mol Cancer Res 2009;7(8):1294–303)
NGFI-B Nuclear Orphan Receptor Nurr1 Interacts with p53 and Suppresses Its Transcriptional Activity
Authors: Zhang Tao , Wang Pingping , Ren Haigang , Fan Jun , Wang Guanghui 
Published: August 2009

Abstract
Nurr1 is a member of the NGFI-B nuclear orphan receptor family which includes two other members, Nur77 and Nor-1. Nurr1 is essential for the development and survival of dopaminergic neurons. It was reported that Nurr1 has antiapoptotic functions, however, the mechanisms by which Nurr1 mediates these effects remain unknown. Here, we show that overexpression of Nurr1 decreases Bax expression whereas knockdown of Nurr1 increases Bax expression. Nurr1 also interacts with p53 and represses its assembly. Furthermore, Nurr1 represses p53 transcriptional activity in interaction-dependent and dose-dependent manners. Moreover, Nurr1 protects cells from doxorubicin-induced apoptosis. These findings provide evidence that Nurr1 promotes cell survival through its interacting with and repressing p53, thus implicating that Nurr1 may play an important role in carcinogenesis and other diseases. (Mol Cancer Res 2009;7(8):1408–15)
A Novel Function of CXCL13 to Stimulate RANK Ligand Expression in Oral Squamous Cell Carcinoma Cells
Authors: Yuvaraj Sambandam , Griffin Alfred C. , Sundaram Kumaran , Kirkwood Keith L. , Norris James S. , Reddy Sakamuri V. 
Published: August 2009

Abstract
Oral squamous cell carcinomas (OSCC) are malignant tumors with a potent activity of local bone invasion/osteolysis. The chemokine ligand, CXCL13, has been identified as a prognostic marker for OSCC development and progression. Here in, we show that recombinant hCXCL13 treatment of OSCC cells stimulates (5-fold) RANK ligand (RANKL), a critical bone resorbing osteoclastogenic factor expression. Anti-CXCR5 chemokine receptor antibody abrogates CXCL13-induced RANKL expression in these cells. Also, CXCL13 stimulated (3.0-fold) hRANKL gene promoter activity in SCC14a cells. SuperArray screening for transcription factors by real-time RT-PCR identified significant increase in the levels of c-Jun and NFATc3 mRNA expression in CXCL13-stimulated OSCC cells. CXCL13 treatment significantly increased (3.5-fold) phospho-c-Jun levels in these cells and a c-Jun-NH2-kinase inhibitor abolished CXCL13-stimulated RANKL expression. Furthermore, we show that CXCL13 stimulation induced nuclear translocation of NFATc3 in OSCC cells. Chromatin-immune precipitation assay confirmed NFATc3 binding to the RANKL promoter region. We also show that overexpression of NFATc3 stimulates RANKL expression/promoter activity and that siRNA suppression of NFATc3 abolished CXCL13-stimulated RANKL expression. Thus, our results suggest that NFATc3 is a downstream target of the CXCL13/CXCR5 axis to stimulate RANKL expression in OSCC cells and implicates CXCL13 as a potential therapeutic target to prevent OSCC bone invasion/osteolysis. (Mol Cancer Res 2009;7(8):1399–407)
Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells
Authors: Kim Young Mee , Park Soo-Yeon , Pyo Hongryull 
Published: August 2009

Abstract
Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E2, gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2–overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2–overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2–overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy. (Mol Cancer Res 2009;7(8):1367–77)
Cathepsin G–Mediated Activation of Pro–Matrix Metalloproteinase 9 at the Tumor-Bone Interface Promotes Transforming Growth Factor-β Signaling and Bone Destruction
Authors: Wilson Thomas J. , Nannuru Kalyan C. , Singh Rakesh K. 
Published: August 2009

Abstract
Increased transforming growth factor-β (TGF-β) signaling has been observed at the tumor-bone interface of mammary tumor–induced osteolytic lesions despite no observed transcriptional up-regulation of TGF-β. To this point, the mechanism for enhanced TGF-β signaling remains unclear. The bulk of TGF-β that is released at the tumor-bone interface is in an inactive form secondary to association with β-latency–associated protein and latency TGF-β binding protein. We hypothesized that the observed increase in TGF-β signaling is due to increased cathepsin G–dependent, matrix metalloproteinase 9 (MMP9)–mediated activation of latent TGF-β. MMP9 is capable of activating latent TGF-β, and we observed that decreased production of MMP9 was associated with reduced TGF-β signaling. Similar to TGF-β, MMP9 is released in an inactive form and requires proteolytic activation. We showed that cathepsin G, which we have previously shown to be up-regulated at the tumor-bone interface, is capable of activating pro-MMP9. Inhibition of cathepsin G in vivo significantly reduced MMP9 activity, increased the ratio of latent TGF-β to active TGF-β, and reduced the level of TGF-β signaling. Our proposed model based on these results is that cathepsin G is up-regulated through tumor-stromal interactions and activates pro-MMP9, active MMP9 cleaves and releases active TGF-β, and active TGF-β can then promote tumor growth and enhance osteoclast activation and subsequent bone resorption. Thus, for the first time, we have identified cathepsin G and MMP9 as proteases involved in enhanced TGF-β signaling at the tumor-bone interface of mammary tumor–induced osteolytic lesions and have identified these proteases as potential therapeutic targets. (Mol Cancer Res 2009;7(8):1224–33)