Oncology Research 20(1) Abstracts

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Oncology Research, Vol. 20, pp. 1–6, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196010
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Role of the Cysteine-Rich Domain and Netrin-Like Domain of Secreted Frizzled-Related Protein 4 in Angiogenesis Inhibition In Vitro

David Longman,* Frank Arfuso,* Helena M. Viola,† Livia C. Hool,† and Arunasalam M. Dharmarajan*‡

*School of Anatomy and Human Biology, Faculty of Life and Physical Sciences, The University of Western Australia, Crawley, Western Australia
†The School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, Western Australia
‡School of Biomedical Sciences, Faculty of Health Sciences, Curtin University and Curtin Health Innovation Research Institute (CHIRI), Perth, Western Australia

Secreted frizzled-related protein 4 (sFRP4) is a Wnt signaling antagonist. Classically, sFRP4 antagonizes the canonical Wnt signaling pathway, resulting in decreased cellular proliferation and increased apoptosis. Recent research from our laboratory has established that sFRP4 inhibits angiogenesis by decreasing proliferation, migration, and tube formation of endothelial cells. The objective of this study was to examine the role of sFRP4’s cysteine-rich domain (CRD) and netrin-like domain (NLD) in angiogenesis inhibition. Experiments were carried out to examine cell death and tube formation of endothelial cells after treatment with the CRD and the NLD. The CRD was seen to inhibit tube formation of endothelial cells, which suggests that this domain is important to sFRP4’s antiangiogenesis property. In addition, the NLD promoted endothelial cell death and may also inhibit angiogenesis. Furthermore, treatment with the CRD and the NLD increased endothelial intracellular calcium levels. Our findings implicate a role for both the CRD and NLD in angiogenesis inhibition by sFRP4. It is suggestive of alternative antiangiogenic downstream targets of canonical Wnt signaling and a possible importance of the noncanonical Ca2+ Wnt signaling pathway in sFRP4-mediated angiogenesis inhibition.

Key words: Secreted firzzled-related protein 4 (sFRP4); Angiogenesis; Apoptosis; Calcium signaling

Address correspondence to Dr. Frank Arfuso, School of Anatomy and Human Biology, Faculty of Life and Physical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009. Tel: +61 8 6488 3796; Fax: +61 8 6488 1051; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 7–14, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196056
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Structure–Activity Relationship of 9-Methylstreptimidone, a Compound That Induces Apoptosis Selectively in Adult T-Cell Leukemia Cells

Masatoshi Takeiri,* Eisuke Ota,* Shigeru Nishiyama,* Hiromasa Kiyota,† and Kazuo Umezawa‡

*Center for Chemical Biology, Faculty of Science and Technology, Keio University, Yokohama, Japan
†Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
‡Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Nagakute, Japan

We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-κB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure–activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (±)-4,α-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

Key words: Macrophage; Adult T-cell leukemia; Apoptosis; 9-Methylstreptimidone; Streptovitacin

Address correspondence to Masatoshi Takeiri, Center for Chemical Biology, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan. Tel: +81-45-566-1558; Fax: +81-45-566-1551; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 15–24, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196092
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

TLR4 Signaling Promotes Immune Escape of Human Colon Cancer Cells by Inducing Immunosuppressive Cytokines and Apoptosis Resistance

Xiaoyan Tang* and Youqing Zhu†

*General Department of Zhongnan Hospital, Wuhan University, Wuhan, Hebe Province, P.R. China
†Gastroenterology Department of Zhongnan Hospital, Wuhan University, Wuhan, Hebe Province, P.R. China

This study investigated the expression and biological role of TLR4 in human colon cancer cells’ growth and survival, and its potential as a target for colon cancer therapy. Reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry (FCM) were used to detect the expression level of TLR4. MTT analysis was performed to evaluate cell proliferation and enzyme-linked immunosorbent assay (ELISA) to test the production of IL-8, VEGF, and TGF-β. MAPKs and NF-κB were analyzed by Western blotting. Apoptosis was analyzed by flow cytometry with Annexin V and propidium iodide staining. The results showed that the human colon cancer cells HT-29, SW480, and Lovo all expressed TLR4 at both mRNA and protein levels, and TLR4 ligand LPS could not affect the expression of TLR4 and the proliferation of colon cancer cells. LPS increased phosphorylation of ERK1/2 and p38 and activated NF-κB. LPS promoted cytokine production, such as IL-8, VEGF, and TGF-β. In addition, LPS induced resistance of human colon cancer cells to TRAIL-induced apoptosis and NF-κB activation was necessary for apoptosis resistance. The study identified the expression level of TLR4 in human colon cancer cells and TLR4 was functionally active. TLR4 may play important roles in promoting immune escape of human colon cancer cells by inducing immunosuppressive factors and apoptosis resistance.

Key words: TLR4; Colon cancer; Immune escape; Apoptosis resistance

Address correspondence to Youqing Zhu, Ph.D., Gastroenterology Department of Zhongnan Hospital, Wuhan University, East-lake Road No. 169, Wuhan, 430071, Hubei Province, P.R. China. Tel: +86-27-67813275; Fax: +86-27-67813275; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 25–30, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196137
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Lack of Association of Genetic Variations of Deoxycytidine Kinase With Toxicity or Survival of Non-Small-Cell Lung Cancer Patients Treated With Gemcitabine Plus Cisplatin

Jeong-Seon Ryu,* Hyun-Jung Kim,* Eun-Soon Shin,† Hae-Seong Nam,* Jae-Hwa Cho,* and Jong-Eun Lee†

*Department of Internal Medicine and Center for Lung Cancer, Inha University Hospital, Incheon, South Korea
†DNA Link, Seoul, South Korea

The aim of this study was to determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Three tSNPs (−201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Hematologic toxicity such as neutropenia, thrombocytopenia, and anemia were not different by the three tSNPs or haplotypes (CGT, CAT, and CAC) of DCK. The genetic variations did not affect survival of the patients (log-rank p: 0.248 for −201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0.556 for CGT, 0.453 for CAT, and 0.845 for CAC). In a Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95% CI: 0.954 and 0.611 to 1.489 for −201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT, and 1.043 and 0.701 to 1.550 for CAC). This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.

