bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5529: Imaging and therapy with rituximab anti-CD20 immunotherapy in an animal model of central nervous system lymphoma
Authors: Muldoon Leslie L. , Lewin Seth J. , Dosa Edit , Pagel Michael A. , Doolittle Nancy D. , Neuwelt Edward A.
Published: June 2012

Purpose: To evaluate monoclonal antibody (mAb) delivery, tumor volumetrics on magnetic resonance imaging (MRI), and efficacy in a rat model of central nervous system (CNS) lymphoma when delivery of rituximab and/or methotrexate to the brain was optimized with osmotic blood-brain barrier disruption (BBBD).

Experimental Design: Female nude rats with intracerebral human MC116 B-cell lymphoma xenografts underwent baseline MRI and were randomized into five groups (n = 6/group): 1) BBBD saline control; 2) methotrexate with BBBD; 3) rituximab with BBBD; 4) rituximab and methotrexate with BBBD; and 5) intravenous rituximab. Tumor volumes were assessed by MRI at 1 week and rats were followed for survival.

Results: BBBD increased delivery of 90Y-radiolabeled mAb in the CNS lymphoma model. Control rats showed 201 +/- 102% increase in tumor volume on MRI 1 week after entering the study and median 14 day survival (range 6-33). Tumor growth on MRI was slowed in the methotrexate treatment group, but survival time (median 7 days, range 5-12) was not different from controls. Among 17 evaluable rats treated with rituximab, 10 showed decreased tumor volume on MRI. All rituximab groups had increased survival compared to control, with a combined median of 43 days (range 20-60, P<0.001). There were no differences by route of delivery or combination with methotrexate.

Conclusions: Rituximab was effective at decreasing tumor volume and improving survival in a CNS lymphoma model, and was not affected by combination with methotrexate or by BBBD. We suggest that rituximab warrants further study in human primary CNS lymphoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2011-5529
Abstract 553: Discovery of novel TRK/FMS dual inhibitors as therapeutic candidates for pancreatic cancer
Authors: Tsai James , Zhang Jiazhong , West Brian L. , Wong Bernice , Burton Betsy , Habets Gaston , Marimuthu Adhirai , Light Emily , Powell Ben , Shellooe Rafe , Carias Heidi , Shi Songyuan , Spevak Wayne , Nguyen Hoa , Tsang Garson , Zhang Ying , Ewing Todd , Zhang Chao , Ibrahim Prabha , Bollag Gideon
Published: June 2012

Pancreatic cancer is a deadly malignancy in need of effective treatments. The most common driving oncogenes in pancreatic cancer – KRAS, p53, SMAD4, CDKN2A and CTNNB1 – historically have been difficult drug targets to modulate pharmacologically. An alternative approach could be to target regulators of tumor-stroma interactions. Pancreatic cancer invasion into neural tissue precedes tumor expansion. This perineural invasion is strongly associated with neural hypertrophy, pain and poor survival, and neurotrophins and their receptors (TRKs) are key suspects in mediating this process. At the same time, infiltrating macrophages are an additional component of the tumor microenvironment that supports tumor growth, invasion and inflammation, and the receptor for CSF-1 (FMS) is a key mediator of the function and survival of these macrophages. Both TRKs and FMS are transmembrane proteins with tyrosine kinase activities that can be inhibited with small molecule agents.

We have developed a series of TRK/FMS dual inhibitors to target cancers that exhibit both neural and inflammatory components. These compounds inhibit biochemical TRK and FMS kinases with IC50<20nM and inhibit the proliferation of BaF3 cells engineered to express active TRK and FMS with IC50<50nM. In counterscreens across a broad kinase panel, these inhibitors are highly selective against non-target kinases. The lead compounds show good oral bioavailability in pharmacokinetic tests. Utilizing the engineered BaF3-TRK and BaF3-FMS cells injected into mice as pharmacology models, the lead candidates show growth inhibition of >80% at doses of 20 mg/kg qd, and without body weight changes, showing that efficacy is not due to nonspecific toxicity. In a mouse Complete Freund's Adjuvant (CFA) model, robust efficacy was demonstrated in readouts of paw edema, thermal hyperalgesia and mechanical allodynia, showing that these compounds reduce swelling and pain. In the TRK-driven SK-N-SH xenograft model, tumor growth reduction of >50% was observed. These compounds also showed anti-tumor efficacy of >40% in an orthotopic Panc-1 (pancreatic cancer) model. Evaluation of compound effects on perineural invasion and inflammation is ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 553. doi:10.1158/1538-7445.AM2011-553
Abstract 5537: Ubiquitination of RRM1 by Ring1B (RNF2) promotes its degradation and nuclear export
Authors: Zhang Yingtao , Li Xin , Chen Zhengming , Freeman Scott , Zhou Jun , Bepler Gerold
Published: June 2012

