bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor
Authors: Moretti Luigi , Kim Kwang Woon , Jung Dae Kwang , Willey Christopher D. , Lu Bo 
Published: May 2009

Abstract
Despite recent advances in the management of breast and lung cancer, novel treatment strategies are still needed to further improve patient outcome. The targeting of cell death pathways has therefore been proposed to enhance therapeutic ratio in cancer. In this study, we examined the in vitro and in vivo effects of Z-VAD, a broad-spectrum caspase inhibitor, on breast and lung cancer in association with radiation. Using clonogenic assays, we observed that Z-VAD markedly radiosensitized breast and lung cancer cells, with a radiation dose enhancement ratio of 1.31 (P &lt; 0.003). For both models, the enhanced tumor cytotoxicity was associated with induction of autophagy. Furthermore, we found that administration of Z-VAD with radiation in both breast and lung cancer xenograft produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo and thus represents an attractive anticancer therapeutic strategy. In conclusion, this preclinical study supports the therapeutic potential of Z-VAD as a radiosensitizer in breast and lung cancer. This study also suggests caspase inhibition as a promising strategy to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are needed to determine the potential of this combination therapy in cancer patients. [Mol Cancer Ther 2009;8(5):OF1–10]
Effective gene-viral therapy of leukemia by a new fiber chimeric oncolytic adenovirus expressing TRAIL: in vitro and in vivo evaluation
Authors: Jin Jie , Liu Hui , Yang Chunmei , Li Gongchu , Liu Xinyuan , Qian Qijun , Qian Wenbin 
Published: May 2009

Abstract
Conditionally replicating adenoviruses (CRAd) have been under extensive investigations as anticancer agents. Previously, we found that ZD55, an adenovirus serotype 5-based CRAd, infected and killed the leukemia cells expressing coxsackie adenovirus receptor (CAR). However, majority of leukemic cells lack CAR expression on their cell surface, resulting in resistance to CRAd infection. In this study, we showed that SG235, a novel fiber chimeric CRAd that has Ad35 tropism, permitted CAR-independent cell entry, and this in turn produced selective cytopathic effects in a variety of human leukemic cells in vitro and in vivo. Moreover, SG235 expressing exogenous tumor necrosis factor-related apoptosis-inducing ligand (SG235-TRAIL) effectively induced apoptosis of leukemic cells via the activation of extrinsic and intrinsic apoptotic pathway and elicited a superior antileukemia activity compared with SG235. In addition, normal hematopoietic progenitors were resistant to the inhibitory activity of SG235 and SG235-TRAIL. Our data suggest that these novel oncolytic agents may serve as useful tools for the treatment of leukemia. [Mol Cancer Ther 2009;8(5):1387–97]
The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt
Authors: Maksimovic-Ivanic Danijela , Mijatovic Sanja , Miljkovic Djordje , Harhaji-Trajkovic Ljubica , Timotijevic Gordana , Mojic Marija , Dabideen Darrin , Cheng Kai Fan , McCubrey James A. , Mangano Katia , Al-Abed Yousef , Libra Massimo , Garotta Gianni , Stosic-Grujicic Stanislava , Nicoletti Ferdinando 
Published: May 2009

AbstractApplication of the HIV protease inhibitor saquinavir (Saq) to cancer chemotherapy is limited by its numerous side effects. To overcome this toxicity, we modified the original compound by covalently attaching a nitric oxide (NO) group. We compared the efficacy of the parental and NO-modified drugs in vitro and in vivo. The novel compound saquinavir-NO (Saq-NO) significantly reduced the viability of a wide spectrum of human and rodent tumor cell lines at significantly lower concentration than the unmodified drug. In contrast to Saq, Saq-NO had no effect on the viability of primary cells and drastically reduced B16 melanoma growth in syngeneic C57BL/6 mice. In addition, at the equivalent of the 100% lethal dose of Saq, Saq-NO treatment caused no apparent signs of toxicity. Saq-NO blocked the proliferation of C6 and B16 cells, up-regulated p53 expression, and promoted the differentiation of these two cell types into oligodendrocytes or Schwann-like cells, respectively. Although it has been well documented that Saq decreases tumor cell viability by inhibiting Akt, the anticancer properties of Saq-NO were completely independent of the phosphatidylinositol 3-kinase/Akt signaling pathway. Moreover, Saq-NO transiently up-regulated Akt phosphorylation, delivering a protective signal that could be relevant for primary cell protection and the absence of drug toxicity in vivo. It was unlikely that released NO was independently responsible for these drug effects because Saq-NO treatment increased intracellular and secreted NO levels only slightly. Rather, the chemical modification seems to have produced a qualitatively new chemical entity, which may have a unique mode of action against cancer cells.[Mol Cancer Ther 2009;8(5):1169–78]
Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity
Authors: Perera Yasser , Farina Hernán G. , Gil Jeovanis , Rodriguez Arielis , Benavent Fernando , Castellanos Lila , Gómez Roberto E. , Acevedo Boris E. , Alonso Daniel F. , Perea Silvio E. 
Published: May 2009

