bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90
Authors: Lundgren Karen , Zhang Hong , Brekken John , Huser Nanni , Powell Rachel E. , Timple Noel , Busch David J. , Neely Laura , Sensintaffar John L. , Yang Yong-ching , McKenzie Andres , Friedman Jessica , Scannevin Robert , Kamal Adeela , Hong Kevin , Kasibhatla Srinivas R. , Boehm Marcus F. , Burrows Francis J. 
Published: April 2009

Abstract
Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.[Mol Cancer Ther 2009;8(4):921–9]
A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines
Authors: Martinez-Balibrea Eva , Plasencia Carmen , Ginés Alba , Martinez-Cardús Anna , Musulén Eva , Aguilera Rodrigo , Manzano José Luis , Neamati Nouri , Abad Albert 
Published: April 2009

Abstract
We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatin-resistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r = −0.846, P = 0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P = 0.026). High PK-M2 levels were associated with high p53 levels (P = 0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatin-treated colorectal cancer.[Mol Cancer Ther 2009;8(4):771–8]
Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer
Authors: Liu Dong , Kojima Toru , Ouchi Masaaki , Kuroda Shinji , Watanabe Yuichi , Hashimoto Yuuri , Onimatsu Hideki , Urata Yasuo , Fujiwara Toshiyoshi 
Published: April 2009

Abstract
A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301–mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer.[Mol Cancer Ther 2009;8(4):980–7]
Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model
Authors: Sung Bokyung , Kunnumakkara Ajaikumar B. , Sethi Gautam , Anand Preetha , Guha Sushovan , Aggarwal Bharat B. 
Published: April 2009

Abstract
Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of nuclear factor-κB (NF-κB), a transcription factor closely linked to chemoresistance in multiple myeloma cells. Whether curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with multiple myeloma, was investigated in vitro and in xenograft model in nude mice. Our results show that curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by down-regulating the constitutive activation of NF-κB and Akt, and this correlated with the suppression of NF-κB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and vascular endothelial growth factor. Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P &lt; 0.001, vehicle versus bortezomib + curcumin; P &lt; 0.001, bortezomib versus bortezomib + curcumin), and this correlated with suppression of Ki-67 (P &lt; 0.001 versus control), CD31 (P &lt; 0.001 versus vehicle), and vascular endothelial growth factor (P &lt; 0.001 versus vehicle) expression. Collectively, our results suggest that curcumin overcomes chemoresistance and sensitizes multiple myeloma cells to thalidomide and bortezomib by down-regulating NF-κB and NF-κB-regulated gene products. [Mol Cancer Ther 2009;8(4):959–70]
Growth inhibition of human cancer cells by 5-aza-2′-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status
Authors: Xiong Jingbo , Epstein Richard J. 
Published: April 2009

Abstract
The cytotoxicity of 5-aza-2′-deoxycytidine (DAC) has been linked to demethylation of the INK4a/ARF tumor suppressor gene locus in various cell systems, but the causality of this association remains unproven. To test this assumption, we have examined the effects of DAC in two human cancer cell lines of differing INK4a/ARF promoter methylation status: MDA-MB-468 breast cancer cells in which INK4a/ARF is unmethylated and normally expressed, and DLD-1 colorectal cancer cells in which INK4a/ARF is methylated and repressed. In MDA-MB-468 cells, DAC induces cytotoxicity in the absence of any detectable increase of p14 or p16 expression, whereas small interfering RNA knockdown of p16/p14 expression fails to attenuate DAC cytotoxicity. In DLD-1 cells, DAC demethylates INK4a/ARF and restores both p16 and p14 expression at concentrations that fail to cause detectable growth inhibition or apoptosis; moreover, neither ARF nor INK4a transgene expression inhibits DLD-1 cell growth despite normalization of p14 and p16 expression. These data imply that neither of these cell lines depends on up-regulated expression of INK4a/ARF for DAC cytotoxicity. We propose that optimal anticancer use of this drug will await unambiguous identification of those DAC target genes primarily responsible for triggering growth inhibition, followed by clarification as to whether these upstream events are caused by hypomethylation or DNA damage.[Mol Cancer Ther 2009;8(4):779–85]
Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target
Authors: Bier Andrew , Oviedo-Landaverde Irene , Zhao Jing , Mamane Yael , Kandouz Mustapha , Batist Gerald 
Published: April 2009

