ognizant Communication Corporation

ONCOLOGY RESEARCH
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS

ABSTRACTS
VOLUME 17, NUMBER 1

Oncology Research, Vol. 17, pp. 1-9
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Hyperinduction of Wnt Activity: A New Paradigm for the Treatment of Colorectal Cancer?

Michael Bordonaro,1 Darina L. Lazarova,2 and Alan C. Sartorelli1

1Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
2Howard Hughes Medical Institute, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06519, USA

Constitutive canonical Wnt signaling, resulting from mutations in the adenomatous polyposis coli (APC), beta-catenin, or axin genes, has been implicated in the initiation of most human colorectal cancers (CRCs). Some of the proposed approaches for CRC prevention and treatment involve the downregulation of canonical Wnt activity in an attempt to inhibit proliferation and promote apoptosis of the neoplastic cells. However, a number of studies have shown an association between high levels of canonical Wnt transcriptional activity and apoptosis. This relationship is also supported by the "just right hypothesis" for CRC formation where, in CRC patients, a selection for APC mutations occurs that results in a moderate level of canonical Wnt signaling and mutations leading to high levels of Wnt signaling are selected against, presumably due to apoptosis. In comparative studies of 10 human CRC cell lines, we found that inhibitors of histone deacetylases (HDACis), one of which is used clinically, promote apoptosis of CRC cells, at least partially by hyperinduction of canonical Wnt signaling. Based upon these findings, we propose a new paradigm for the activity of HDACis in the prevention and treatment of CRCs and other Wnt signaling-positive cancers. Herein, we review the evidence for the relationship between hyper-induced canonical Wnt activity and enhanced apoptosis in HDACi-treated CRC cells, discussing the implications of this relationship for cancer prevention and treatment, and pointing out the possible caveats of treating these tumors with HDACis.

Key words: Colorectal cancer; Wnt; Histone deacetylase inhibitors; Butyrate; Apoptosis; Beta-catenin

Address correspondence to Michael Bordonaro, Department of Pharmacology and Developmental Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, SHM B221, PO Box 208066, New Haven, CT 06520, USA. Tel: 1-203-785-4390; Fax: 1-203-785-2494; E-mail: michael.bordonaro@yale.edu




Oncology Research, Vol. 17, pp. 11-21
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Epoxyquinol B Shows Antiangiogenic and Antitumor Effects by Inhibiting VEGFR2, EGFR, FGFR, and PDGFR

Hiroshi Kamiyama,1,2 Hideaki Kakeya,2* Takeo Usui,2,3 Kiyohiro Nishikawa,4 Mitsuru Shoji,5** Yujiro Hayashi,5 and Hiroyuki Osada1,2

1Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
2Antibiotics Laboratory, RIKEN Discovery Research Institute, Saitama 351-0198, Japan
3Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan
4Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo 115-8588, Japan
5Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Tokyo 162-8601, Japan

Angiogenesis is the development of new blood vessels to provide oxygen and nutrients and is indispensable for solid tumor growth. Therefore, the inhibition of angiogenesis is an important modality for cancer chemotherapy. Here we report the antiangiogenic mechanism and antitumor effects of epoxyquinol B (EPQB), which was isolated from fungal metabolites. Short-term treatment of EPQB resulted in the reduction of tumor growth and the number of blood vessels directed to the tumor in a murine xenografts model. Furthermore, EPQB inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation in human umbilical vein endothelial cells (HUVECs) without cytotoxicity. VEGF-stimulated phosphorylation of VEGF receptor 2 (VEGFR2), phospholipase Cg-1 (PLCg1), and p44/42 MAP kinases (ERK) was inhibited by EPQB in a dose-dependent manner, and in vitro assay using kinase domain of VEGFR2 showed that EPQB covalently bound and inhibited the VEGFR2 kinase. Its binding site on VEGFR2 was different from SU5614, a well-known VEGFR2 kinase inhibitor. Interestingly, EPQB inhibited growth factor-induced activation of not only VEGFR2 but also epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR), suggesting that EPQB is a novel multiple kinase inhibitor. These findings suggest that EPQB would be a good lead compound for the development of potent antiangiogenic and antitumor drugs.

Key words: Antiangiogenesis; Antitumor; Epoxyquinoid; Vascular endothelial growth factor (VEGF)

Address correspondence to Hiroyuki Osada, Antibiotics Laboratory, RIKEN Discovery Research Institute, Wako, Saitama 351-0198, Japan. Tel: +81-48-467-9541; Fax: +81-48-462-4669; E-mail: hisyo@riken.jp

*Present address: Department of System Chemotherapy, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
**Present address: Department of Chemistry, Graduate School of Science, Tohoku University 6-3 Aramaki-Aza, Aoba, Sendai 980-8578, Japan.




Oncology Research, Vol. 17, pp. 23-32
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Hepatocyte Growth Factor Promotes Cell Survival by Phosphorylation of BAD in Gastric Cancer Cells

Kyung Hee Lee,1 Eun Young Choi,1 Min Kyoung Kim,1 Myung Soo Hyun,1 Jong Ryul Eun,2 Byung Ik Jang,2 Tae Nyeun Kim,2 Sang Woon Kim,3 Sun Kyo Song,3 Jung Hye Kim,4 and Jae-Ryong Kim4,5

1Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea
2Department of Gastroenterology, College of Medicine, Yeungnam University, Daegu, Korea
3Department of Surgery, College of Medicine, Yeungnam University, Daegu, Korea
4Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, Korea 5Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Korea

Hepatocyte growth factor (HGF) is one of the survival factors with a potent ability to promote cell survival by inhibiting apoptosis. However, the mechanism by which HGF inhibits apoptosis is not completely understood. To explore the genes associated with stomach cancer cell survival by HGF, we used cDNA microarray technology and selected 26 genes up- or downregulated in NUGC-3 cells during HGF treatment. Among them, BAD was confirmed to be upregulated at the RNA and protein levels by HGF treatment. We investigated the effect of BAD induced by HGF on cell survival. HGF treatment inhibited apoptosis induced by BAD overexpression and enhanced BAD phosphorylation. Pretreatment of NUGC-3 cells with PI3K inhibitors, LY 294002, decreased HGF-induced BAD phosphorylation on Ser136 whereas an MEK inhibitor, PD 98059, decreased BAD phosphorylation on Ser112. In conclusion, increases in BAD levels as well as BAD phosphoryation by HGF might contribute to HGF-mediated cell survival in NUGC-3 cells.