Abstract
CIGB-300, formerly known as P15-tat, is a proapoptotic peptide with established antiproliferative activity in vitro and antitumoral activity in vivo. This hypothesis-driven peptide was initially selected for its ability to impair the in vitro CK2-mediated phosphorylation in one of its substrates through direct binding to the conserved acidic phosphoaceptor domain. However, the actual in vivo target(s) on human cancer cells among the hundreds of CK2 substrates as well as the subsequent events that lead to apoptosis on tumor cells remains to be determined. In this work, we identified the multifunctional oncoprotein nucleophosmin/B23 as a major target for CIGB-300. In vivo, the CIGB-300–B23 interaction was shown by pull-down experiments and confirmed by the early in situ colocalization of both molecules in the cell nucleolus. Moreover, CIGB-300 inhibits the CK2-mediated phosphorylation of B23 in a dose-dependent fashion both in vitro and in vivo as shown using the recombinant GST fusion protein and the metabolic labeling approach, respectively. Such phosphorylation impairment was correlated with the ability of CIGB-300 to induce nucleolar disassembly as documented by the use of established markers for nucleolar structure. Finally, we showed that such a sequence of events leads to the rapid and massive onset of apoptosis both at the molecular and cellular levels. Collectively, these findings provide important clues by which the CIGB-300 peptide exerts its proapoptotic effect on tumor cells and highlights the suitability of the B23/CK2 pathway for cancer-targeted therapy. [Mol Cancer Ther 2009;8(5):OF1–8]
In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I
Authors: Lu Jie , Chan Lai , Fiji Hannah D.G. , Dahl Russell , Kwon Ohyun , Tamanoi Fuyuhiko 
Published: May 2009

Abstract
Protein geranylgeranyltransferase-I (GGTase-I) catalyzes protein geranylgeranylation, which is critical for the function of proteins such as Rho, Rac, and Ral. We previously identified several small-molecule inhibitors of GGTase-I from an allenoate-derived compound library and showed that these compounds exhibit specific inhibition of GGTase-I resulting in the inhibition of proliferation associated with the induction of G1 cell cycle arrest of a variety of cancer cell lines. Because inhibition of GGTase-I is expected to suppress tumor growth, we investigated in vivo effects of one of these GGTase-I inhibitors (GGTI), P61A6, by using a human pancreatic cancer xenograft model in mice. The new compound GGTI P61A6 showed an excellent antitumor effect. I.p. administration of P61A6 significantly suppressed tumor growth of the PANC-1 xenograft. Even once per week administration of GGTI was enough to suppress tumor growth. Immunohistochemical examination indicated the inhibition of cell proliferation in the tumors by P61A6 treatment, but neither apoptosis nor antiangiogenesis was observed. Increased cytosolic localization of proteins such as Rap1 and RhoA in tumors was observed. In addition, the enzyme activity of GGTase-I in tumors was inhibited. Pharmacokinetic analysis showed that the plasma half-life of GGTI is ∼6 h, suggesting its prolonged effect. These data suggest that the novel GGTI compound P61A6 is an excellent chemotherapeutic drug candidate for human pancreatic cancer. They also provide evidence that protein GGTase-I may be a valid target for cancer therapy. [Mol Cancer Ther 2009;8(5)1218–26]
Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells
Authors: Vander Griend Donald J. , Antony Lizamma , Dalrymple Susan L. , Xu Yi , Christensen S. Brogger , Denmeade Samuel R. , Isaacs John T. 
Published: May 2009

