bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model
Authors: Ilagan Romyla , Zhang Liquin Joann , Pottratz Jill , Le Kim , Salas Sussan , Iyer Meera , Wu Lily , Gambhir Sanjiv S. , Carey Michael 
Published: March 2006

Abstract
The current understanding of the response of androgen receptor to pharmacologic inhibitors in prostate cancer is derived primarily from serum prostate-specific antigen (PSA) levels. In this study, we test whether a novel androgen receptor–specific molecular imaging system is able to detect the action of the antiandrogen flutamide on androgen receptor function in xenograft models of prostate cancer. Adenoviruses bearing an optical imaging cassette containing an androgen receptor–responsive two-step transcriptional amplification system were injected into androgen-dependent and hormone-refractory tumors of animals undergoing systemic time-controlled release of the antiandrogen flutamide. Imaging of tumors with a cooled charge-coupled device camera revealed that the response of AdTSTA to flutamide is more sensitive and robust than serum PSA measurements. Flutamide inhibits the androgen signaling pathway in androgen-dependent but not refractory tumors. Analysis of androgen receptor and RNA polymerase II binding to the endogenous PSA gene by chromatin immunoprecipitation revealed that flutamide treatment and androgen withdrawal have different molecular mechanisms. The application of imaging technology to study animal models of cancer provides mechanistic insight into antiandrogen targeting of androgen receptor during disease progression.
Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo
Authors: Koblish Holly K. , Zhao Shuyuan , Franks Carol F. , Donatelli Robert R. , Tominovich Rose M. , LaFrance Louis V. , Leonard Kristi A. , Gushue Joan M. , Parks Daniel J. , Calvo Raul R. , Milkiewicz Karen L. , Marugán Juan José , Raboisson Pierre , Cummings Maxwell D. , Grasberger Bruce L. , Johnson Dana L. , Lu Tianbao , Molloy Christopher J. , Maroney Anna C. 
Published: March 2006

Abstract
The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC50s of 14 and 0.7 μmol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage–independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21waf1/cip1 levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors. [Mol Cancer Ther 2006;5(1):160–9]
Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways
Authors: Rice Pamela L. , Peters Stevany L. , Beard K. Scott , Ahnen Dennis J. 
Published: March 2006

Abstract
Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP–dependent protein kinase (PKG); (b) activate c-jun NH2-terminal kinase (JNK); (c) inhibit extracellular signal–regulated kinase 1/2 (ERK1/2); and (d) decrease β-catenin protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if PKG, ERK1/2, JNK, and β-catenin are independent targets for sulindac in vitro. Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or β-catenin protein expression. Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate β-catenin protein expression. Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and β-catenin. These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and death rate from colorectal cancer. [Mol Cancer Ther 2006;5(3):746–54]
Targeting stathmin in prostate cancer
Authors: Mistry Sucharita J. , Bank Alexander , Atweh George F. 
Published: March 2006

Abstract
Stathmin is the founding member of a family of microtubule-destabilizing proteins that regulate the dynamics of microtubule polymerization and depolymerization. Stathmin is expressed at high levels in a variety of human cancers and provides an attractive molecule to target in cancer therapies that disrupt the mitotic apparatus. We developed replication-deficient bicistronic adenoviral vectors that coexpress green fluorescent protein and ribozymes that target stathmin mRNA. The therapeutic potential of these recombinant adenoviruses was tested in an experimental androgen-independent LNCaP prostate cancer model. Adenovirus-mediated transfer of anti-stathmin ribozymes resulted in efficient transduction and marked inhibition of stathmin expression in these cells. Cells that were transduced with the anti-stathmin adenoviruses showed a dramatic dose-dependent growth inhibition. This was associated with accumulation of LNCaP cells in the G2-M phases of the cell cycle. A similar dose-dependent inhibition of clonogenic potential was also observed in cells infected with anti-stathmin adenoviruses. Morphologic and biochemical analysis of infected cells showed a marked increase in apoptosis characterized by detachment of the cells, increased chromatin condensation, activation of caspase-3, and fragmentation of internucleosomal DNA. If these findings are confirmed in vivo, it may provide an effective approach for the treatment of prostate cancer. [Mol Cancer Ther 2005;4(12):1821–9]
Sensitization of DNA damage–induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3σ and survivin
Authors: Vaziri Susan A.J. , Hill Jason , Chikamori Kenichi , Grabowski Dale R. , Takigawa Nagio , Chawla-Sarkar Mamta , Rybicki Lisa R. , Gudkov Andrei V. , Mekhail Tarek , Bukowski Ronald M. , Ganapathi Mahrukh K. , Ganapathi Ram 
Published: March 2006