RRM1 (ribonucleotide reductase M1) is a key enzyme involved in deoxyribonucleotide (dNTP) synthesis and DNA damage repair. It also plays a critical role in acquired resistance to the chemotherapy drug gemcitabine, which directly inhibits the RR holoenzyme. Despite its significant importance, however, the mechanisms that control RRM1 abundance and subcellular localization are unclear. We have identified a ubiquitin E3 ligase, Ring1B (RNF2), as an RRM1-associated protein in a yeast two-hybrid screen. RRM1 interacts with Ring1B both in endogenous and exogenous situations. Additionally, immunofluorescent staining has shown that Ring1B clearly co-localized with RRM1 in a pattern of diffuse nuclear speckles. We found that the protein level of RRM1 is regulated by a proteasome-mediated degradation pathway. Ring1B induces poly-ubiquitination of RRM1 in vivo. Formation of poly-ubiquitin chains on RRM1 is through both Lys48 (K48) and Lys63 (K63) of the ubiquitin. Our study demonstrates that the cytoplasmic fraction of RRM1 was increased upon Ring1B or ubiquitin overexpression, but significantly decreased after nuclear export inhibition by leptomycin B (LMB). This indicates that RRM1 ubiquitination promotes the translocation of RRM1 from the nucleus to the cytoplasm. We also show that hydrogen peroxide (H2O2) promotes the degradation of RRM1 in dose and time-dependent manners. H2O2 can increase the poly-ubiquitination of RRM1, which suggests that RRM1 ubiquitination may participate in cellular responses to oxidative stress-induced DNA damage repair. In summary, our data propose that Ring1B-induced ubiquitination regulates RRM1 activity through RRM1 degradation and nuclear export.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2011-5537
Abstract 5541: The dual effects of H6D polymorphism of NAG-1/GDF15 in prostate cancer carcinogenesis
Authors: Wang Xingya , Xu Zongli , Chrysovergis Kali , Bienstock Rachelle , Shim Minsub , Bensen Jeannette T. , Fontham Elizabeth , Smith Gary J. , Mohler James , Taylor Jack , Eling Thomas E.
Published: June 2012

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a divergent member of the transforming growth factor beta superfamily. NAG-1 has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis, in several types of cancers. Evidence from recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D (G) of the NAG-1 protein is associated with lower incidence, but higher rate of mortality, of prostate cancer. The objective of the current study was to determine the activity of the NAG-1 H6D variant in prostate cancer using two different approaches. First, DU145 cells stably transfected with the H6D NAG-1 gene, wild-type NAG-1 gene, and empty pLXIN vector were injected into nude mice subcutaneously and tumor growth monitored for eight weeks. The H6D variant was less tumorigenic than the wild-type NAG-1, and significantly inhibited tumor growth, 67% by volume and 59% by tumor weight compared to control mice. The growth inhibition by the H6D variant of NAG-1 was associated with significant reduction of serum levels of adiponectin, leptin, and IGF-1, and expression of Cyclin D1 in tumor samples. Second, we examined whether the sequence variant in the NAG-1 gene was associated with prostate cancer tumor aggressiveness in blood samples from the North Carolina-Louisiana Prostate Cancer Project (PCaP). A total of 449 Caucasians Americans and 413 African Americans were examined for allele frequencies using Taqman SNP genotyping assay. Although statistically insignificant, African Americans carrying the H6D (G) allele had an increased risk of more aggressive prostate cancer than those carrying two copies of the C allele (Odds ratio, 1.63; 95% CI, 0.903-2.95; P = 0.25). This result may help to explain the higher mortality rate of prostate cancer in African Americans. In conclusion, our data suggest that the H6D polymorphism of NAG-1 may have a dual effect during the early and late stages of prostate cancer carcinogenesis. More studies are needed to further examine the association of H6D variant of NAG-1 with prostate cancer incidence and progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2011-5541
Abstract 5546: Screening the RbBP6 gene for abnormal alternative splicing in colon cancer
Authors: Dlamini Zodwa , Mbita Zukile
Published: June 2012

