bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2478: Early and enhanced development of N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic adenocarcinomas by high-fat diet
Authors: Takahashi Mami , Hori Mika , Kitahashi Tsukasa , Imai Toshio , Ishigamori Rikako , Takasu Shinji , Mutoh Michihiro , Sugimura Takashi , Wakabayashi Keiji 
Published: February 2011

Abstract
Epidemiologically, obesity is associated with pancreatic cancer risk, but the mechanisms of obesity-associated carcinogenesis have not yet been clearly understood. Hypertrophic white adipose tissues secrete many adipokines and inflammatory factors, which are expected to enhance cancer development. Syrian golden hamsters, which are used in pancreatic carcinogenesis studies, are in a hyperlipidemic state even under normal diet conditions. We previously have shown that pioglitazone, a PPAR γ ligand, improves hyperlipidemia and suppresses N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic ductal carcinoma development. In the present study, effects of a high-fat diet (HFD) on hyperlipidemia and pancreatic carcinogenesis in BOP-treated hamsters were examined. Six-week-old female Syrian golden hamsters were subcutaneously injected with BOP (10 mg/kg body weight) four times in a week and from 8 weeks of age, the animals in the HFD groups were fed Quick Fat Diet (CLEA Japan, crude fat 14.3 %) for 6 or 17 weeks. At 14 weeks of age, serum levels of triglycerides, total cholesterol, free fatty acids and leptin were significantly elevated in hamsters fed the HFD, and pancreatic ductal adenocarcinomas were already observed in the BOP + HFD group. Pancreatic fatty infiltration was observed to increase in BOP-treated and HFD-fed hamsters. At 25 weeks of age, serum levels of total cholesterol and free fatty acids were further increased in each group and pancreatic ductal adenocarcinomas developed both in the BOP + standard diet group and BOP + HFD group. The numbers of dysplasia and adenocarcinomas in the pancreas were significantly higher in the BOP + HFD group than in the BOP + standard diet group. Apparent fatty infiltration was observed in relatively large adenocarcinomas in the BOP + HFD group. In conclusion, the HFD aggravated the hyperlipidemia, shortened the latency periods of cancer and increased numbers of BOP-induced pancreatic precancerous lesions and adenocarcinomas. Fatty infiltration was apparent in the pancreas of the HFD group and may be associated with pancreatic cancer development in hamsters.
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 2478.
Abstract 2490: The flavonoid quercetin interferes with the activity of anti-microtubule drugs
Authors: Samuel Temesgen , Fadlalla Khalda , Turner Timothy , Yehualaeshet Teshome 
Published: February 2011

Abstract
Dietary compounds with anticancer properties such as polyphenols are intensively studied for their chemopreventive or therapeutic potentials. Quercetin is a polyphenolic flavonoid with anticancer properties and is abundantly available in fruits and green vegetables. In this study, we examined the effects of quercetin on the cell cycle, viability and proliferation of colorectal and prostate cancer cells, either singly or in combination with the microtubule targeting drugs taxol or nocodazole. Quercetin inhibited cell proliferation in a dose dependent manner in both HCT116 colorectal and PPC1 prostate cancer cells. However, unexpectedly, combination treatment of the cells with 50µM or lower quercetin and taxol or nocodazole neutralized the ability of both drugs to induce G2/M arrest and to decrease cell viability. BrdU incorporation was inhibited by quercetin or quercetin-drug combination treatment of cells, but the microtubule targeting of taxol or nocodazole was not inhibited. Moreover, colony formation by both wild type and p53-null HCT116 colorectal cancer cells was inhibited by the same dose of quercetin that neutralized G2/M arrest by Taxol and nocodazole, suggesting a p53-independent effect. We conclude that while quercetin by itself may reduce cell proliferation and survival, in the short-term, the interference of quercetin with cell cycle progression diminishes the ability of taxol and nocodazole to arrest cells at G2/M. Our study adds microtubule targeting drugs to the list of anticancer drugs the activity of which might be antagonized by flavonoids such as quercetin. Further studies are needed to examine the mechanisms of interactions between anticancer drugs and polyphenolic dietary components or supplements, and how these interactions may influence outcomes of cancer therapy, survivorship or recurrence.
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 2490.
Abstract 2494: A non-covalent binding platinum drug, TriplatinNC, induces a G1 phase cell cycle arrest and p53-independent mechanisms of apoptosis
Authors: Kabolizadeh Peyman , Kipping Ralph , Menon Vijay , Ryan John , Peterson Erica , Povirk Lawrence , Farrell Nicholas 
Published: February 2011

