bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4512: The novel HSP90 inhibitor, PF-04929113, inhibits AR activity and osteoclastogenesis and delays castrate-resistant LNCaP prostate cancer tumor growth
Authors: Lamoureux Francois , Yin Min-Jean , Zoubeidi Amina , Gleave Martin E. 
Published: February 2011

Abstract
Introduction and Objective: Prostate cancer responds initially to anti-androgen therapies, however, progression to castration resistant disease frequently occurs. Consequently there is an urgent need for novel therapeutic agents that can prevent the emergence of the castration resistant form of disease. Heat shock protein (HSP) 90 is a molecular chaperone involved in the maturation and stability of the Androgen Receptor (AR). In this study, we assessed the in vitro and in vivo antitumor properties of a novel synthetic HSP90 inhibitor, PF-04928473 in vitro and PF-04929113 in vivo, in prostate cancer and bone metastasis development.
Methods: The effects of the HSP90 inhibitor were evaluated in vitro on LNCaP, C4-2, PC3 and DU145 cell growth and apoptosis. AR transactivation and other biochemical assays studied AR/HSP90 interaction. The consequence of HSP90 therapy in vivo was evaluated in athymic mice bearing castration resistant LNCaP xenografts. The consequence of PF-04928473 therapy on bone metastasis was studied using a osteoclastogenesis in vitro assay.
Results: In our panel of prostate tumor cell lines, PF-04928473 inhibited cell growth in a dose-dependent manner (IC50 ± 30nM) and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of AR and PSA, AR transactivation, inhibition of Akt and Erk activation, and modulation of HSP expression. When administered orally 3 times/week (50mg/kg) to mice bearing castration resistant LNCaP tumors, PF-04929113 significantly inhibited tumor growth by 160% and prolonged survival compared to controls, but a small reduction in total bodyweight was observed. In contrast to 17-AAG, the novel PF-04928473 compound was not observed to activate src but did block osteoclast differentiation in vitro.
Conclusions: Targeting HSP90 using PF-04928473 and PF-04929113 inhibited castration resistant LNCaP tumor growth in vitro and in vivo in part through a mechanism involving disruption of the AR signaling axis and appears to inhibit bone metastasis by blocking osteoclastogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4512.
Abstract 4514: Proteasome inhibition causes regression of leukemia in part through regulation of forkhead tumor suppressors
Authors: Singh Amrik , Ye Min , Song Keli , Bucur Octavian , Khosravi-Far Roya 
Published: February 2011

Abstract
BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also show that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor-related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. Our data delineate the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4514.
Abstract 4519: Small cell lung cancers lack expression of argininosuccinate synthase (ASS) and are sensitive to arginine deprivation using arginine deiminase-PEG20 (ADI-PEG20)
Authors: Kelly Marcus P. , Jungbluth Achim A. , Wu Bor-Wen , Bomalaski John , Ritter Gerd , Old Lloyd J. 
Published: February 2011