Abstract
There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell-penetrant sequiterpene-lactone that once inside cells inhibits (IC50, ∼10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b, and CWR22Rv1), TG inhibition of SERCA pumps consistently results in depletion of the endoplasmic reticulum Ca+2 coupled with μmol/L elevation in the intracellular free Ca+2 initiating a molecular cascade that: (a) inhibits Cap-dependent AR protein synthesis resulting in 90% depletion of AR protein by 24 hours of TG exposure, (b) arrests the cells in G0, and (c) induces their apoptotic death. Unfortunately, due to its highly lipophilic nature, TG is not deliverable as a systemic agent without host toxicity. Therefore, TG analogues containing amino acids were developed, which retain ability to deplete AR protein and induce cell death and which can be covalently linked to peptide carriers producing water soluble prodrugs for systemic delivery. Specific amino acid sequences are used to restrict the liberation of cytotoxic amino acid containing TG analogues from the peptide prodrug by prostate-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing clinical development. [Mol Cancer Ther 2008;8(5):1340–9]
Changes in choline metabolism as potential biomarkers of phospholipase Cγ1 inhibition in human prostate cancer cells
Authors: Beloueche-Babari Mounia , Peak Joanna C. , Jackson L. Elizabeth , Tiet May-Yung , Leach Martin O. , Eccles Suzanne A. 
Published: May 2009

AbstractPhosphoinositide-specific phospholipase Cγ1 (PLCγ1) is activated downstream of many receptor tyrosine kinases to promote cell motility. Inhibition of this protein is being explored as a therapeutic strategy for blocking cancer cell invasion and metastasis. The clinical development of such cytostatic therapies requires the implementation of pharmacodynamic biomarkers of target modulation. In this study, we use magnetic resonance spectroscopy to explore metabolic biomarkers of PLCγ1 down-regulation in PC3LN3 prostate cancer cells. We show that inhibition of PLCγ1 via an inducible short hairpin RNA system causes a reduction in phosphocholine levels by up to 50% relative to the control as detected by 1H and 31P magnetic resonance spectroscopy analyses. This correlated with a rounded-up morphology and reduced cell migration. Interestingly, the fall in phosphocholine levels was not recorded in cells with constitutive PLCγ1 knockdown where the rounded-up phenotype was no longer apparent. This study reveals alterations in metabolism that accompany the cellular effects of PLCγ1 knockdown and highlights phosphocholine as a potential pharmacodynamic biomarker for monitoring the action of inhibitors targeting PLCγ1 signaling.[Mol Cancer Ther 2009;8(5):1305–11]
MDA-7/IL-24–induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK–dependent mechanism
Authors: Park Margaret A. , Walker Teneille , Martin Aditi Pandya , Allegood Jeremy , Vozhilla Nicollaq , Emdad Luni , Sarkar Devanand , Rahmani Mohammed , Graf Martin , Yacoub Adly , Koumenis Costas , Spiegel Sarah , Curiel David T. , Voelkel-Johnson Christina , Grant Steven , Fisher Paul B. , Dent Paul 
Published: May 2009

Abstract
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on clarifying the mechanism(s) by which glutathione S-transferase (GST)-MDA-7 altered cell survival of human renal carcinoma cells in vitro. GST-MDA-7 caused plasma membrane clustering of CD95 and the association of CD95 with procaspase-8. GST-MDA-7 lethality was suppressed by inhibition of caspase-8 or by overexpression of short-form cellular FLICE inhibitory protein, but only weakly by inhibition of cathepsin proteases. GST-MDA-7–induced CD95 clustering (and apoptosis) was blocked by knockdown of acidic sphingomyelinase or, to a greater extent, ceramide synthase-6 expression. GST-MDA-7 killing was, in parallel, dependent on inactivation of extracellular signal–regulated kinase 1/2 and on CD95-induced p38 mitogen-activated protein kinase and c-jun NH2-terminal kinase-1/2 signaling. Knockdown of CD95 expression abolished GST-MDA-7–induced phosphorylation of protein kinase R–like endoplasmic reticulum kinase. GST-MDA-7 lethality was suppressed by knockout or expression of a dominant negative protein kinase R–like endoplasmic reticulum kinase that correlated with reduced c-jun NH2-terminal kinase-1/2 and p38 mitogen-activated protein kinase signaling and maintained extracellular signal–regulated kinase-1/2 phosphorylation. GST-MDA-7 caused vacuolization of LC3 through a mechanism that was largely CD95 dependent and whose formation was suppressed by knockdown of ATG5 expression. Knockdown of ATG5 suppressed GST-MDA-7 toxicity. Our data show that in kidney cancer cells GST-MDA-7 induces ceramide-dependent activation of CD95, which is causal in promoting an endoplasmic reticulum stress response that activates multiple proapoptotic pathways to decrease survival.[Mol Cancer Ther 2009;8(5):OF1–12]
Topoisomerase IIα-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin
Authors: Yan Tiandong , Deng Shiwei , Metzger Annegret , Gödtel-Armbrust Ute , Porter Andrew C.G. , Wojnowski Leszek 
Published: May 2009