Abstract
Connexin43 (Cx43) is often deregulated in breast cancer tissue compared with normal adjacent tissue. Stable reexpression of Cx43 in cancer slows growth and renders the cells more sensitive to cytotoxic chemotherapeutics. Pseudogenes are often considered nonfunctional copies of DNA. The Cx43 pseudogene (ΨCx43) possesses all the features of an expressed gene and is exclusively transcribed in breast cancer cell lines and not in normal cells. ΨCx43 can be translated in vivo, and its protein exhibits growth-suppressive behavior similar to Cx43. We showed that ΨCx43 binds to the polyribosomes in breast cancer cells and that exogenous expression of ΨCx43 induces translational inhibition of Cx43. Furthermore, ΨCx43 is translated and binds more efficiently to the translational machinery than does Cx43 in an in vitro system. Following knockdown of ΨCx43 in breast cancer cells, we observed an increase in Cx43 RNA and protein. This results in increased cellular sensitivity to cytotoxic chemotherapy. Our results show that ΨCx43 acts as a posttranscriptional regulator of Cx43 in breast cancer cells, and that this represents an example of the regulation of genes by pseudogenes with potential therapeutic implications in cancer. [Mol Cancer Ther 2009;8(4):786–93]
Resolving conflicting data on expression of the Tn antigen and implications for clinical trials with cancer vaccines
Authors: Li Qian , Anver Miriam R. , Butcher Donna O. , Gildersleeve Jeffrey C. 
Published: April 2009

Abstract
The tumor-associated Tn antigen has been investigated extensively as a biomarker and therapeutic target. Cancer vaccines containing the Tn antigen as a single tumor antigen or as a component of a polyvalent vaccine have progressed into phase I and II clinical trials. One major focus of Tn-based vaccines is the treatment of prostate cancer patients. Although expression of the antigen on prostate tumors is a critical prerequisite, previous reports investigating Tn expression in prostate tumors have produced conflicting results. Using a combination of immunohistochemistry and carbohydrate microarray profiling, we show that only 4% to 26% of prostate tumors express the Tn antigen. Based on our results, the majority of prostate cancer patients do not express the appropriate antigen. Therefore, efforts to preselect the subset of prostate cancer patients with Tn-positive tumors or apply Tn vaccines to other cancers with higher rates of antigen expression could significantly improve clinical response rates. Because conflicting information on carbohydrate expression is a general problem for the field, the approach described in this article of analyzing antigen expression with multiple antibodies and using carbohydrate microarray profiles to interpret the results will be useful for the development of other carbohydrate-based cancer vaccines and diagnostics.[Mol Cancer Ther 2009;8(4):971–9)
Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers
Authors: Santarosa Manuela , Del Col Laura , Tonin Elena , Caragnano Angela , Viel Alessandra , Maestro Roberta 
Published: April 2009

AbstractBRCA1-associated tumors are characterized by an elevated genomic instability and peculiar expression profiles. Nevertheless, tailored treatments for BRCA1 mutation carriers have only been partially investigated up to now. The implementation of therapeutic strategies specific for these patients has been in part hindered by the paucity of proper preneoplastic and neoplastic BRCA1-deficient tumor cell models. In this study, we took advantage of the RNA interference technology to generate a series of partially transformed (HBL100) and tumorigenic (MCF7 and T47D) breast cancer cell lines in which BRCA1 expression was silenced at different levels. These cell models were probed by clonogenic assay for their response to several DNA-damaging agents commonly used in cancer therapy (mitomycin C, cisplatin, doxorubicin, and etoposide). Our models confirmed the peculiar sensitivity to interstrand cross-link inducers associated with BRCA1 deficiency. Intriguingly, the increased sensitivity to these compounds displayed by BRCA1-defective cells was not correlated with the extent of apoptotic cell death but rather associated to an increased fraction of growth-arrested, enlarged, multinucleated β-galactosidase–positive senescent cells. Overall, our results support a role for BRCA1 in the regulation of interstrand cross-link–induced premature senescence and suggest a reconsideration of the therapeutic power of mitomycin/platinum-based treatments in BRCA1 carriers. Moreover, our data further prompt the setup of strategies for the imaging of the senescence response in vivo. [Mol Cancer Ther 2009;8(4):844–54]
KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer
Authors: Yeh Jen Jen , Routh Elizabeth D. , Rubinas Tara , Peacock Janie , Martin Timothy D. , Shen Xiang Jun , Sandler Robert S. , Kim Hong Jin , Keku Temitope O. , Der Channing J. 
Published: April 2009