Abstract
TriplatinNC, is a novel trinuclear derivative of the Phase II clinical drug, BBR3464. The binding to DNA is through non-covalent (hydrogen bonding and electrostatic) interactions. The absence of substation-labile leaving groups results in insensitivity to glutathione concentration in vitro while the high (8+) charge results in enhanced cellular accumulation compared to BBR3464 and especially cisplatin. The antitumor activity of TriplatinNC was examined in vivo showing higher activity against 2008 ovarian carcinoma cells than c-DDP at the doses administered. Studies using HCT116 colon carcinoma cells have shown that TriplatinNC is cytotoxic in the presence and absence of p53. Cell cycle studies show that TriplatinNC differs from BBR3464 in inducing a G1 arrest rather than a G2 arrest in HCT116 cells. A p53-independent activation of caspase 8 and caspase 9 leading to the cleavage of caspase 3 and its downstream substrate, PARP-1, may indicate that TriplatinNC induces both intrinsic and extrinsic pathways of cell death. Our study illustrates fundamental differences in the mechanisms of action between non-covalent binding drugs like TriplatinNC and related covalent binding drugs such as c-DDP, oxaliplatin, and BBR3464.
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 2494.
Abstract 2498: BNC105 is a tubulin polymerization inhibitor that exhibits vascular disruptive activity in renal cancer and causes upregulation in HIF1alpha, HIF2alpha and mTOR
Authors: Leske Annabell F. , Beaumont Donna M. , Lavranos Tina C. , Gasic Jelena , Coles Carolyn J. , Matthews Clayton A. , Phillips Renee J. , Kremmidiotis Gabriel 
Published: February 2011

Abstract
BNC105 is a tubulin polymerization inhibitor. This agent selectively disrupts the vasculature in tumors, and in addition acts as a direct cytotoxic against cancer cells. BNC105 has demonstrated single agent efficacy in a number of cell lines and tumor models, including breast, colon, prostate, brain and lung cancer. We have investigated the activity of BNC105 in renal cancer cell lines and renal tumor xenografts. BNC105 exhibits cytotoxic activity with EC50 values in the range of 1-20nM. A number of other chemotherapeutic and targeted agents exhibit activity that is comparable or considerably lower than BNC105. Furthermore, we investigated the activity of BNC105 in disrupting the vasculature of tumors arising from human renal cancer cell lines. Our investigations included the renal cell lines Caki-1 and A498. Caki-1 cells express the wild type of the VHL gene, whereas A498 cells expresses a non-functional mutant form of VHL. In addition A498 cells do not express HIF1alpha. Somatic mutation of the VHL gene is the most frequent genetic alteration observed in renal cell carcinoma leading to inappropriate accumulation of HIF1alpha and HIF2alpha. Single dose BNC105 treatment of mice bearing tumor xenografts arising from these cell lines resulted in substantial tumor vascular disruption giving rise to large areas of tumor necrosis. Immunohistochemistry analysis revealed that expression of HIF1alpha was dramatically increased following BNC105 treatment in tumors arising from the renal cell line Caki-1. HIF1alpha expression in A498 tumors was restricted to endothelial cells and did not change following BNC105 treatment. HIF2alpha expression was found to be upregulated in cells surrounding areas of BNC105 induced necrosis in both Caki-1 and A498 tumors. These findings suggest that vascular disruption and necrosis caused by BNC105 lead to an angiogenic rebound effect that may contribute to tumor recovery from the vascular disruption insult. Given the key role of mTOR signaling in upregulation of HIF we examined the expression of phosphorylated mTOR in renal tumor xenografts following treatment with BNC105. Expression of phosphorylated mTOR was distinctly upregulated in viable cell zones surrounding tumor VDA-induced necrotic areas in both Caki-1 and A498 tumors. These findings suggest that tumor recovery from the necrotic insult of BNC105 is mediated through upregulation of mTOR activity. The potential benefit of combining BNC105 with mTOR inhibitors on the growth of renal tumors is currently being investigated.
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 2498.
Abstract 2501: Rapamycin inhibits epidermal cell proliferation in a xenograft model of tuberous sclerosis skin tumors
Authors: Li Shaowei , Thangapazham Rajesh , Wang Ji-an , Rajesh Sangeetha , Moss Joel , Darling Thomas N. 
Published: February 2011

