bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 54: Role of aldehyde dehydrogenase 1 in breast cancer stem cell survival
Authors: Zhang Min , Hogan Dale , Reddy Aramati Bindu , Ramana Kota , Srivastava Satish , Ansari Naseem H. 
Published: February 2011

Abstract
Tumor initiation and progression are mainly driven by a small subset of stem cells- like cancer cells (CSCs), which represent &lt;1 % of malignant breast tumors. Most importantly breast CSCs are highly resistant to radiation- and chemo-therapy. Such resistance could be attributed to the high expression of the enzyme, Aldehyde dehydrogenase I (ALDH1), which in recent years has been suggested to be a prognostic marker of breast cancer. However, the mechanism(s) of ALDH1's involvement in CSCs’ function and resistance to radiation/chemotherapy (oxidative stress) and its role in breast cancer progression are not known. Toxicity of most of the chemotherapeutic drugs is known to be via increased oxidative stress which generates lipid aldehydes such as 4-hydroxynonenal (HNE), a potent apoptotic agent. In CSCs the levels of ALDH1 are much higher than the normal breast cell as well as cancer cells. It is likely that the resistance of CSCs to chemotherapeutic drugs is due to increased levels of ALDH1 which is known to detoxify HNE generated by oxidative stress caused by chemotherapeutic drugs. Increased HNE could kill the cells by causing increased apoptosis. To test this hypothesis we inhibited ALDH1 in the tumoregenic human breast cancer cells, MDA-MB-468, by diethylaminobenzaldehyde (DEAB) and measured HNE-induced toxicity by evaluating the levels of protein-HNE adducts which, as previously demonstrated by us, increase in oxidation-induced apoptosis. ALDH1hi/CD44+ and ALDH1low/ CD44+ cells were sorted by flow cytometry using ALDEFLUO-FITC & mouse anti-Human CD44-APC. The DEAB-treated cells when subjected to oxidative stress by H2O2, showed increased formation of protein -HNE adducts with a concomitant increase in apoptosis and decrease in cell viability. Furthermore, our results also displayed increased activation of the transcription factor, NF-kB which could be responsible for up-regulating the death genes leading to apoptosis. In addition, four specimens of human malignant breast cancer tissues and two of benign breast tumors were analyzed by double immunostaining. Compared to benign tumors, elevated levels of ALDH1 and CSC-like cells (high ALDH1/high CD44/lowCD24) were observed in the breast cancer tissues. Furthermore, levels of ALDH1 in these specimens appeared to be proportional to the grade of cancer. Our results thus suggest that disrupting ALDH1-mediated HNE detoxification in CSCs could be a novel preventive approach against breast cancer progression and metastasis.
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 54.
Abstract 5402: Pre-clinical treatment of adrenal cortical carcinoma with a combination of small molecule inhibitors to IGF-1R and mTOR
Authors: Frome Lauren , Ignatoski Kathy 
Published: February 2011

Abstract
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer of the adrenal cortex. The five-year survival rate is 10-20% due to late diagnosis and lack of effective systemic therapy. The only treatment options available are surgical resection and chemotherapy in the form of mitotane; however, up to 95% of patients are not responsive to treatment, so new therapies are needed. Research has shown that the mitogenic hormone insulin-like growth factor 2 (IGF-2) is overexpressed in 93% of sporadic cases of ACC. IGF-2 binds to the receptor tyrosine kinase IGF receptor 1 (IGF-1R). Inhibition of IGF-1R has been shown to be effective against ACC in animal studies using IGF-1R targeted therapies. The major IGF-1R signaling pathway is phosphotidylinositol-3′-kinase (PI3′K), which activates AKT leading to the activation of mTOR, the mammalian target of rapamycin. Recent research has shown that mTOR may be a viable target for inhibition to treat tumors. Work in our lab has shown that a combination of mTOR inhibition by rapamycin and IGF1-R inhibition by either PQ401 or NVP-AEW54 at sub optimal doses blocks proliferation of human ACC H295R cells compared to application of either drug alone. Further investigation will be conducted in a mouse model system to determine the effects of the mTOR inhibitor everlimus (RAD001) alone and in combination with IGF1-R inhibitor OSI-906 to determine possible synergistic effects of the drugs that can be clinically applicable to treat ACC.
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 5402.
Abstract 5409: Ron silencing by shRNA inhibits growth, induces apoptosis and sensitizes tumor response to c-Met inhibitor treatment through down-regulating MAPK signaling in B-Raf mutant colon carcinomas
Authors: Zou Helen Y. , Li Qiuhua , Qiu Ming , Tatsukawa Keith , Wu Karen , Fang Douglas , Cui Jean , Bender Steve , Gibson Neil W. , Smeal Tod 
Published: February 2011