Cancer arises after a series of mutations that result in uncontrolled cellular differentiation and growth. These result because the genes required for normal cell growth and apoptotic processes are abnormally regulated and thus the progression of cancer and survival is favoured. The RbBP6 gene is amongst the genes which are down-regulated in cancerous cells. RbBP6 is a gene that has been shown to regulate cell cycle control and apoptosis. RbBP6 isoform 3 has been shown to regulate G2/M cell cycle checkpoint while the alternatively spliced RbBP6 transcript 1 product has been implicated in apoptosis regulation and cancer. Expression and regulation of the gene in colon cancer was examined by amplifying cDNA of RNA extracted from three colon adenocarcinoma cell lines obtained from different stages of colon cancer, using RT-PCR with the RbBP6 exon 16 primers and confirmation of the 2 splice variants by NCBI BLAST. Two bands appeared on a 1% Agarose gel, the ratio of the intensity of the two bands was found to be 1:1 in the primary cell line compared to down-regulation in grade II cell line while these alternatively spliced products could hardly be amplified in grade III cell line. RbBP6 has two splice isoforms which are regulated by alternative splicing in colon cancer. The expression of these splice variants was found to be indirectly proportional to colon cancer progression. The primary colon cancer cell line showed more expression of these alternatively spliced products, which decreased significantly in grade II and III. This suggests that RbBP6 alternatively spliced products could be anti-carcinogenic but are de-regulated in favour of carcinogenesis and this further suggests that RbBP6 gene might be somehow involved in the development and progression of colon adenocarcinoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2011-5546
Abstract 5547: Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis
Authors: Singhal Sharad S. , Yadav Sushma , Wickramachchi Dilki , Singhal Jyotsana , Leake Kathryn , Vatsyayan Rit , Chaudhary Pankaj , Awasthi Yogesh , Awasthi Sanjay
Published: June 2012

Targeted depletion of the RALBP1 encoded 76 kDa splice variant, RLIP76, causes marked and sustained regression of human xenografts of lung, colon, prostate, and kidney cancer without toxicity in nude mouse models. We proposed that the remarkable efficacy and broad-spectrum of RLIP76-targeted therapy is because its glutathione-conjugate (GS-E) transport-activity is required for clathrin-dependent endocytosis (CDE) that regulates all ligand-receptor signaling and that RLIP76 is required not only for survival of cancer cells, but also for their very existence. We studied RLIP76 mutant proteins and the functional consequences of their expression into RLIP76−/− MEFs which identified key residues for GS-E binding in RLIP76, established the requirement of RLIP76-mediated GS-E transport for CDE and demonstrated a direct correlation between GS-E transport activities with CDE. Depletion of RLIP76 near completely blocked signaling down-stream of EGF in a CDE-dependent manner and Wnt5a signaling in a CDE-independent manner. The seminal prediction of this hypothesis, that RLIP76−/− mice will be deficient in chemical neoplasia, was confirmed. Benzo[a]pyrene, dimethylbenzanthracene and phorbol esters are ineffective in causing neoplasia in RLIP76−/−. PMA-induced skin carcinogenesis in RLIP76+/+ mouse was suppressed completely by depletion of either PKCα or RLIP76 by siRNA or antisense and could be restored by topical application of RLIP76 protein in RLIP76−/− mouse skin. Likewise, chemical pulmonary carcinogenesis was absent in female and nearly absent in male RLIP76−/− mice. In RLIP76−/− mice, p53, p38, and JNK activation did not occur in response to either carcinogen. Our findings demonstrate a fundamental role of RLIP76 in chemical carcinogenesis. (Supported in part by NIH grant CA 77495 (SA), CA 155350, Cancer Research Foundation of North Texas, and Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education (SS))

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5547. doi:10.1158/1538-7445.AM2011-5547
Abstract 555: 3D tumor models for the assessment of molecular targeted therapies
Authors: Onion David , Argent Richard H. , Kumari Rajendra , Axel Amy , Hall Brett , Watson Susan A.
Published: June 2012

It is becoming increasingly apparent that the interaction between the tumor and the surrounding stromal cells is critical to tumor growth, invasion and metastasis. These paracrine interactions can profoundly alter EMT profiles and modulate key growth factor signaling cascades which can lead to altered responsiveness to molecular targeted therapies such as EGF-R TKI inhibitors. We have developed a novel 3D tumor growth assay, where the paracrine interaction between tumor derived fibroblasts and epithelial cells are restored. Utilizing luminescent and fluorescent labeled cell populations we are able to monitor tumor-microenvironment driven tumor growth in the presence of targeted therapies in comparison to standard platinum dublet therapies. Primary tumor associated fibroblasts and mesenchymal stem cells drive growth and proliferation of non-small cell lung cancer cell lines of adenocarcinoma (A549, NCI-H358, NCI-H460) and squamous subtypes (SK-MES1, H226) as well as early stage disease (NCI-H322M). The paracrine interaction promotes 3D structure formation and invasion into laminin rich basement membrane extract. Cells grown in 3D assays show a slowed proliferation and lower sensitivity to anti-mitotic agents such as paclitaxel. As proof of concept we show that responsiveness to EGF-R TKI is significantly decreased in the presence of HGF secreting stromal cells irrespective of EGF-R and KRAS mutational status. The 3D growth assay provides a more tumor microenvironment relevant model for pre-clinical testing of molecular targeted therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 555. doi:10.1158/1538-7445.AM2011-555
Abstract 5562: High-fat diet feeding increases tumor growth and metastasis of mammary carcinoma cells in the 4T1 orthotopic BALB/c mouse model
Authors: Kim Eun Ji , Choi Mi-Ran , Park Heesook , Kim Minhee , Hong Ji Eun , Lee Jae-Yong , Park Jung Han Yoon
Published: June 2012