Abstract
Proteasome inhibition following DNA damage results in the synergistic induction of apoptosis via a nuclear factor-κB–independent mechanism. In this study, we identify the role of p53 in mediating apoptosis by the sequence-specific treatment involving the DNA-damaging, topoisomerase I–targeting drug SN-38 followed by the proteasome inhibitor PS-341 (SN-38→PS-341). The p53-dependent sensitization of DNA damage–induced apoptosis by PS-341 is accompanied by persistent inhibition of proteasome activity and increased cytosolic accumulation of p53, including higher molecular weight forms likely representing ubiquitinated species. In contrast, pretreatment with PS-341 followed by treatment with SN-38 (PS-341→SN-38), which leads to an antagonistic interaction, results in transient inhibition of proteasome activity and accumulation of significantly lower levels of p53 localized primarily to the nucleus. Whereas cells treated with PS-341→SN-38 undergo G2 + M cell cycle arrest, cells treated with SN-38→PS-341 exhibit a decreased G2 + M block with a concomitant increase in the sub-G1 population. Decreased accumulation of cells in the G2 + M phase of the cell cycle in SN-38→PS-341–treated cells compared with PS-341→SN-38–treated cells correlates with enhanced apoptosis and reduced expression of two p53-modulated proteins, 14-3-3σ and survivin, both of which play critical roles in regulating G2 + M progression and apoptosis. The functional role of 14-3-3σ or survivin in regulating the divergent function of p53 in response to SN-38→PS-341 and PS-341→SN-38 treatment in inducing apoptosis versus G2 + M arrest/DNA repair, respectively, was confirmed by targeted down-regulation of these proteins. These results provide insights into the mechanisms by which inhibition of proteasome activity modulates DNA damage–induced apoptosis via a p53-dependent pathway. [Mol Cancer Ther 2005;4(12):1880–90]
Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak
Authors: Singh Shivendra V. , Zeng Yan , Xiao Dong , Vogel Victor G. , Nelson Joel B. , Dhir Rajiv , Tripathi Yamini B. 
Published: March 2006

Abstract
The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone-mediated suppression of PC-3 cell proliferation was not due to perturbation in cell cycle progression but caused by apoptosis induction characterized by appearance of subdiploid cells and cytoplasmic histone-associated DNA fragmentation. Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak. Interestingly, the expression of antiapoptotic proteins Bcl-2 and Bcl-xL was initially increased in guggulsterone-treated PC-3 cells but declined markedly following a 16- to 24-hour treatment with guggulsterone. Ectopic expression of Bcl-2 in PC-3 cells failed to confer significant protection against guggulsterone-induced cell death. On the other hand, SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to guggulsterone-induced cell killing compared with wild-type cells. Guggulsterone treatment resulted in cleavage (activation) of caspase-9, caspase-8, and caspase-3, and guggulsterone-induced cell death was significantly attenuated in the presence of general caspase inhibitor as well as specific inhibitors of caspase-9 and caspase-8. In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak.
Drugs aimed at targeting characteristic karyotypic phenotypes of cancer cells
Authors: Wallqvist Anders , Huang Ruili , Covell David G. , Roschke Anna V. , Gelhaus Kristen S. , Kirsch Ilan R. 
Published: March 2006

Abstract
The karyotypic features of cancer cells have not been a particular focus of anticancer drug targeting either as guidance for treatment or as specific drug targets themselves. Cancer cell lines typically have considerable, characteristic, and variable chromosomal aberrations. Here, we consider small-molecule screening data across the National Cancer Institute's 60 tumor cell line drug screening panel (NCI-60) analyzed for specific association with karyotypic variables (numerical and structural complexity and heterogeneity) determined for these same cell lines. This analysis is carried out with the aid of a self-organizing map allowing for a simultaneous assessment of all screened compounds, revealing an association between karyotypic variables and a unique part of the cytotoxic response space. Thirteen groups of compounds based on related specific chemical structural motifs are identified as possible leads for anticancer drug discovery. These compounds form distinct groups of molecules associated with relatively unexplored regions of the NCI-60 self-organizing map where anticancer agents currently standard in the clinic are not present. We suggest that compounds identified in this study may represent new classes of potential anticancer agents.
Subsieve-size agarose capsules enclosing ifosfamide-activating cells: a strategy toward chemotherapeutic targeting to tumors
Authors: Sakai Shinji , Kawabata Kenji , Tanaka Shinji , Harimoto Norifumi , Hashimoto Ichiro , Mu Changjun , Salmons Brian , Ijima Hiroyuki , Kawakami Koei 
Published: March 2006