Abstract
RON, the receptor for macrophage-stimulating protein, belongs to the MET receptor tyrosine kinase family and shares many common features with MET. Inappropriate activation of RON signaling plays an important roll in colon carcinoma cell proliferation, survival, migration and invasive growth. Ron and Met are overexpressed in patient colon tumors, where co-overexpression of both Ron and Met correlates with the worst patient survival compared to the overexpression of Ron or Met alone. BRaf-activating mutations occur in about 10% of colorectal carcinomas. Mutant BRaf has constitutive kinase activity and causes hyperactivation of the mitogen-activated protein kinase (MAPK) pathway, and BRaf mutant cancers are generally resistant to standard therapies. Here we report that knockdown of the Ron gene by Ron shRNA in BRafV600E mutant HT29 colon carcinoma cells induced HT29 tumor apoptosis and resulted in significant tumor growth inhibition (TGI) by 59%, which is comparable to that observed with the selective EGFR inhibitor-Erlotinib treatment (57% TGI), but more potent than that of the selective Met inhibitor-PF-04217903 treatment (38% TGI). When Ron shRNA knockdown and treatment with the selective Met inhibitor were combined, enhanced tumor growth inhibition (76%) was observed. Comparable experiments using the BRaf mutant Colo205 model yielded similar results. Western Blot analysis showed that combination of Ron shRNA and Met inhibition in HT29 cells decreased phosho-ERK, elevated cleaved caspase-3 and, surprisingly, increased total Ras protein levels. No significant changes in total and phospho-AKT levels were observed. In vitro, the stable HT29-shRon cells initially grew more slowly compared to HT29-vector cells, but the growth rate gradually increased, approaching that observed in normal cell culture conditions. Interestingly, when co-culturing stable HT29-shRon or HT29-vector cells with bone marrow derived mesenchymal stem cells, the selective Met inhibitor-PF-04217903 induced significant cell death only in the HT29-shRon cells under hypoxic conditions (1% oxygen). No cell death was observed with either HT29-shRon cells under normoxia or HT29-vector cells under hypoxia or normoxia conditions, indicating the collaborative roll of Ron and Met in colon cancer cell survival during hypoxia. In summary, inhibiting both Ron and Met pathways in BRaf mutant colon cancer cells down- regulated ERK activity, induced apoptosis and led to enhanced antitumor efficacy in vivo.
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 5409.
Abstract 5412: Synergistic interactions between histone deacetylase inhibitors and aurora kinase inhibitor KW2449 Ph+ cells
Authors: Nguyen Tri K. , Kolla Sarah , Dai Yun , Grant Steven 
Published: February 2011