We previously observed that chronic consumption of a high fat-diet (HFD) increased the breast cancer-related mortality in the 4T1 orthotopic mouse breast cancer model. In the present study, we determined whether feeding mice with a HFD for a prolonged period increases solid tumor growth and metastasis of breast cancer cells using the 4T1 orthotopic model. 4-week old, female BALB/c mice were fed a purified diet containing 60 kcal% fat (HFD) or 10 kcal% fat (control diet) for a period of 16 weeks. After 16 weeks, 4T1 mammary carcinoma cells (5 × 104 cells) were injected into the inguinal mammary fat pad of syngeneic female BALB/c mice and the mice were continuously fed the same diets. Solid tumor growth was increased in the HFD group as compared to the control diet group. Additionally, chronic consumption of the HFD markedly increased the number and volume of tumor nodules in the lung and liver. The expression of cyclin-dependent kinase (CDK)2, CDK4, cyclin D1, cyclin A, Ki67, vascular endothelial growth factor, CD31 (an angiogenesis marker), and CD45 (a monocyte/macrophage marker) was markedly increased in the tumor tissues in the HFD group as compared to control diet group. The protein levels of urokinase-type plasminogen activator (uPA), intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule-1 were significantly increased but those of plasminogen activator inhibitor-1 were decreased in the lung tissues of the HFD group as compared to control diet group. The serum levels of complement fragment 5a (C5a), interleukin (IL)-6, macrophage colony stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, and triggering receptor expressed on myeloid cells (TREM)-1 were up-regulated in the HFD group as compared to control diet group. We conducted in vitro assays to determine effect of these cytokines, which had been increased in the sera of mice fed on the HFD, on the cell proliferation, adhesion, and migration of 4T1 cells. sICAM-1 increased the viability of 4T1 cells. TREM-1, M-CSF, and sICAM-1 significantly increased the migration of 4T1 cells. Additionally, the capacity of 4T1 cells to adhere to strips coated with human collagen type I was increased by C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1. These results indicate that, in addition to adhesion molecules, metalloproteases and pro-angiogenic factors, the cytokines C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 play important roles in the metastasis of mammary cancer cells in mice fed on a HFD for a prolonged period.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5562. doi:10.1158/1538-7445.AM2011-5562
Abstract 5576: Rhamnetin inhibits human prostate cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators and survival molecules
Authors: Shukla Sanjeev , Bhaskaran Natarajan , Gupta Sanjay
Published: June 2012

Development of effective agents for treatment of prostate cancer has become a national medical priority. Rhamnetin (3,5,3,4-tetrahydroxy-7-methoxyflavone), a natural compound known as O-methylated flavonol, abundantly present in cloves, sweet annie, annual wormwood, green vegetables and orchard grass has shown to possess anti-inflammatory and antioxidant properties. However, the anticancer properties of rhamnetin have not been fully elucidated. In the present study we demonstrated the molecular mechanism of cell growth inhibition and induction of apoptosis in human prostate carcinoma LNCaP and PC-3 cells by rhamnetin. Treatment of these cells with rhamnetin resulted in a dose (5, 10, 20, 40 microM) and time (24, 48 and 72 h) dependent inhibition of growth, G2-S phase arrest of the cell cycle and DNA fragmentation. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk) 2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. Rhamnetin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome-c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly (ADP-ribose) polymerase (PARP). Further, rhamnetin treatment resulted in down modulation of XIAP, survivin, and c-Myc protein expressions. Taken together, we concluded that molecular mechanisms during rhamnetin-mediated growth inhibition and induction of apoptosis in both androgen-responsive, LNCaP and androgen-refractory, PC-3 cells was due to modulation in cell-cycle machinery, disruption of mitochondrial function, and inhibition of cell survival machinery. For the first time we provide evidence that rhamnetin acts on potential molecular targets of cell cycle regulation and survival to elicit anticancer effects in prostate cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2011-5576
Abstract 5580: Simvastatin induces expression of miRNA-200a and let-7c, leading to mRNA and protein expression of E-cadherin and reduced cell migration in PC-3 cells
Authors: Liu Shuman , Li Xuesen , Liu Zhongbo , Xu Xia , Blair Christopher , Simoneau Anne , Zi Xiaolin
Published: June 2012