AbstractCoadministration of the iron chelator dexrazoxane reduces by 80% the incidence of heart failure in cancer patients treated with anthracyclines. The clinical application of dexrazoxane is limited, however, because its ability to inhibit topoisomerase IIα (TOP2A) is feared to adversely affect anthracycline chemotherapy, which involves TOP2A-mediated generation of DNA double-strand breaks (DSB). Here, we investigated the apoptotic effects of dexrazoxane and the anthracycline doxorubicin, alone and in combination, in a tumor cell line with conditionally regulated expression of TOP2A. Each drug caused apoptosis that was only partly dependent on TOP2A. Unexpectedly, dexrazoxane was found to cause TOP2A depletion, thereby reducing the doxorubicin-induced accumulation of DSB. Despite this latter effect, dexrazoxane showed no adverse effect on doxorubicin-induced apoptosis. This could be explained by the TOP2A-independent apoptotic effects of each drug: those of doxorubicin included TOP2A-independent DSB formation and depletion of intracellular glutathione, whereas those of dexrazoxane were caspase independent. In conclusion, both doxorubicin and dexrazoxane induce apoptosis via TOP2A-dependent and TOP2A-independent mechanisms, the latter compensating for the reduction in cell killing due to dexrazoxane-induced TOP2A depletion. These observations suggest an explanation for the absence of adverse dexrazoxane effects on clinical responses to doxorubicin. [Mol Cancer Ther 2009;8(5):1075–85]
Making Diabetes Education Accessible for People With Visual Impairment
Authors: Williams Ann S. 
Published: May 2009

Purpose The purpose of this study was to identify changes needed to make the diabetes education materials and programs of the Diabetes Association of Greater Cleveland (DAGC) accessible for people who have visual impairment and diabetes (PVID). Methods Using the principles and techniques of participatory action research (PAR), 5 PVID and 4 staff members of a local diabetes association met once a month for a year to plan, implement, and evaluate progress toward full accessibility of all diabetes education materials and programs. The researcher served as facilitator. Results Four “transformational moments” are presented through which the PAR process enabled PVID and diabetes professionals to learn to understand and trust each other. Changes made to increase accessibility included production of 2 recordings for providing access to print information about diabetes; planning public education program publicity and locations for access; development of guidelines to help speakers make their diabetes education presentations accessible for people who cannot see slides and gestures; and presentation of an inservice for the entire staff of the diabetes association, including information about how they live with visual impairment, and common courtesies that make communication with PVID more effective. Conclusions Diabetes education programs should include planning for full accessibility for PVID. Diabetes organizations should publish teaching materials in accessible format.
The Effect of Abduction and Rotation on Footprint Contact for Single-Row, Double-Row, and Modified Double-Row Rotator Cuff Repair Techniques
Authors: Park Maxwell C. , Pirolo Joseph M. , Park Chong J. , Tibone James E. , McGarry Michelle H. , Lee Thay Q. 
Published: May 2009