Abstract
Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors of the skin that have increased dermal fibroblast-like cells and a thickened epidermis. Our previous studies indicate that dermal cells are neoplastic, showing loss of TSC1/TSC2 function and activation of signaling through the mTORC1 pathway, and that overlying epidermal keratinocytes are reactive. The goals of this study were to determine whether TSC skin tumor cells induce epidermal changes and to assess the potential utility and mechanism of action of rapamycin, an mTORC1 inhibitor. TSC2-null skin tumor cells or fibroblasts from patient normal-appearing skin were incorporated into collagen gels overlaid with normal human neonatal keratinocytes, and these constructs were grafted to the backs of nude mice. Mice grafted with TSC tumor cells (n=27) or TSC normal fibroblasts (n=23) received rapamycin (2 mg/kg) (n=24) or an equal volume of vehicle (n=26) by intraperitoneal injection on alternate days for 12 weeks beginning 5 weeks after grafting. Mice were sacrificed 24 hours after the last injection for analysis of the grafts by immunohistochemistry. Grafts containing TSC tumor cells showed greater activation of the mTORC1 signaling pathway than grafts with normal fibroblasts, as shown by greater numbers of dermal cells staining for phosphorylated ribosomal protein S6 (p-S6). Xenografted epidermis overlying TSC tumor cells also showed stronger p-S6 staining than epidermis overlying TSC fibroblasts, replicating what we had observed in TSC skin tumors. Rapamycin treatment of tumor xenografts dramatically inhibited p-S6 staining in both epidermal and dermal cells. Tumor xenografts showed greater epidermal cell proliferation (as determined by staining with anti-Ki-67 specific antibody) than normal xenografts (p=0.009). Rapamycin treatment decreased the number of Ki-67 positive epidermal cells in grafts containing TSC tumor cells (p=0.046) but not in grafts with TSC normal fibroblasts. These results indicate that TSC tumor cells stimulate mTORC1 signaling and proliferation of overlying epidermal cells, and suggest that one of rapamycin effects on TSC skin tumors is through decreasing epidermal cell proliferation.
This work was supported by an Idea Development Award (TS080064) from the Congressionally Directed Medical Research Program to Dr. Darling. Dr. Moss was supported by the Intramural Research Program, NIH, NHLBI.
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 2501.
Abstract 2505: Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells
Authors: Takezawa Ken , Okamoto Isamu , Yonesaka Kimio , Yamada Yuki , Hatashita Erina , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: February 2011

Abstract
Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non-small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G1 arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G1 arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G1 arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G1 arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G1 arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS.
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 2505.
Abstract 2506: Palomid 529, a PI3K/Akt/mTOR dual TORC1/2 inhibitor, is a radiosensitizer with effect in both subcutaneous and orthotopic U251 glioblastoma tumor xenograft models
Authors: Cerna David , Carter Donna , Flaherty Siobhan , Cao Liang , Sherris David , Yoo Stephen S. 
Published: February 2011

Abstract
Palomid 529 (P529) is a small molecule drug created through three generations of computational design. P529 is an anti-tumor agent able to target and inhibit the PI3K/Akt/mTOR signal transduction pathway, specifically as an allosteric dual TORC1/TORC2 inhibitor causing the dissociation of the TORC complexes. Furthermore, P529 has been shown to broadly inhibit cell lines of the NCI 60 cell screen, inhibit HIF-1α, and show tumor growth delay in murine tumor xenograft models. P529 is able to cross the blood-brain barrier and show little or no effect of two transporters (P-gp and Bcrp1) in brain uptake of P529. Here we show that P529 has a more than additive radiation sensitizing activity inhibiting tumor growth in U251 glioblastoma tumor xenograft models both subcutaneous and orthotopic. P529 was administered in a dose-dependent manner at 25, 50 and 95 mg/kg oral dosing every day for 5 days with 4 Gy radiation given on day three. Tumor xenografts in both subcutaneous and orthotopic models were evaluated daily for tumor size or survival respectively up to 40 days post tumor implantation. P529 treatment alone showed marked decrease in tumor growth (subcutaneous) and increase in survival (orthotopic). With addition of radiation, there was a synergistic increase in activity of P529 on the inhibition of U251 tumor growth and survival. All in all, work described here provides evidence that P529 has activity as a radiosensitizer in murine models of glioblastoma and the possibility of efficacious activity in treatment of human patients under a novel mechanism of inhibition of the PI3K/Akt/mTOR pathway.
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 2506.
Abstract 2509: CDDO-Im induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells
Authors: Kim Eun-Hee , Sporn Michael B. , Liby Karen T. 
Published: February 2011