Simvastatin is a widely used cholesterol-lowering drug. Emerging evidence suggests that statins including simvastatin have other biological effects linked to a reduced risk of prostate cancer recurrence. We have examined the effect of simvastatin on invasive capacity of PC-3 cells, a cell line derived from a prostate cancer bone metastasis specimen. Our results showed that simvastatin treatment of PC3 cells at concentrations of 0.5 and 1 μM for 8 hours significantly increased the expression of miRNA-200a and let-7c. miRNA-200a and let-7c have been reported to be involved in epithelial to mesenchymal transition (EMT). At the same concentrations, simvastatin significantly induced the protein and mRNA expression of E-cadherin, a hallmark for EMT. In addition, simvastatin treatment of PC-3 cells caused markedly increased activities of Rho GTPases including RhoA, Cdc42 and Rac1. Collectively, these molecular events caused by simvastatin led to a significant reduction of PC-3 cell migration in a wound-healing experiment. Therefore, simvastatin exhibits a novel anti-migration activity against metastatic prostate cancer, suggesting a potential role for simvastatin in prevention of prostate cancer recurrence after prostatectomy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2011-5580
Abstract 5581: Korean Angelica gigas Nakai (AGN) and Oriental herbal cocktail ka-mi-kae-kyuk-tang (KMKKT) inhibit prostate carcinogenesis in TRAMP model
Authors: Wang Lei , Zhang Yong , Zhang Jinhui , Nkata Katai , Quealy Emily , Li Li , Lee Hyo-Jeong , Jeong Soo-Jin , Liao Joshua , Jiang Cheng , Kim Sung-Hoon , Lu Junxuan
Published: June 2012

The ka-mi-kae-kyuk-tang (KMKKT) is a formula of ten Oriental herbs containing Korean Angelica gigas Nakai (AGN) root. Previous studies by our collaborative team found that the KMKKT ethanol extract exerted anti-angiogenesis, apoptosis and anti-metastasis in vitro and in vivo (carcinogenesis 2006). We also showed that AGN extract suppressed DU-145 & PC-3 xenograft growth (Am J Chin Med 1009).

In the present study, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) spontaneous primary carcinogenesis model to establish the chemoprevention efficacy of KMKKT and AGN and to explore cellular and molecular correlates of the in vivo anti-cancer effects. Male C57BL6 TRAMP mice were given a daily gavage (5 times per wk, 5 mg/mouse) as KMKKT and AGN beginning at 8 weeks of age (1% Tween-80 as vehicle n=13; KMKKT n=14; AGN n=17). We treated wild-type littermates also with KMKKT and AGN. All mice were terminated at 24 weeks of age, unless earlier euthanasia was necessitated by large tumor size.

The results show that the genitourinary (GU) tract weight was decreased in both KMKKT (66.4%) and AGN (57.6%) treated groups compared to vehicle group (100%). The dorsal-lateral prostate (DLP) weight was significantly lower in KMKKT and AGN groups compared to control group (P=0.02), with no difference found in the wild-type mice cohorts. In TRAMP and wild-type mice that received KMKKT and AGN vs. vehicle, there is no significant difference of the body weight and main organs (liver and kidney) (P>0.05). Additionally, macroscopical prostate tumors were found 46.2% (6/13) in control group, but just 14.3% (2/14) and 17.6% (3/17) in KMKKT and AGN group (Chi-square analysis P=0.07 and P=0.09). The average tumor burden was 0.81g/mouse in control group, 0.27 and 0.12 g/mouse in KMKKT and AGN group, respectively. All these macroscopical tumors are T-antigen (+), synaptophysin(+), androgen-receptor(−) and E-cadherin(−) poorly differentiated neuro-endocrine carcinoma (NECa). Furthermore, KMKKT and AGN-treated NECa contained lower basic fibroblast growth factor (bFGF) detectable by WB, antibody array and IHC. Decursinol, the hydrolysis product of decursin and DA was detectable in the plasma of AGN-treated mice.

In summary, results from this pilot study indicate that oral administration of KMKKT and AGN may inhibit prostate primary carcinogenesis in the TRAMP model. Additional chemoprevention studies are merited. [Grant support: NCCAM 1R21AT005383, NCI R01CA136953, R01CA126880 and Korean KOSEF-MEST No. 2009-0063466].

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5581. doi:10.1158/1538-7445.AM2011-5581
Abstract 5587: Bitter melon (Momordica charantia) extract suppresses adrenocortical cancer cell proliferation and growth through modulation of the cell cycle pathway and steroidogenic activity
Authors: Brennan Victoria C. , Wang Chiung-Min , Yang Wei-Hsiung
Published: June 2012