Abstract
Resistance to tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) remains a major therapeutic challenge in Bcr/abl+ leukemia. Consequently, novel and more effective therapeutic strategies are urgently needed in this setting. KW-2449 is a multi-kinase inhibitor which inhibits Bcr/abl, aurora kinase, and FLT3, among other targets, and which has shown activity against T315I “gatekeeper” mutant Bcr/abl cells. Previous studies have shown that histone deacetylase inhibitors (HDACIs) such as vorinostat sharply promote the antileukemic effects of Bcr/abl and aurora kinase inhibitors such as MK-0457 in CML cells (Dai et al., Blood 112:793-804, 2008). However, MK-0457 is not currently under clinical development. The purpose of this study was to assess the effects of HDACIs (e.g., SBHA, MS-275) on responses to the dual aurora kinase-Bcr/abl inhibitor (KW-2449) in various Bcr/Abl + cells. Coadministration of HDACIs synergistically increased KW-2449 lethality in CML (K562, LAMA84) and Ph+ ALL cells (TOM-1, SD-1, SUP-B15, BV173). Notably, HDACI/KW-2449 regimens were also highly active against multiple imatinib resistant cells including BV-173/E255K, BaF3/Bcr-Abl/T315I, as well as Bcr/Abl -overexpressing and Bcr/abl-independent K562 cells. Combined treatment with HDACIs and KW-2449 was associated with inactivation and down-regulation of Bcr/Abl and its downstream target CrkL in CML and ALL cell lines including BaF3/T315I. Moreover treatment with KW-2449/HDACi resulted in a pronounced increase in DNA damage (γH2A.X) documented by Western blot and confocal microscopy. In addition, coadministration of HDACIs and KW-2449 strikingly blocked phosphorylation of histone H3, a marker of aurora kinase inhibition, and diminished HDACI-induced p21CIP1 expression. Notably, down-regulation of Bim by siRNA significantly diminished the lethality of the HDACI/KW-2449 regimen. Treatment of K562 cells with HDACIs alone resulted in G1S arrest, an effect abrogated by KW-2449, and which resulted in pronounced cellular endoreduplication. Furthermore, knockdown of either Aurora A or Aurora B in K562 cells dramatically increased the HDACI-mediated cell death. Finally, cotreatment with KW-2449 and HDACIs significantly increased cell death in seven CML primary samples (including both naïve and imatinib-resistant specimens, one carrying the I242T, Y257C mutations) compared to treatment with either agent alone, while exhibiting minimal toxicity to normal CD34+ progenitors. Together, these findings indicate that HDACIs strikingly increase KW-2449 activity against IM-sensitive and -resistant Bcr/Abl+ cells, and suggest that this strategy warrants further attention in Bcr/abl+ leukemias.
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 5412.
Abstract 5427: Combination of aflibercept (VEGF trap) and docetaxel produces increased antitumor effects associated with enhanced changes to tumor vasculature
Authors: Abrahams Cristina , Li Baosheng , Parveen Asma , Thurston Gavin 
Published: February 2011

Abstract
VEGF blockade in combination with chemotherapy has shown increased anti-tumor efficacy in preclinical models and clinical studies. However, the mechanism by which combination treatments result in enhanced effects is not well understood. In this study, we sought to characterize the mechanism for improved effects of aflibercept plus docetaxel on HT1080, a human fibrosarcoma line that is resistant to anti-VEGF treatment. Immunodeficient SCID mice bearing subcutaneous HT1080 tumors (size ∼100 mm3) were treated with either control protein (hFc) plus docetaxel vehicle, aflibercept (25 mg/kg s.c.), docetaxel (4.5 mg/kg i.v.), or the combination. Following three treatments administered every 3-4 days, tumors were left to grow and harvested when the average size of the treatment group reached ∼600mm3. We found that combination treatment with aflibercept plus docetaxel was significantly more efficacious than either single agent. Although treatments with docetaxel alone and in combination with aflibercept both initially regressed tumor size, the combination was significantly more effective at delaying long-term tumor regrowth. In tumors harvested 24 hrs after the last treatment, combination treatment produced a dramatic decrease in the number of proliferating cells and a concomitant increase in pyknotic cells. Aflibercept or docetaxel alone had only modest effects on the vessels in this tumor, whereas the combination treatment resulted in pruned vessels with less branching, some vessels with punctate endothelial cell staining, and an increase in TUNEL-positive endothelial cells. These results suggest that combination of aflibercept plus taxols (docetaxel) causes enhanced effects on the tumor vessels, thus improving efficacy in tumors with vasculature that exhibit resistance to VEGF blockade. Further understanding the mechanistic basis underlying these combination treatments may provide insight into improving current strategies to manage tumors resistant to antiangiogenic therapy.
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 5427.
Abstract 5462: Enhancing efficacy of drugs by targeting CXCR2 receptor signaling for the treatment of malignant breast cancer
Authors: Sharma Bhawna , Nawandar Dhananjay , Varney Michelle L. , Nannuru Kalyan C. , Singh Rakesh K. 
Published: February 2011