AbstractLocalized activation of the prodrug ifosfamide in or close to tumors by implanting encapsulated ifosfamide-activating cells is an efficacious strategy for tumor therapy. The aim of this study was to evaluate the feasibility of subsieve-size agarose capsules for enclosing the cells in this application. Compared with many conventional microcapsules, subsieve-size agarose capsules are about one-tenth the size and have both higher mechanical stability and allow better molecular exchangeability than other systems. Cells that have been genetically modified to express cytochrome P450 2B1 enzyme were encapsulated in subsieve-size agarose capsules of ∼90 μm in diameter and implanted into preformed tumors in nude mice. Living cells were detected for &gt;1 month after encapsulation in vitro and showed enzymatic activity (i.e., they were able to activate ifosfamide). More significant regression of preformed tumors was observed in the recipients implanted with cell-enclosing capsules compared with those implanted with empty capsules. These results suggest that the strategy of using subsieve-size agarose capsules enclosing cytochrome P450 2B1–expressing cells is feasible for tumor therapy by chemotherapeutic targeting in combination with ifosfamide administration.
Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy
Authors: Lee Yean Kit , Isham Crescent R. , Kaufman Scott H. , Bible Keith C. 
Published: March 2006

Abstract
Up-regulated signal transducers and activators of transcription (STAT)–mediated signaling is believed to contribute to the pathogenesis of a variety of solid and hematologic cancers. Consequently, inhibition of STAT-mediated signaling has recently been proposed as a potential new therapeutic approach to the treatment of cancers. Having shown previously that the pan–cyclin-dependent kinase inhibitor flavopiridol binds to DNA and seems to kill cancer cells via that process in some circumstances, we evaluated the hypothesis that flavopiridol might consequently disrupt STAT3/DNA interactions, attenuate STAT3-directed transcription, and down-regulate STAT3 downstream polypeptides, including the antiapoptotic polypeptide Mcl-1. SDS-PAGE/immunoblotting and reverse transcription-PCR were used to assess RNA and polypeptide levels, respectively. DNA cellulose affinity chromatography and a nuclear elution assay were used to evaluate the ability of flavopiridol to disrupt STAT3/DNA interactions. A STAT3 luciferase reporter assay was used to examine the ability of flavopiridol to attenuate STAT3-directed transcription. Colony-forming assays were used to assess cytotoxic synergy between flavopiridol and AG490. Flavopiridol was found to (a) disrupt STAT3/DNA interactions (DNA cellulose affinity chromatography and nuclear elution assay), (b) attenuate STAT3-directed transcription (STAT3 luciferase reporter assay), and (c) down-regulate the STAT3 downstream antiapoptotic polypeptide Mcl-1 at the transcriptional level (reverse transcription-PCR and SDS-PAGE/immunoblotting). Furthermore, flavopiridol, but not the microtubule inhibitor paclitaxel, could be combined with the STAT3 pathway inhibitor AG490 to achieve cytotoxic synergy in A549 human non–small cell lung cancer cells. Collectively, these data suggest that flavopiridol can attenuate STAT3-directed transcription in a targeted fashion and may therefore be exploitable clinically in the development of chemotherapy regimens combining flavopiridol and other inhibitors of STAT3 signaling pathways. [Mol Cancer Ther 2006;5(1):138–48]
Enhancement of UVB radiation–mediated apoptosis by sanguinarine in HaCaT human immortalized keratinocytes
Authors: Reagan-Shaw Shannon , Breur Jorien , Ahmad Nihal 
Published: March 2006