Malignant adrenal tumors or adrenocortical carcinomas are relatively rare; however, this form of cancer is highly malignant and presents with extremely poor prognosis as a consequence of metastasis or local invasion at the time of diagnosis. One of the approaches to control cancer progression and reduce cancer risk is prevention through diet. Bitter melon is widely consumed as a vegetable and especially as a traditional medicine in China, India, Japan, and Taiwan. In this study, we have used human and mouse adrenocortical cancer cells, H295R and Y1, respectively, as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. First, we find that BME treatment of adrenocortical cancer cells results in a significant dose-dependent decrease in cell proliferation and growth. We also find that bitter melon extract has stronger anti-proliferation effect than blueberry extract on adrenocortical cancer cells. As expected, extracts from Acorn squash and Zucchini, two vegetables from the same Family of Cucurbitaceae as bitter melon, do not decrease cell proliferation in adrenocortical cancer cells. Second, apoptosis of adrenocortical cancer cells is accompanied by increased caspase activation and poly(ADP-ribose) polymerase cleavage. Further studies reveal that BME treatment enhances p53, p21, Mdm2, and ATF3 and inhibits cyclin D1, cyclin D2, cycline D3, mTOR, and JNK expression, suggesting an additional mechanism involving cell cycle regulation, cell motility, cell survival, and cell differentiation. Third, BME treatment also decreases steroidogenic activities in adrenocortical cancer cells by Western blotting and reporter gene assay. BME treatment of adrenocortical cancer cells results in a significant dose-dependent decrease in levels of NR5A1/SF1, MC2R, StAR proteins. Interestingly, we find that BME treatment decreases the level of phospho-CDK7, which is required, at least in part, for NR5A1/SF1 activation. Taken together, these data illustrate that inhibitory effect of bitter melon on the growth and proliferation of adrenocortical cancer cells through modulation of the cell cycle regulation and steroidogenic pathways. Therefore, BME can be used as a dietary supplement for prevention of adrenocortical cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5587. doi:10.1158/1538-7445.AM2011-5587
Abstract 5620: Polymorphisms in steroid hormone genes and endometrial cancer risk
Authors: Doherty Jennifer A. , Weiss Noel S. , Fish Sherianne , Fan Wenhong , Loomis Melissa M. , Rossing Mary Anne , Zhao Lue Ping , Chen Chu
Published: June 2012

The incidence of endometrial cancer is increased in the presence of elevated circulating levels of estrogens, especially when inadequately opposed by progestins. Estrogens are catabolized via catechol estrogen formation, oxidation, glucuronidation, and sulfation. Thus, it is possible that interindividual variation in these pathways might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 26 SNPs in the genes CYP17, CYP1A1, CYP1B1, CYP3A4, CYP3A5, COMT, SULT1A1, UGT1A1, UGT1A8, UGT2B4, UGT2B7, and UGT2B15 was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 727 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age, county and reference year. Analyses were restricted to non-Hispanic white women and adjusted for frequency matching variables. Only SNPs in CYP1A1 (involved in the formation of 2-hydroxyestrogens) and SULT1A1 (involved in estrogen sulfation) were associated with endometrial cancer risk. The CYP1A1 rs4646903 C allele was associated with a decreased risk of endometrial cancer (per C allele odds ratio (OR) 0.75, 95% confidence interval (CI) 0.58-0.95; ORs and 95% CIs for CT and CC vs TT were, respectively: 0.81, 0.61-1.07, and 0.38, 0.15-0.93). The SULT1A1 rs9282861 A allele was associated with increased risk of endometrial cancer (per A allele OR 1.22, 95% CI 1.04-1.42; ORs and 95% CIs for AG and AA vs GG were, respectively: 1.20, 0.96-1.50, and 1.50, 1.06-2.12). Both of these polymorphisms have been reported to be associated with alterations in the ability to metabolize estrogens; the CYP1A1 rs4646903 C allele may be associated with increased inducibility and increased endometrial expression of CYP1A1, and therefore could be associated with potentially higher levels of the 2-hydroxyestrogens in the target tissue. The SULT1A1 rs9282861 A allele is associated with reduced sulfotransferase activity, which could possibly allow the accumulation of estrogens. Thus, the observed associations with each SNP are consistent with their putative biologic function. However, several studies have examined variation in these and other genes in the steroid hormone metabolism pathways and endometrial cancer risk, and there are reports of both positive and negative findings for many of the SNPs studied. If a small effect size is expected, then additional studies and pooled analyses are needed to clarify possible associations with each of these polymorphisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5620. doi:10.1158/1538-7445.AM2011-5620
Abstract 579: Cell death induction end-points to identify new cancer indications with high likelihood of response to dual PI3K /mTOR inhibitors
Authors: Huang Alan , Lehar Joseph , Pradhan Elina , Tomaso Emmanuelle Di , Villarroel Maria , Hackl Wolfgang , Quadt Cornelia , Fritsch Christine , Weiss Andreas , Brachmann Saskia , Schlegel Robert , Hofmann Francesco , Maira Michel
Published: June 2012

Constitutive activation of the PI3K pathway is driven by a variety of genetic and epigenetic abnormalities, such as PTEN deletions, mutations, genesilencing, PIK3CA mutations and/or enhanced engagement through genetic abnormalities in upstream RTKs. Targeted therapies against specific components of the PI3K pathway are therefore expected to produce positive outcome as single agents or in combination in cancers presenting these abnormalities. Two molecular entities are in full clinical development: NVP-BEZ235, a dual PI3K/mTOR inhibitor and NVP-BKM120, a pan-class I PI3K inhibitor without mTOR activity. In order to best position these agents clinically, we investigated their efficacy in models bearing PIK3CA, PTEN, HER2, or KRAS genetic alterations.