Background An abduction pillow and abduction and rotation exercises are commonly used after rotator cuff repair. The effect of glenohumeral abduction and rotation on footprint contact has not been elucidated. Hypothesis Abduction will decrease tendon-to-bone contact for all repairs. A modified double-row repair will maintain footprint contact more effectively at each position of humeral abduction and rotation than double- or single-row repairs. Study Design Controlled laboratory study. Methods In 6 fresh-frozen human shoulders, a modified double-row supraspinatus tendon repair was performed; a suture limb from each of 2 medial anchors was bridged over the tendon and fixed laterally. Double- and single-row repairs were performed sequentially; a total of 3 repairs were tested. For all repairs, a Tekscan pressure sensor was fixed at the tendon-footprint interface. The tendon was loaded with 30 N. The shoulders were tested at 0°, 30°, and 60° of abduction with 0° of rotation. For both dual-row repairs, 5 rotation positions were tested. Results The greatest contact areas at neutral rotation were achieved at 0° of abduction for the modified double-row, double-row, and single-row repairs (151.3 ± 10.7 mm2, 80.7 ± 30.0 mm2, and 61.3 ± 26.1 mm2, respectively), with values decreasing as abduction increased. Each repair was significantly different from one another at each abduction angle (P <. 05), except between single-and double-row repairs at 0° of abduction. Mean interface pressure exerted over the footprint was greater for the modified double-row technique than for the other techniques at each abduction angle (P <. 05). With respect to rotation, the modified double-row repair had significantly more footprint contact than did the double-row repair at each position tested (P <. 05). Conclusion For a given repair, increasing abduction at neutral rotation reduced footprint contact. Internal rotation to 60° provided among the highest contact measurements. The modified double-row technique provided the most contact. Clinical Relevance Results are consistent with the practice of immobilizing the shoulder with 30° or less of abduction and up to 60° of internal rotation to optimize footprint contact. A dual-row repair may maximize contact when initiating rehabilitation that involves abduction and rotation.
Noninvasive in vivo imaging of CD4 cells in simian-human immunodeficiency virus (SHIV)–infected nonhuman primates
Authors: Di Mascio Michele , Paik Chang H. , Carrasquillo Jorge A. , Maeng Jin-Soo , Jang Beom-Su , Shin In Soo , Srinivasula Sharat , Byrum Russ , Neria Achilles , Kopp William , Catalfamo Marta , Nishimura Yoshiaki , Reimann Keith , Martin Malcolm , Lane H. Clifford 
Published: May 2009

AbstractSince the earliest days of the HIV epidemic, the number of CD4+ T cells per unit volume of blood has been recognized as a major prognostic factor for the development of AIDS in persons with HIV infection. It has also been generally accepted that approximately 2% of total body lymphocytes circulate in the blood. In the present study, we have used a nondepleting humanized anti-CD4 monoclonal antibody labeled with the gamma emitter indium-111 to visualize the CD4+ T-cell pool in vivo in nonhuman primates with simian HIV infection. A strong correlation was noted between radiotracer uptake in spleen, tonsil, axillary lymph nodes, and peripheral blood CD4 T-cell counts (ρ = 0.75, 0.93, and 0.85, respectively, P < .005). The relationship between radiotracer retention in lymphoid tissues and CD4+ T-cell counts in the circulation was governed by an exponential law. These data provide an estimate for the total number of lymphocytes in the body as being between 1.9 and 2.9 × 1012 and suggest that the partition between peripheral blood and lymphoid tissue is between 0.3% and 0.5%.
EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines
Authors: Tsai Shu-Chun , Lin Sue-Jane , Chen Po-Wen , Luo Wen-Yi , Yeh Te-Huei , Wang Hsei-Wei , Chen Chi-Ju , Tsai Ching-Hwa 
Published: May 2009

AbstractEpstein-Barr virus (EBV) infection can modify the cytokine expression profiles of host cells and determine the fate of those cells. Of note, expression of interleukin-13 (IL-13) may be detected in EBV-associated Hodgkin lymphoma and the natural killer (NK) cells of chronic active EBV-infected patients, but its biologic role and regulatory mechanisms are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells early during EBV infection. Furthermore, the EBV lytic protein, Zta (also known as the BZLF-1 product), which is a transcriptional activator, was found to induce IL-13 expression following transfection. Mechanistically, induction of IL-13 expression by Zta is mediated directly through its binding to the IL-13 promoter, via a consensus AP-1 binding site. Blockade of IL-13 by antibody neutralization showed that IL-13 is required at an early stage of EBV-induced proliferation and for long-term maintenance of the growth of EBV immortalized lymphoblastoid cell lines (LCLs). Thus, Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of EBV-associated lymphoproliferative disorders, such as posttransplantation lymphoproliferative disease (PTLD) and Hodgkin lymphoma.