Key words: Deoxycytidine kinase; Gemcitabine; Lung cancer; Pharmacogenetics; Polymorphism

Address correspondence to Jeong Seon Ryu, M.D., Ph.D., Professor, Department of Internal Medicine and Center for Lung Cancer, Inha University Hospital, 7-206, 3-Ga, Shinheung Dong, Jung Gu, Incheon, 400-103, South Korea. Tel: 82-32-890-3738; Fax: 82-32-882-6578; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 31–37, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196173
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Energy Controllable Steep Pulse (ECSP) Treatment Suppresses Tumor Growth in Rats Implanted With Walker 256 Carcinosarcoma Cells Through Apoptosis and an Antitumor Immune Response

Xiao-Dong Luo,*1 Jiang-Chuan Sun,*1 Feng Liu,† Li-Na Hu,* Xiao-Jing Dong,* Di-Na Sun,* and Jin Xiao*

*Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
†Department of Urinary Surgery, The Children’s Hospital, Chongqing Medical University, Chongqing, China

Electrochemotherapy has been widely used for the treatment of solid tumors, although the underlying mechanism remains unclear. We aimed to investigate the effects of energy controllable steep pulse (ECSP) on the regulation of tumor growth and apoptosis in rats implanted with Walker 256 carcinosarcoma cells. A rat tumor model was established by injection of Walker 256 carcinosarcoma cells into the inguinal area. H&E staining, transmission electron microscopy, and the TUNEL assay were used to detect apoptosis. Concanavalin A-induced lymphocyte transformation and MTT assays were used to assess lymphocyte proliferation. ELISA was used to determine serum cytokine levels. After 2 weeks of ECSP treatment, tumor growth in rats was effectively suppressed, while tumor cell apoptosis was significantly induced compared to the control tumor group. Moreover, ECSP treatment enhanced proliferation and activation of lymphocytes and natural killer (NK) cells. Serum IL-2 and IFN-γ levels were significantly decreased, and IL-4 and IL-10 levels dramatically increased in rats with control tumors compared to rats without tumors and lacking treatment (p < 0.05). In contrast, ECSP treatment increased IL-2 and IFN-γ levels, but reduced IL-4 and IL-10 levels to normal values. Moreover, ECSP also increased TNF-α production, possibly from peritoneal microphages. Our current study demonstrates that ECSP treatment is able to effectively reduce tumors in rats via induction of apoptosis and activation of the rat antitumor immune response. These data provide insightful information for the future application of ECSP-based electrochemotherapy in clinical trials against solid tumors.

Key words: Energy controllable steep pulse (ECSP); Apoptosis; Immune response; Lymphocytes; Walker 256 carcinosarcoma cells

1These authors provided equal contribution to this work.
Address correspondence to Li-Na Hu, Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, 76 Linjiang Rd, Yuzhong District, Chongqing 400010, China. Tel: +86-23-63693484; Fax: +86-23-63693484; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 39–47, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13425470196218
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Nimotuzumab Increases Chemosensitivity of Human Lung Adenocarcinoma Cell Lines to Docetaxel

Hai-Zhu Song,*1 Jun Yi,†1 Jing Chen,* and Long-Bang Chen*

*Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
†Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

Overexpression of epidermal growth factor receptor (EGFR) is common in non-small-cell lung cancer (NSCLC) and has been recently shown to contribute to cancer chemoresistance. It has been reported that the EGFR antibodies such as cetuximab in combination with chemotherapy could lead to an absolute benefit of overall survival (OS) compared with chemotherapy alone. In this study, we investigated the effects of nimotuzumab (h-R3), a humanized anti-EGFR antibody, in combination with docetaxel (DTX), on DTXresistant human lung adenocarcinoma cell line SPC-A1 (SPC-A1/DTX) both in vitro and in vivo. Immunohistochemistry and FCM assays demonstrated that SPC-A1/DTX cells had a relatively higher rate of EGFR overexpression than SPC-A1 cells. Accordingly, SPC-A1/DTX cells were approximately 13.7 times resistant to DTX than SPC-A1 cells. The combined therapy of h-R3 and DTX showed strong synergistic suppressive effect on cell proliferation of SPC-A1/DTX cells in vitro. The synergistic antitumor effect was also observed in SPC-A1/DTX xenograft-bearing nude mice. Further study showed that h-R3 could lead to a significant cell arrest at G1 phase of cell cycle in both SPC-A1/DTX and SPC-A1 cells. A dramatic increase of apoptosis rate was detected in h-R3-treated SPC-A1/DTX but not SPC-A1 cells. Moreover, when combined with DTX, h-R3 brought higher apoptosis rate in SPC-A1/DTX cells rather than in SPC-A1 cells. In conclusion, our results suggested that h-R3 could significantly enhance chemosensitivity of human lung adenocarcinoma cells to DTX, at least partially by induction of G1 phase arrest and cell apoptosis.

Key words: Nimotuzumab (h-R3); Epidermal growth factor receptor (EGFR); Lung adenocarcinoma; Docetaxel (DTX); Chemoresistance

1These authors provided equal contribution to this work.
Address correspondence to Prof. Long-Bang Chen, Department of Medical Oncology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China. Tel: +86-25-80860072; Fax: +86-25-80860123; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it