Abstract
Various tumor types have been shown to lack expression of the enzyme argininosuccinate synthase (ASS) that is required for the synthesis of arginine and thus rely on exogenous sources for protein synthesis requirements. These tumors may be sensitive to arginine deprivation, and the absence of ASS expression may serve as a biomarker for this sensitivity. Arginine deiminase (ADI) is a microbial enzyme that has been shown to efficiently lower peripheral blood arginine. Its therapeutic efficacy has been previously explored in the treatment of melanoma and hepatocellular cancer in early phase clinical trials but clinical efficacy in these tumor types has been limited. However, other tumor types lacking ASS may be more sensitive to arginine depletion. We have investigated ASS expression in human small cell lung cancer (SCLC) tumor tissue by immunohistochemistry (IHC) and have so far found that about 43% (7/16) of SCLC tumors were negative for ASS. SCLC has a robust initial response to chemotherapy but the majority of cases relapse and there remain limited options in the treatment of refractory disease. Based on the IHC findings and the need for novel therapies in recurrent SCLC, we explored the effects of pegylated ADI (ADI-PEG20) mediated arginine deprivation in SCLC in vitro and in vivo. We screened a panel of 10 human SCLC cell lines for ASS mRNA and protein expression by Real Time PCR and Western blot analysis. Little or no ASS was observed in 50% (5 of 10) of the SCLC cell lines examined and this frequency is approximately equivalent to that found in the SCLC tumor tissues. In cell proliferation assays a clear correlation between expression of ASS and sensitivity to ADI-PEG20 was detected. Biochemical analysis of the mechanism of ADI-PEG20 induced cell death in ADI sensitive cell lines revealed induction of autophagy and cell death through caspase independent mechanisms. Assessment of ADI-PEG20 activity in vivo using mice bearing SCLC xenografts demonstrated that ADI-PEG20 treatment of ASS negative SCLC xenografts caused significant and dose dependent inhibition of tumor growth, while no effect was observed with placebo controls. These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this treatment in patients with ASS negative SCLC by IHC has been initiated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4519.
Abstract 4521: Discovery of novel small molecule inhibitors of the antiapoptotic protein Mcl-1 through high-throughput screening approach
Authors: Liu Meilan , Shen Chenxi , Larsen Martha , Yang Chao-Yie , Qiu Su , Tomita York , Krajewski Krzysztof , Roller Peter P. , Stuckey Jeanne , Wang Shaomeng , Nikolovska-Coleska Zaneta 
Published: February 2011

Abstract
Myeloid cell leukemia (Mcl-1) is a multidomain, anti-apoptotic protein, member of the Bcl-2 family proteins, an important survival factor for many cancers. Mcl-1 has a critical and distinct role(s) in maintaining cell survival and emerging as an independent and promising therapeutic target.
Through high throughout screening (HTS) of 53,300 structurally diverse synthetic organic compounds, we have discovered a number of novel inhibitors of Mcl-1. The hits identified by HTS were evaluated in a series of complementary biochemical, biophysical, functional and cellular assays to eliminate false positives and to determine the specificity and mechanism of action of these new compounds and 23 compounds were found to be inhibitors of Mcl-1. The most promising compounds, 59 and 62, have diverse chemical scaffolds. We have shown that these small molecule inhibitors bind to the BH3 binding site in Mcl-1 with IC50 values of 1,200 nM and 200 nM, respectively, and compete with BH3 peptides derived from Bid, Bim, or Noxa proteins. They bind to the Mcl-1 protein showing selectivity over two other Bcl-2 family members, Bcl-2 and Bcl-xL. NMR spectroscopy shows that 59 and 62 bind to the same BH3 domain of Mcl-1 as the Bim BH3 peptide. These initial lead compounds antagonize Mcl-1 on the functional level and they induce release of cytochrome c, inhibit cell growth and induce apoptosis in pancreatic and melanoma cancer cells with high levels of Mcl-1. We have tested several analogues of 59 and 62, both synthetic and commercially available, and established initial structure-activity relationships. One of the compounds tested (77), an analogue of 59, has improved binding affinity to Mcl-1 protein, as well as potent activity in inhibition of cell growth in cancer cells. Furthermore, by using murine embryonic fibroblasts (MEFs), wild type and deficient in both Bax and Bak (double knock out), it was demonstrated that the cytotoxic activity and induction of apoptosis by several analogues of the lead compound 59, depend on Bax and/or Bak, suggesting that they function as BH3 mimetics.
Collectively, these findings provide good promise for chemical modifications of the new identified lead compounds, 59 and 62, and their further optimization toward developing a new class of anticancer drugs, Mcl-1 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4521.
Abstract 4522: Oncogenic stress-induced cell death following Imatinib deprivation in Bcr-Abl overexpressing Imatinib-resistant ALL cells
Authors: Dengler Michael A. , Staiger Annette M. , Gutekunst Matthias , Aulitzky Walter E. , van der Kuip Heiko 
Published: February 2011