Key words: BAD; Apoptosis; Hepatocyte growth factor (HGF); Mitogen activated protein kinase (MAPK); Phosphoinositide 3-kinase (PI3K)

Address correspondence to Kyung Hee Lee, M.D., Ph.D., Department of Hematology-Oncology, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong, Daegu 705-717, Republic of Korea. Tel: 82-53-620-3845; Fax: 82-53-654-6651; E-mail: lkhee@med.yu.ac.kr




Oncology Research, Vol. 17, pp. 33-41
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Silencing of YY1 Downregulates RIZ1 Promoter in Human Osteosarcoma

Ciro Abbondanza,1* Filomena de Nigris,1* Caterina De Rosa,1 Raffaele Rossiello,2 Giovanni Alfredo Puca,1 and Claudio Napoli1

1Department of General Pathology, 1st School of Medicine, II University of Naples, Naples 80138, Italy
2Division of Human Pathology, 1st School of Medicine, II University of Naples, Naples 80138, Italy

RIZ1 isoform, but not RIZ2, is commonly silenced in many types of tumors. In osteosarcoma cells, RIZ1 protein is very abundant. The silencing of YY1 protein, a recent target gene in osteosarcoma cells, reduced the expression of RIZ1 protein. Here we show that RIZ1 overexpression is a transcriptional event documented by Western blot, RT-PCR, and promoter assays. YY1 protein binds and cooperates to positive regulation of the RIZ1 promoter and its presence reduced the dimethyl lysine 9 histone 3 by chromatin immunoprecipitation assays. These results indicate that overexpression of YY1 in osteosarcoma cells plays a key role in positive regulation of RIZ1. The coexpression of RIZ1/YY1 proteins suggests a tandem regulatory mechanism in human osteosarcoma cells and tissues.

Key words: Cancer; RIZ; YY1; Ostosarcoma

Address correspondence to Professor Claudio Napoli, Department of General Pathology, 1st School of Medicine, II University of Naples, Complesso S. Andrea delle Dame 80138 Naples, Italy. E-mail: claudio.napoli@unina2.it

*Equally contributed to this study.




Oncology Research, Vol. 17, pp. 43-49
0965-0407/08 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2008 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Distribution of Microsatellite Instability in Danish Ovarian Tumor Patients and the Prognostic Value in Ovarian Cancer Patients

Farah D. Begum,1 Claus K. Høgdall,1 Susanne K. Kjær,1,2 Jan Blaakær,3 Lise Christensen,4 Andy Ryan,5 Ian J. Jacobs,5 and Estrid V. Høgdall2

1The Gynaecologic Clinic, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen Ø, DK-2100, Denmark
2Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen Ø, DK-2100, Denmark
3Department of Gynaecology and Obstetrics, Aarhus University Hospital, Aarhus N, DK-8200, Denmark
4Department of Pathology, Bispebjerg Hospital, University of Copenhagen, Copenhagen NV, DK-2400, Denmark
5Gynaecology Cancer Research Unit, University College London, London, W1T 7NF, UK

The repeated frequency of microsatellite instability (MSI) in ovarian cancer (OC) ranges from 0% to 50%. Most MSI studies including OC patients have involved relatively small number of tumors, a wide range of different MSI markers, different patient characteristics, and varying criteria for defining tumors as MSI positive. Thus, no conclusive evidence about MSI occurrence in OC has been provided and the large variation has made interpretation of these previous studies difficult. The majority of MSI studies have been performed on OC cases with few borderline ovarian tumor (BOT) cases included. Few BOT studies showed no evidence of MSI, but in one study the frequency of MSI was 27.7% with all tumors of serous type, suggesting that MSI may play a role in the development of serous BOT. The aim of our study was to determine the frequency of MSI using a panel of 16 dinucleotide markers: TP53, D17S250, CACNLB1, D18S58, D19S49, DXS538, DXS454, D5S117, D5S107, D6S284, D6S305, D9S171, D9S15, D11S554, D11S29, and D13S272 in tissue from patients with OC or BOT and to correlate the presence of MSI at these markers with the clinical information, such as FIGO stage, histological type, age, and survival in OC. The overall frequencies of MSI were within 2-10%. We observed MSI at different loci and with different extent (2.3-9.8%) in the different histopathological types. In both BOT and OC cases, we observed that all high MSI (MSI-H) were of serous type. No significant difference in disease specific survival was found between stage III/IV OC patients who presented MSI compared to patients being microsatellite stable (MSS) (p = 0.72). In conclusion, we found no association to any of the clinical parameters evaluated, although a tendency of a higher frequency of MSI was observed among serous OC.

Key words: Microsatellite instability; Ovarian cancer; Borderline ovarian tumors; Frequency; Microsatellite instability-low; Microsatellite instability-high

Address correspondence to Estrid Høgdall, Department of Virus, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark. Tel: 0045-35257621; Fax: 0045-3545 4285; E-mail: hogdall@dadlnet.dk