We previously demonstrated that NVP-BEZ235 in in vitro antiproferative activity was not predictive of preclinical antitumor response, in vivo. However, breast cancer models presenting either HER2 amplification or PIK3CA mutations or both were shown to be very sensitive to the compound and the use of cell death induction as an end-point was found to be predictive of strong antitumor activity in vivo. To further validate this finding, dual PI3K/mTOR targeting was phenocopied using an mTOR shRNA inducible system or an mTOR specific inhibitor (AZD8055) in combination with a pan-PI3K inhibitor, in various tumor models. Strong cell death signals were observed in 2 HER2 amplified / PIK3CA mutant breast cancer models but not in KRAS mutant cells or as PTEN silenced breast cancer cell lines, when subjected of PI3K/mTOR targeting. Moreover, in vivo, combination of a pure pan-PI3K with a pure mTOR inhibitor resulted in strong regression of HER2 amplified /PIK3CA mutant MDA-MB361 tumors.On the basis of these observations, NVP-BEZ235 was retested in a set of more then 150 tumor lines across various lineages, and cell death induction was determined. As expected, HER2 amplified /PIK3CA mutant breast cancer lines scored as sensitive. Other models from different indications and genetic background were also found to be sensitive to NVP-BEZ235. Validation studies of these new models and potential indications will be presented, and implications for further clinical trials of dual PI3K/mTOR or pure PI3K inhibitors discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 579. doi:10.1158/1538-7445.AM2011-579
Abstract 590: Antiproliferative effects and signaling profiles of the novel HSP90 inhibitor NVP-AUY922 in non-small cell lung cancer
Authors: Ueno Tsuyoshi , Toyooka Shinichi , Tsukuda Kazunori , Munenori Takaoka , Soh Junichi , Maki Yuho , Muraoka Takayuki , Tanaka Norimitsu , Asano Hiroaki , Yamane Masaomi , Oto Takahiro , Kiura Katsuyuki , Naomoto Yoshio , Miyoshi Shinichiro
Published: June 2012

Background; Gefitinib and erlotinib, which have been designed to inhibit tyrosine kinase of epidermal growth factor receptor (EGFR), showed drastic anti-tumor effect on NSCLCs with common EGFR mutations, but acquired resistance is a major problem to failure this treatment. Heat shock protein (HSP) 90 inhibitors have been developed as promising anti-cancer agents, because HSP90, a molecular chaperone, plays a pivotal role in NSCLC survival as it stabilizes a large set of client proteins, many of which are important for tumor cell survival and proliferation. In this study, we examined “NVP-AUY922,” a new HSP90 inhibitor, and showed its effects against NSCLCs.

Methods: We used 24 NSCLC cell lines with specific genetic alterations, which are K-ras mutation, B-raf mutation and EGFR mutation. Cell proliferation was determined by modified MTS assay. The expressions of client proteins were assessed by Western Blotting.

Results: NVP-AUY922 exhibited strong antiproliferative effects to most NSCLC cell lines, except H1395 and Calu3. One of resistant cells is a B-raf mutator and another has no specific genetic alterations, but NSCLCs with EGFR mutations were sensitive. The average IC50 of NVP-AUY922 in sensitive cells was 18.7 + 8.32 nM. In most cell lines, higher depletion of both total and phosphorylated client proteins such as MET, HER2, EGFR and AKT, were shown by NVP-AUY922 treatment with higher concentration. But in Calu3, a resistant cell line, they did not decrease in lower concentration. MET, HER2 and EGFR were suppressed for whole duration tested, while the expression of AKT was depleted for 48 hours and then recovered at 72 hours after treatment. The client protein of H1395 decreased in lower concentration and the cause of resistance to NVP-AUY922 has been unknown so far.

Conclusions; NVP-AUY922 was effective to most NSCLC cell lines at low concentration and suggested to be a promising new drug of NSCLCs, even those resistant to EGFR-TKIs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 590. doi:10.1158/1538-7445.AM2011-590
Abstract 595: E-3810 antitumor activity in human xenografts expressing different levels of FGF receptor 1
Authors: Colella Gennaro , Damia Giovanna , D'Incalci Maurizio , Cereda Roberta , Peitz Ingmar , Kelter Gerhard , Cavalletti Ennio , Spinelli Silvano , Camboni Gabriella
Published: June 2012

E-3810 is a novel small molecule that selectively inhibits VEGF receptor-1, -2 and -3 and FGF receptor-1 (FGFR-1) tyrosine kinases currently undergoing a Phase 1 clinical trial in Europe. We have previously shown that the compound has strong anti-angiogenic effects in vivo and displays potent activity in all the human xenograft models in which it has been tested. We have also recently demonstrated that interference with FGF/FGFR pathway could result in a higher drug cytotoxic activity in those cell lines whose growth in vitro was dependent on the pathway. In order to corroborate these findings in an in vivo setting, a panel of human xenografts characterized by different expression of FGFR-1and FGF2 ligand is being screened for the response to E-3810 given at its optimal dose (20 mg/kg per os daily). Athymic female mice were transplanted s.c. with the different human xenografts and, when tumor masses reached the size of 80-120 mg, were randomized to receive vehicle or E-3810 for 14 days. Results are available for 7 models (see table reported below).