Abstract
Imatinib resistance is a major problem in treatment of Bcr-Abl positive leukemias, particularly in patients with ALL and advanced CML. One of the major mechanisms of this resistance is overexpression of Bcr-Abl.
We investigated the effects of Imatinib deprivation in Bcr-Abl overexpressing Imatinib-resistant ALL cell lines. Removal of Imatinib from culture medium led to a huge induction of Bcr-Abl autophosphorylation and concomitant overstimulation of PI3K-, MAPK-, and JAK/STAT signalling leading to an elevated cell size and cellular protein content. Massive induction of cell death was then observed at later time points (48 hours after Imatinib deprivation) accompanied by loss of outer and inner mitochondrial membrane integrity. Using a protein kinase inhibitor library, we identified inhibitors of glycogen synthase kinase-3 (GSK3) and p38-MAPK as the most potent compounds which completely prevented induction of cell death upon removal of Imatinib whereas the same inhibitors had synergistic effects with Imatinib in Imatinib-sensitive ALL cells. In contrast to GSK3- and p38, inhibition of PI3K had no effect on oncogenic stress upon Imatinib withdrawal in the resistant clones.
Importantly, oncogenic stress-induced cell death could not be blocked by the pan-caspase inhibitor z-VAD-fmk whereas the RIP1 inhibitor Necrostatin partially rescued the cells upon Imatinib deprivation. We also detected a posttranslational modification of RIP1 upon Imatinib withdrawal that was completely absent in cells pre-treated with GSK3- or p38 inhibitors indicating a central role of RIP1 for oncogenic stress-induced cell death. In conclusion, we found a massive induction of a necroptosis-like cell death in Bcr-Abl overexpressing ALL cells as a consequence of oncogenic stress upon Imatinib deprivation. GSK3 and p38 turned out to play the most prominent role for oncogenic stress induced cell death. These data implicate that a discontinuous treatment with Imatinib (periods of Imatinib treatment followed by short periods without Imatinib) may prevent the appearance of cell clones with Bcr-Abl overexpression.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4522.
Abstract 4524: Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of a novel Bcl-2 family inhibitor, ABT-737
Authors: Kunami Naoko , Ishitsuka Kenji , Yotsumoto Fusanori , Ishikawa Chie , Katsuya Hiroo , Sawada Shigeki , Tanji Hiroe , Takeshita Morishige , Mori Naoki , Miyamoto Shingo , Kuroki Masahide , Tamura Kazuo 
Published: February 2011