Abstract
Breast cancer is the second most common cause of cancer death in women in the United States after lung cancer and is responsible for more than 40,000 deaths each year. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often due to therapy resistance. Recent reports suggest that malignant cells that survive initial chemo- and radiation therapy often express inflammatory cytokines, which provides survival benefit making tumors resistant to further chemotherapy. The specific objective of the study is to develop strategy to manipulate chemokine-chemokine receptor network for effective therapy with limited toxicity against drug-resistant breast cancer. We investigated whether modulation of CXCR2-dependent signaling in malignant mammary tumor enhances therapeutic efficacy of chemotherapy drugs. We used mammary tumor cells expressing different levels of CXCR2 (Cl66-wt and Cl66-shCXCR2) and examined their response to Paclitaxel and Doxorubicin. We observed significant enhancement of paclitaxel and doxorubicin-mediated toxicity at concentrations 5 and 10nM in Cl66-shCXCR2 cells as compared to Cl66-wt cells. Moreover, the expression of CXCL1, a CXCR2 ligand, was increased in paclitaxel and doxorubicin treated mammary tumor cells. Paclitaxel and doxorubicin induced CXCL-1 levels was significantly lower in Cl66-shCXCR2 cells as compared to Cl66-wt cells. In vivo studies using wild type and knockdown cells showed no significant difference in the tumor growth. However, we observed a difference in the tumor growth between wild type and knockdown tumors in mice treated with 10mg/kg concentration of paclitaxel for 3 weeks after starting the treatment. When these studies were further extended there wasn't any difference between the two groups. Furthermore, we extended these studies using human breast cancer cell lines (MDA-MB231, MDA-MET, and SKBR3). MDA-MB231 and MDA-MET are triple negative and considered to be more metastatic and drug resistant than SKBR3 which is HER2-over expressing cell line. We observed differential expression of CXCR2 and its ligands in these cells. Our observation also showed significant difference in the paclitaxel and doxorubicin-mediated inhibitory response in MDA-MB231 and MDA-MET cells as compared to SKBR3 cells. Together these studies demonstrate that manipulating CXCR2-dependent activity in malignant breast cancer cells significantly enhanced therapeutic efficacy of paclitaxel and doxorubicin.
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 5462.
Abstract 5474: Targeting endothelial tubulogenesis for anticancer therapeutic development
Authors: Roy Anshu Mittal , Zhai Ling , Wennerberg Krister , Waud William R. , Gormon Gregory S. , Coward Lori , Li Rongbao , Ananthan Subramaniam , Qu Zhican 
Published: February 2011