All the selected tumors displayed similar growth rates, except for RXF_486 that grew more slowly. Tumor growth resumed upon drug withdrawal, at a rate seemingly higher where FGFR-1 was highly expressed. These preliminary results confirm the strong activity of E-3810 in a large panel of tumours, with growth control and, sometimes, regressions. Studies are ongoing to enlarge the panel of models and to confirm the observed trend suggesting a somewhat higher sensitivity to E-3810 in tumors expressing higher FGFR-1 and\or FGF ligand.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 595. doi:10.1158/1538-7445.AM2011-595
Abstract 596: ABCG2 is upregulated in SN-38 resistant colorectal cancer cells
Authors: Costich Tara L. , Sill Kevin , Rios-Doria Jonathan
Published: June 2012

Irinotecan, a member of the camptothecin chemotherapeutic drug family, is a first and second line therapy for patients with colorectal cancer. However, as with most chemotherapeutic therapies, patients’ tumors eventually develop drug resistance. Therefore, identifying mechanisms of chemotherapeutic resistance will allow for the development of additional molecular therapeutic targets. In this study SN-38, the highly insoluble active metabolite of irinotecan, was used to investigate corollary resistance to irinotecan. SN-38 resistant HT-29 cells were generated and compared to parental untreated HT-29 cells. Cells were characterized following treatment with either DMSO soulubilized SN-38 or IVECT encapsulated SN-38, a triblock copolymer micelle, in aqueous solution. The ATP-binding cassette transmembrane transporter protein, ABCG2, was found to have more than 40-fold expression in the SN-38 resistant HT-29 cells compared to the parental line. The increased expression of ABCG2 protein correlated with increased resistance to SN-38 in HT-29 cells and also with increased cell efflux. Cytotoxicity studies demonstrated that SN-38 resistant HT-29 cells were affected in a similar manner by IVECT polymer encapsulated SN-38 micelles and DMSO dissolved free SN-38. Cell cycle analysis showed that SN-38 resistant cells had an abrogated S phase arrest compared to parental cells. Cell treatment with free SN-38 was limited by its solubility in addition to DMSO toxicity. Further, IVECT polymer encapsulation improved SN-38 aqueous solubility allowing for increased concentration administration. Efflux proteins such as ABCG2 have been found to be upregulated in numerous types of cancers by several classes of chemotherapeutic drugs. Since transporter proteins have an important role in cell efflux, ABCG2 overexpression could serve as an additional target for pharmacological modulation. Finally, the increased solubility of SN-38 by IVECT polymer encapsulation allows for potential in vivo clinical applications of SN-38, a molecule that is 1000 times more active than its prodrug irinotecan.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 596. doi:10.1158/1538-7445.AM2011-596
Abstract 603: Overexpression of G protein-coupled receptor kinase 2 in hepatocellular carcinoma cells suppresses proliferation by inducing G2/M phase arrest
Authors: Wei Zhengyu , Hurtt Reginald , Doria Cataldo
Published: June 2012

G protein-coupled receptor kinase 2 (GRK2) was originally identified as a key player in G protein-coupled receptors desensitization. A growing body of evidence has demonstrated that GRK2 may have broader ‘effector” functions by interacting with a variety of non-receptor signaling proteins and involves in the regulation of many cellular processes such as proliferation, cell cycle progression and migration. In this study, we investigated the role of GRK2 in human hepatocellular carcinoma (HCC) cells. We screened five HCC cell lines and found that Huh7 and Mahlavu had the highest and lowest of basal GRK2 expression levels respectively. We then overexpressed wild type (WT) GRK2 and its kinase-dead mutant (K220R) in these two HCC cells using recombinant adenoviruses. We found that only WT GRK2 overexpression but not the K220R mutant overexpression significantly reduced cell viability. We thus performed BrdU incorporation assay and found that only WT GRK2 overexpression reduced cell proliferation. We further examined this anti-proliferative function by propidium iodide staining to analyze cell cycle progression. Our data showed that enhanced WT GRK2 induced cell cycle arrest at G2/M phase, from 21.4% to 41.8% in Huh7 and 25.9% to 48.4% in Mahlavu, respectively. Furthermore, our western blotting results showed that overexpression of GRK2 induced the up-regulation of p53 (Ser15) phosphorylation and Cyclin B1 in a dose dependent manner. Our results indicated that overexpression of GRK2 had a profound suppressive effects on HCC cell growth and suggested that gene transfer of GRK2 may open a new therapeutic option for the treatment of human HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 603. doi:10.1158/1538-7445.AM2011-603