Abstract
Adult T-cell lymphoma/leukemia (ATLL) is a T-cell malignancy caused by the human T-lymphotrophic virus type I (HTLV-I), and its therapeutic outcome still remains extremely poor. Therefore, novel therapeutic strategies are needed to improve treatment outcomes. In this study, we elucidated the therapeutic potential of targeting the anti-apoptotic Bcl-2 family proteins for the treatment of ATLL using ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. We first validated the rationale of this study by immunohistochemically assessing the expression of Bcl-2 family proteins in 25 lymph-node specimens derived from ATLL patients. The Bcl-2 and/or Bcl-XL proteins were expressed in 80% of specimens. We next examined the cytotoxicity of ABT-737 against three ATLL cell lines by the Colorimetric method. ABT-737 significantly inhibited growth of MT-1, MT-2 and HuT 102 cells with concentrations of 50 percent inhibition of 2.4, 0.23 and 0.008μM at 72 h, respectively. We then tried to clarify the mechanism of growth inhibition induced with ABT-737 using MT-1 and MT-2 cells. ABT-737 induced apoptosis in both cells with cleavage of caspases 9 and 3, and PARP. ABT-737 also induced apoptosis in fresh tumor cells derived from patients with ATLL. We also tested if ABT-737 enhances the cytotoxicity induced by conventional chemotherapeutic agents or novel agents. The interactions between them were evaluated using the Chou-Talalay method. ABT-737 synergistically enhanced the cytotoxicity and apoptosis induced by doxorubicin, vincristine or etoposide and bortezomib or suberolyanilide hydroxamic acid, which are current key drugs and promising candidates for the treatment of ATLL, respectively. Finally, we investigated the growth inhibition of ABT-737 in ATLL-xenografted mice. The mean tumor volume and weight, and mean serum level of soluble interleukin-2 receptor α at day 21 of the treated mice with ABT-737 (100mg/kg/day) were significantly lower than those of vehicle-treated mice. Moreover, massive induction of apoptosis was observed in tumors treated with ABT-737 by the TUNEL assay. These results suggest that the use of ABT-737, either alone, or in combination with other conventional cytotoxic and novel drugs, represents a promising novel targeted approach to overcome drug resistance and to improve patient outcome in ATLL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4524.
Abstract 4525: Targeting ROS to kill cisplatin-resistant cells
Authors: Wangpaichitr Medhi , Wu Chunjing , Kuo M.t. , You Min , Dinh Vy , Feun Lynn , Savaraj Niramol 
Published: February 2011

Abstract
Cisplatin (CP) resistance remains a major problem in the treatment of both small cell and non small cell lung cancer. We have previously shown that inhibiting mTOR can restore CP sensitivity; however, not all CP resistant cell lines are sensitive to mTOR inhibitor. Our findings have led us to search for an alternative target in these CP resistant cells. We have discovered that CP resistant cells share one common biochemical parameter which is increased reactive oxygen species (ROS) when compared to normal cells and their parental cells counterpart. Thus, further increased ROS in these CP resistant cells can push them beyond their tolerance limit which ultimately leads to cell death. We have found that increased expression of NADPH oxidase 4 (NOX4) and lower levels of thioredoxin (Trx) correlate with the high levels of ROS seen in CP resistant cell lines. Using elesclomol (N′1, N′3-dimethyl-N′1, N′3- bis [phenylcarbonothioyl] propanedihydrazide (formerly STA-4783, provided by Synta Pharmaceuticals)), an agent which is known to increase ROS, we demonstrated that elesclomol can increase H2O2 levels in CP resistant lung cancer cell lines (CP-R). Moreover, elesclomol is also significantly more cytotoxic toward CP-R with the ID50 dosage of 4-10 fold less than their parental cells (PC) counterpart and normal cells, BJ-1 (see table below). The percentage of apoptosis is also significantly higher in CP-R (65%) vs. PC (3%). The cytotoxic effect of elesclomol in CP-R is accompanied by further decrease in Trx and glutathione (GSH) antioxidant systems, while opposite results were found in PC and normal cells. This cytotoxic effect can be reversed by an antioxidant, N-acetylcysteine (NAC, 0.1mM). Furthermore, we have also found that elesclomol also increased intracellular CP and hence enhanced CP sensitivity in CP-R cells. We conclude that elesclomol is highly effective in CP resistant cells which express high basal levels of ROS and should be considered for treatment of CP resistant tumor.ID50 Dosage of Elesclomol in Parental (PC) vs. Cisplatin Resistant (CP-R) Lung Cancer Cell Lines SCLC1(PC)SCLCSR2(CP-R)SCLCB(PC)SCLCBC (CP-R)NSCLCS(PC)NSCLCSC(CP-R)BJ1Elesclomol(nM)50+/−2.55+/−0.541+/−3.89+/−1.259+/−4.610+/−2.265+/−5.5
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4525.
Abstract 4527: p53-Reactivating Small Molecules Induce Apoptosis in Head and Neck Cancer
Authors: Roh Jong-Lyel , Kang Sung Koo , Kim Myung Sook , Cho Yong Gu , Califano Joseph A. , Sidransky David , Koch Wayne M. 
Published: February 2011