Abstract
The clinical successes of VEGF-targeted agents in recent years have demonstrated that antiangiogenic therapy can be developed as effective anti-cancer treatment. However, the field of oncology is facing a new challenge of overcoming the resistance to VEGF-targeted therapy; therefore, novel angiogenesis inhibitors are required for new therapeutic development. During the growth of new blood capillaries, following proliferation and migration, endothelial cells undergo morphological changes and adhere to each other forming tubular structures as a process of tubulogenesis, which presents a unique target for inhibitory action of antiangiogenic agents. Southern Research angiogenesis research team has identified a structurally related series of heterocyclic compounds SRI-24637 and its analogs as a new class of antiangiogenic agents. SRI-24637 demonstrated selective potent inhibition of endothelial tube-formation and significant activity in blocking tumor-induced blood vessel formation using an ex vivo human cancer xenograft-CAM assay model system. The mechanism of action of SRI-24637 is different from the clinical VEGF-targeted drugs; therefore, it may provide a complementary mechanism to overcome the resistance to VEGF-targeted therapies. Bioavailability studies showed that SRI-24637 dosed at 40 mg/kg in DMSO/PEG400 reached systemic concentration levels much higher than the IC50 concentration for in vitro endothelial tube-formation. Comparing with the clinical VEGF-targeted drug Sunitinib, the cytotoxic activities of SRI-24637 against normal human fibroblast and epithelial cells suggest that the toxic side effects of SRI-24637 may be within a tolerable range. Ongoing preclinical efficacy studies with animal tumor models will aid in the development of SRI-24637 as an anti-cancer drug. Based on the outcome of these studies, further lead optimization will be done if required, before entering it into the clinical Phase I and II trials using protocols similar to those employed for Sunitinib and Sorafenib, or other investigational small molecules targeting tumor angiogenesis.
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 5474.
Abstract 5477: Gefitinib enhances arsenic trioxide (AS2O3)-induced differentiation of acute promyelocytic leukemia cell line
Authors: Noh Eui-Kyu , Kim Hawk , Park Min Jae , Baek Jin Ho , Park Jae-Hoo , Cha Seung Joo , Min Young Joo 
Published: February 2011

Abstract
Gefitinib (Iressa, ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits growth, invasion and colony formation of various cancer cells. However, little is known about the effect of combination of gefitinib and arsenic trioxide (ATO) on differentiation of acute promyelocytic leukemia (APL). Therefore, we investigated whether gefitinib had any role in the ATO-induced differentiation of NB4 cells (APL cell line). Gefitinib induced the expression of differentiation markers including CD11b and CD14 in ATO-treated NB4 cells and facilitated ATO-induced morphologic changes and ROS generation. The results were evident that the combination of gefitinib and ATO could induce more effectively functional differentiation of leukemic cells to macrophage-like cells. Moreover, the extracellular-signal regulated kinase (ERK) pathway was necessary for the enhancement of gefitinib in ATO-induced differentiation, measured by CD11b and CD14 expression on NB4 cells. Therefore, our data indicated that gefitinib can play a potential role as an adjunctive differentiation agent in APL.
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 5477.
Abstract 5544: ASPM is a novel participant in DNA double-strand break repair and a potential target for radiotherapy
Authors: Fujimori Akira , Kato Takamitsu 
Published: February 2011

Abstract
Comprehensive serach for human cellular response to ionizing radiation (IR) is indispensable strategy to understand the molecular basis under tumor radiotherapy. In a previous study using HiCEP, we found that ASPM (Abnormal spindle-like microcephaly-associated) or the most common-type microcephaly (MCPH5) gene is selectively down-regulated by IR. Here we first demonstrate that down-regulation of ASPM by siRNA synergistically enhanced radiosensitivity in some immortalized human cell lines. Both constant-field gel electrophoresis and gamma-H2AX foci assay exhibited impaired DNA double-strand breaks (DSB) in the cells treated with the siRNA. Greater extent of chromosomal instability was also common in the treated cells than untreated control. Getting together, ASPM (MCPH5) is a novel participant in the DNA double-strand break repair pathways. Although roles of microcephalins (MCPH1, pericentrin, ATR) have recently been proposed on DNA damage repair and check point regulation, this is the first report on ASPM. In clinical aspects, ASPM would be a promising target for the future cancer treatment as well as a useful biomarker in the prognostic strategy.
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 5544.