Abstract
The breast cancer-associated gene 1 (BRCA1) is the most frequently mutated tumor suppressor gene in familial breast cancers. BRCA1 mutations also predispose to other types of cancers, pointing to a fundamental role of this pathway in tumor suppression. BRCA1 plays important roles in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole (CDDO-Im) is a promising anticancer agent with potent anti-proliferative and apoptotic activities against a wide variety of cancer types. However the mechanisms responsible for the selective apoptotic effects of CDDO-Im in cancer cells remain elusive. In the present work, treatment of BRCA1-mutated mammary tumor cells with CCDO-Im (0.3-1 μM) led to apoptosis as characterized by decreased thymidine incorporation, increased annexin V-binding, and cleavage of PARP and caspases-3. In addition, 0.3 μM CDDO-Im treatment depleted the G1 population of cells, which was accompanied by an accumulation of cells at G2 phase. CDDO-Im also activated the DNA damage response by inducing the phosphorylation of Chk1/2 and the up-regulation of p21, prior to the induction of apoptosis in BRCA1-mutated cancer cells. The inhibition of Chk1 by UCN-01, a Chk1 inhibitor abrogated G2/M arrest induced by CDDO-Im. To investigate how CDDO-Im activates the DNA damage response in BRCA1-mutated breast cancer cells, we performed a comet assay and Western Blot for γH2AX, a marker of DNA damage. CDDO-Im induced DNA damage and the phosphorylation of H2AX in BRCA1-mutated mammary tumor cells. Pretreatment with 0.3 μM CDDO-Im sensitized BRCA1-mutated cancer cells to carboplatin, a DNA-damaging agent, suggesting that CDDO-Im potentiates the effect of this drug. Moreover, CDDO-Im also induced reactive oxygen species (ROS) generation in these tumor cells, which is associated with the induction of DNA damage. The inhibition of ROS generation by uric acid prevented CDDO-Im-induced DNA damage. Furthermore, treatment with CDDO-Im was not cytotoxic to normal mouse 3T3 fibroblasts, highlighting a selective therapeutic potential of CDDO-Im for BRCA1-associated breast cancer. Taken together, our results demonstrate that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest and finally apoptosis in Brca1-mutated cancer cells. These findings are being explored in vivo to determine whether CDDO-Im could be used therapeutically for BRCA1-associated breast cancer.
This study was supported by Breast Cancer Research Foundation.
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 2509.
Abstract 2516: Antitumor effects of TAK-733, a novel MEK1/2 inhibitor, against mesothelioma cells
Authors: Miyake Hiroshi , Tsuchiya Shuntarou , Hoshino Takashi , Hori Akira , Vincent Patrick W. 
Published: February 2011

Abstract
Malignant mesothelioma (MM) is a highly aggressive tumor characterized by local invasion of the pleura and metastasis, and is regarded as an almost incurable cancer with increasing incidence worldwide. Various cytokines and growth factors are reported to play important roles in the physiology of MM, possibly through MEK/ERK cascade. Thus, antitumor effects of TAK-733, a highly potent, selective, and non-ATP competitive inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), were investigated against MM cell lines, NCI-H226, MSTO-211H, NCI-H2052, NCI-H2452, and NCI-H28 harboring wild-type KRAS and BRAF and display moderate levels of basal ERK phosphorylation.
TAK-733 completely inhibited the ERK phosphorylation of 5 mesothelioma cell lines at 1-10 nM. TAK-733 also inhibited the proliferation of these cell lines in a dose dependent manner (IC50 = 4.9-240 nM). Treatment with TAK-733 clearly induced G1 cell cycle arrest with cyclin D1 down regulation and without up regulation of cleaved PARP in NCI-H226 and MSTO-211H cells. Once daily, oral administration of 1, 3, and 10 mg/kg TAK-733 potently inhibited the tumor growth of MSTO-211H xenograft in nude mice with T/C values of 31, 8, and −4% (T/C: treated per control on tumor volume growth over treatment period), respectively, with good tolerability. TAK-733 also showed potent antitumor activities against NCI-H226 and NCI-H2052 xenografts. Additionally, in an intrapleural MSTO-211H xenograft nude mouse model, daily oral administration of 3 and 10 mg/kg TAK-733 for 14 days significantly increased survival. These results demonstrate that TAK-733 is useful for the treatment of malignant mesothelioma with an activate MEK-ERK pathway.
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 2516.