Abstract
Phase II clinical trials of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors are ongoing and ERK1/2 activation is frequently used as a biomarker. In light of the mutational activation of BRAF and KRAS in colorectal cancer, inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase are anticipated to be promising. Previous studies in pancreatic cancer have found little correlation between BRAF/KRAS mutation status and ERK1/2 activation, suggesting that identifying biomarkers of MEK inhibitor response may be more challenging than previously thought. The purpose of this study was to evaluate the effectiveness of MEK inhibitor therapy for colorectal cancer and BRAF/KRAS mutation status and ERK1/2 activation as biomarkers for MEK inhibitor therapy. First, we found that MEK inhibitor treatment impaired the anchorage-independent growth of nearly all KRAS/BRAF mutant, but not wild-type, colorectal cancer cells. There was a correlation between BRAF, but not KRAS, mutation status and ERK1/2 activation. Second, neither elevated ERK1/2 activation nor reduction of ERK1/2 activity correlated with MEK inhibition of anchorage-independent growth. Finally, we validated our cell line observations and found that ERK1/2 activation correlated with BRAF, but not KRAS, mutation status in 190 patient colorectal cancer tissues. Surprisingly, we also found that ERK activation was elevated in normal colonic epithelium, suggesting that normal cell toxicity may be a complication for colorectal cancer treatment. Our results suggest that although MEK inhibitors show promise in colorectal cancer, KRAS/BRAF mutation status, but not ERK activation as previously thought, may be useful biomarkers for MEK inhibitor sensitivity. [Mol Cancer Ther 2009;8(4):834–43]
The selective hypoxia inducible factor-1 inhibitor PX-478 providesin vivoradiosensitization through tumor stromal effects
Authors: Schwartz David L. , Powis Garth , Thitai-Kumar Arun , He Yi , Bankson James , Williams Ryan , Lemos Robert , Oh Junghwan , Volgin Andrei , Soghomonyan Suren , Nishii Ryuichi , Alauddin Mian , Mukhopadhay Uday , Peng Zhenghong , Bornmann William , Gelovani Juri 
Published: April 2009

AbstractHypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element–specific micro–positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1–dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms. [Mol Cancer Ther 2009;8(4):947–58]
HDAC2 regulates chromatin plasticity and enhances DNA vulnerability
Authors: Marchion Douglas C. , Bicaku Elona , Turner Joel G. , Schmitt Morgen L. , Morelli Dawn R. , Munster Pamela N. 
Published: April 2009

Abstract
Histone deacetylases (HDAC) may have a prominent role in the development of cancer and the response to anticancer therapy. However, the therapeutic relevance and tissue specificity of individual HDAC enzymes remain largely unknown. HDAC inhibitors may function as sensitizing agents to chemotherapies that target DNA through their effects on chromatin structure and plasticity. Here, we report a new role for HDAC2 as a regulator of chromatin compaction status and the mediator of HDAC inhibitor-induced sensitization to chemotherapy. The selective depletion of HDAC2 by small interfering RNA led to reduced expression of heterochromatin maintenance proteins and morphologic changes indicative of chromatin decondensation. Furthermore, depletion of HDAC2 but not HDAC1 or HDAC6 was sufficient to sensitize breast cancer cells to topoisomerase inhibitor-induced apoptosis. The levels of HDAC2 expression appear to correlate with the degree of HDAC inhibitor-induced histone acetylation in a surrogate tissue in patients. These data suggest that HDAC2 may be a relevant pharmacologic and biological target for combination therapy involving drugs that target DNA.[Mol Cancer Ther 2009;8(4):794–801]
Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug
Authors: Guillermet-Guibert Julie , Davenne Lise , Pchejetski Dimitri , Saint-Laurent Nathalie , Brizuela Leyre , Guilbeau-Frugier Céline , Delisle Marie-Bernadette , Cuvillier Olivier , Susini Christiane , Bousquet Corinne 
Published: April 2009

Abstract
Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.[Mol Cancer Ther 2009;8(4):809–20]
Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737
Authors: Hauck Paula , Chao Bo H. , Litz Julie , Krystal Geoffrey W. 
Published: April 2009

Abstract
To understand the molecular basis for variable sensitivity to the BH3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of small cell lung cancer cell lines whose sensitivity varied over a 2-log range. Elevated Noxa and Bcl-2 levels directly correlated with sensitivity to ABT-737, whereas Mcl-1 levels were similar in all cell lines tested regardless of sensitivity. Transgenically enforced expression of Noxa but not Bcl-2 resulted in increased sensitivity to ABT-737 in multiple cell lines. This increase was especially pronounced in the H209 cell line in which expression of Noxa resulted in a proportionate decline in Mcl-1 expression. Although overexpression of Noxa enhanced sensitivity of the H526 and H82 cell lines to ABT-737, it did not result in altered Mcl-1 levels. Similarly, small interfering RNA–mediated knockdown of Noxa expression in the H146 cell line, which increased resistance to ABT-737, did not result in altered Mcl-1 levels. Therefore, three of four cell lines studied failed to show Noxa-mediated regulation of Mcl-1 expression. However, despite failure to regulate Mcl-1 levels, Noxa blocked binding of Bim to Mcl-1 following its release from Bcl-2 by ABT-737. Finally, we observed that a 24-hour incubation of the H526 and WBA cell lines with ABT-737 resulted in increased Noxa expression, suggesting that Noxa may play a direct role in ABT-737–mediated apoptosis. These results indicate that Noxa expression is the critical determinant of ABT-737 sensitivity and loss of Noxa-mediated regulation of Mcl-1 expression may be an important feature of small cell lung cancer biology. [Mol Cancer Ther 2009;8(4):883–92]