Abstract
Novel small molecules have been reported to restore the p53 tumor suppressor function inducing cell cycle arrest and apoptosis. The p53-targeting therapy may overcome the resistance to chemotherapeutic agents. This study evaluated whether small molecules induce p53-dependent apoptosis in head and neck squamous cell carcinoma (HNSCC) lines. PRIMA-1, CP-31398, RITA, and nutlin-3 were tested in 6 HNSCC cell lines with different p53 status and MDM2 expression levels. Cell growth, viability, cell cycle, and apoptosis after the treatment or combined treatment with common chemotherapeutic agents were assessed. The p53 reactivation was observed in mutant TP53-carrying cell lines by PRIMA-1 or CP-31398 treatment and in wild-type TP53-carrying cell lines by nutlin-3 treatment. The cell cycle arrest and apoptosis by the small molecules was associated with up-regulation of p21, Bax, and cleaved caspase-3. PRIMA-1 or CP-31398 induced also significant apoptosis in cell lines without p53 protein expression. Nutlin-3 or RITA showed maximal suppression in tumors with MDM2-induced tumor degradation. The small molecules enhanced the antitumor activity of the cell lines with a combination of cisplatin, 5-fluorouracil, paclitaxel, or erlotinib. The small molecules effectively restored p53 tumor suppressive function in HNSCC with mutant or wild-type p53. The p53 reactivating agents may be used for HNC with a combination of commonly-used chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4527.
Abstract 4530: The anti-tumor effect of MDM2 antagonist nutlin-3 in gastric cancer cell in vitro and in vivo
Authors: Endo Shinji , Suzuki Hideo , Hirai Sachiko , Hyodo Ichinosuke , Yamato Kenji 
Published: February 2011

Abstract
Purpose: The mortality of gastric cancer is still high accounting for an estimated 50,000 deaths in Japan. The chemotherapies based on fluoropyrimidine and platinum complexes are widely used for unresectable advanced gastric cancer, however, development of new strategies including molecular targeting therapies are urgently required to obtain further effectiveness. Recent studies demonstrate that 70% of gastric cancers has wild-type p53 gene and its function thought to be inhibited by over-expression of murine double minute 2 (MDM2), a regulator of p53 turnover by binding p53 and acting as a ubiquitin E3 ligase. Nutlin-3 is a small-molecule MDM2 antagonist that efficiently activates p53 and its tumor suppresser function has been shown in retinoblastoma and hematological malignancy but not in gastrointestinal carcinoma. In this study, we investigated the antitumor effects of nutlin-3 in gastric cancer cells in combination with 5-fluorouracil or cisplatin in vitro and in vivo.
Experimental Design: Human gastric cancer cell lines carrying wild-type (4 cell lines) or mutated p53 gene (3 cell lines) were incubated with nutlin-3 alone or combination with 5-fluorouracil or cisplatin in time dependent manner. Cell viability was calculated by WST assay. Western blot analysis for MDM2 and p53 are also performed to investigate protein expression. In vivo study, mice xenografted gastric cancer cells were treated with nutlin-3 alone or combination with 5-fluorouracil intraperitoneally. The tumor size was measured and histochemistry was done after 3 weeks administration.
Results: Nutlin-3 showed strong cytotoxicity in gastric cancer cells carrying wild-type p53 gene not mutated p53 gene, regardless of expression level of MDM2 protein. Anti-tumor effect of Nutlin-3 was also observed in xenografted mice model. Histochemical analysis indicated nutlin-3 induced apoptotic cell death in tumor tissue. Furthermore, combined treatment with nutlin-3 and 5-fluorouracil or cisplatin revealed enhanced cytotoxicity in gastric cancer cells with wild-type p53 gene.
Conclusions: Our results present new option in exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment for gastric cancer patients with wild-type p53 gene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4530.