AbstractIn this article, we studied the chemopreventive effects of sanguinarine on UVB-mediated responses in human HaCaT immortalized keratinocytes. For our studies, HaCaT cells were treated with a low dose (50 nmol/L) of sanguinarine for 24 hours followed by irradiation with UVB (15 or 30 mJ/cm2). Our data showed that UVB exposure, at both doses, resulted in decreased cell viability and increased apoptosis. Interestingly, pretreatment of the cells with sanguinarine caused a significant enhancement in the antiproliferative response of UVB. These responses on UVB and/or sanguinarine treatments were associated with (a) decrease in Bcl-2 and Bcl-XL and (b) increase in Bax, Bid, and Bak protein levels. Bax knockdown and Bcl-2 overexpression resulted in a rescue of HaCaT cells from sanguinarine-mediated apoptosis. DNA cell cycle analysis revealed that UVB treatment resulted in an accumulation of cells in the G2-M phase of the cell cycle, whereas pretreatment of sanguinarine resulted in a significant shift of cells in the S phase at a low UVB dose and a further accumulation of cells in the G2-M phase at a higher UVB dose. These effects on cell cycle were accompanied with modulations in the protein levels of cyclin (B1, E, and A) and cdc2 and cyclin-dependent kinase 1. Furthermore, sanguinarine treatment was found to result in significant modulations in p53, p66Shc, MsrA, and superoxide dismutase levels. Based on our data, we suggest the sanguinarine may protect skin cells from UVB-mediated damages via apoptotic elimination of damaged cells that escape programmed cell death and therefore possess a potential of clonal expansion. [Mol Cancer Ther 2006;5(2):418–29]
Anti-CD70 antibodies: a potential treatment for EBV+ CD70-expressing lymphomas
Authors: Israel Bruce F. , Gulley Margaret , Elmore Sandra , Ferrini Silvano , Feng Wen-hai , Kenney Shannon C. 
Published: March 2006

AbstractA monoclonal antibody (Rituximab) directed against the B-cell surface antigen, CD20, is increasingly used as a therapy for B-cell lymphomas. However, CD20 is expressed on all normal mature B cells and hence is not a specific tumor target. In contrast, CD70 is expressed on highly activated lymphocytes as well as on many B-cell and T-cell lymphomas but is not expressed on the great majority of B cells and T cells. In this report, we have explored the potential utility of anti-CD70 monoclonal antibodies for treatment of CD70+ EBV+ B-cell lymphomas. Using two Burkitt's lymphoma lines (Raji and Jijoye) that express surface CD70 and a CD70− Burkitt's lymphoma line (Akata), we show that two different monoclonal antibodies directed against human CD70 allow rabbit and human complement to kill EBV+ B cells in a CD70-dependent manner in vitro. In the absence of complement, neither anti-CD70 antibody induced in vitro killing of CD70+ cell lines. Importantly, i.p. injection of anti-CD70 antibodies also inhibited the growth of CD70+ Burkitt's lymphoma cells in severe combined immunodeficient mice but did not inhibit the growth of CD70− Burkitt's lymphoma cells. These results suggest that anti-CD70 antibodies may be useful for the treatment of CD70+ B-cell lymphomas. [Mol Cancer Ther 2005;4(12):2037–44]
Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels
Authors: Wild Robert , Fager Krista , Flefleh Christine , Kan David , Inigo Ivan , Castaneda Stephen , Luo Feng (Roger) , Camuso Amy , McGlinchey Kelly , Rose William C. 
Published: March 2006

Abstract
Although Erbitux (cetuximab) has proven therapeutic benefit in the clinical setting, the molecular determinants predicting responsiveness to this agent are still not very well understood. Here, we assessed the relationship between basal total and activated (pY1068) epidermal growth factor receptor (EGFR) levels in a tumor and the responsiveness to cetuximab monotherapy or combination-based treatment using human xenograft models. Cetuximab treatment alone (0.25–1 mg/mouse/injection, q3d, i.p.) effectively delayed the growth of GEO and L2987 tumors by a minimum of 10 days corresponding to log cell kill values of ≥1.0. Borderline activity was seen in the A549 and WiDr xenografts. However, cetuximab failed to show any significant antitumor activity in the HT29, HCT116, LOVO, Colo205, LX-1, HCC70, and N87 models. All of the studied tumors had detectable yet variable levels of EGFR. For combination regimens, cetuximab (1 mg/mouse/injection, q3dx5, i.p.) and cisplatin (4.5 mg/kg/injection, q3dx5, i.v.) proved to be significantly more efficacious than individual monotherapies in the cisplatin-refractory yet cetuximab-responsive GEO tumor model (P &lt; 0.001). However, no therapeutic enhancement was observed in the cisplatin and cetuximab weakly responsive A549 xenograft. Similarly, combinations of CPT-11 (48 mg/kg/injection, q3dx5, i.v.) with cetuximab (1 mg/mouse/injection, q3dx5, i.p.) failed to show any improvements over individual monotherapies in the cetuximab resistant/weakly responsive HT29, A549, and WiDr models. We conclude that preclinical activity associated with cetuximab monotherapy does not correlate directly with relative basal levels of total or activated (pY1068) EGFR in a tumor. Moreover, robust single-agent activity by cetuximab may be the best predictor for this agent to potentiate chemotherapy-mediated antitumor activities. [Mol Cancer Ther 2006;5(1):104–13]