Oncology Research 20(12) Abstracts

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Oncology Research, Vol. 20, pp. 545–555, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13728687793353
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Hydroxyurea Potentiates the Caspase-Independent Killing of B-Cell Lines by Rituximab and GA101

Ian Daniels,*1 Abdulmunem Abulayha,†1 and Andrew P. Haynes*

*David Evans Medical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
†Biotechnology Research Centre, Twisha, Libya

Anti-CD20 monoclonal antibodies have revolutionized the treatment of non-Hodgkin’s lymphoma over the last decade. Unfortunately, a significant number of patients treated by these antibodies exhibit innate or acquired antibody resistance and fail to respond to treatment. Strategies to improve antibody function and overcome resistance include the development of new “engineered” antibodies and the use of new drug combination therapies. In this report, we show that the antimetabolite hydroxyurea significantly enhances the ability of two therapeutic monoclonal antibodies to directly kill some human B-cells. The two anti-CD20 antibodies studied were a clinically well-established type 1 therapeutic antibody, namely rituximab and GA101, an antibody representing the new breed of type 2 glycoengineered monoclonals. Hydroxyurea specifically enhanced the direct caspase-independent killing pathway of both of these antibodies as exemplified by the resistance to broad spectrum caspase inhibitors, lack of internucleosomal DNA laddering, and lack of activation of caspases 3, 8, and 9. Both rituximab and GA101 appear to preferentially kill cells in the G0/G1 cell cycle phase. One of the many reported effects of hydroxyurea is cell arrest in this phase. Arresting antibody-sensitive cells in this stage of the cell cycle by means other than hydroxurea also sensitized the cells to caspase-independent antibody-mediated death, suggesting that the potentiating effect of hydroxyurea may be mediated via its effects upon the cell cycle. The possible combination of hydroxyurea and anti-CD20 monoclonal antibodies may offer new possibilities for combination therapies in the clinic.

Key words: Rituximab; GA101; CD20; Apoptosis; Lymphoma; Hydroxyurea

1These authors provided equal contribution to this work.
Address correspondence to Dr. Ian Daniels, David Evans Medical Research Centre, Nottingham University Hospitals NHS Trust, City Campus, Nottingham, UK, NG5 1PB. Tel: +44(0)1159627650; Fax: +44(0)1159858864; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 557–564, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13775486749254
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

MiR-378 Inhibits Progression of Human Gastric Cancer MGC-803 Cells by Targeting MAPK1 In Vitro


Bojian Fei*† and Haorong Wu*

*Department of General Surgery, The Second Affiliated Hospital of Soochow University, SooChow, Jiangsu, PR China
†Department of Surgical Oncology, The Fourth People’s Hospital of Wuxi, Wuxi, Jiangsu, PR China

Gastric cancer (GC) is one of the most common cancers and the leading cause of cancer-related deaths globally. The discovery of microRNAs (miRNAs) provides a new avenue for GC diagnostic and treatment regiments. Currently, a large number of miRNAs have been reported to be associated with the progression of GC, among which miR-378 has been examined to be downregulated in GC tissues and several cell lines. However, the function of miR-378 on GC cells and the mechanisms were less known. Here we found that ectopic expression of miR-378 could inhibit cell proliferation, cell cycle progression, cell migration as well as invasion, and induced cell apoptosis in GC cell line MGC-803. Moreover, we found that oncogene mitogen-activated protein kinase 1 (MAPK1) was a target gene of miR-378 in GC cells, and the tumor-suppressive role of miR-378 might be achieved by the direct interaction with MAPK1. Taken together, our results showed that miR-378 might act as tumor suppressors in GC, and it may provide novel diagnostic and therapeutic options for human GC clinical operation in the future.

Key words: MiR-378; Gastric cancer (GC); MAPK; Cell progression

Address correspondence to Haorong Wu, Department of General Surgery, The Second Affiliated Hospital of Soochow University, SooChow, Jiangsu 21500, PR China. Tel/Fax: +86-0510-88682989; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 565–570, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13775486749290
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Zinc Finger X-Chromosomal Protein (ZFX) Promotes Solid Agar Colony Growth of Osteosarcoma Cells

Rui Jiang,* Jin-cheng Wang,* Mei Sun,† Xing-yi Zhang,‡ and Han Wu*

*Department of Orthopedic Surgery, China–Japan Union Hospital of Jilin University, Changchun, PR China
†Department of Pathology, The Second Hospital of Jilin University, Changchun, PR China
‡Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, PR China

Zinc finger X-chromosomal protein (ZFX) is a member of the zinc finger family of proteins. The importance of ZFX in several cancer types, including prostate cancer, laryngeal squamous cell carcinoma, and glioma, has been addressed. However, the role of ZFX in human osteosarcoma remains unknown. Here we investigated the phenotype of ZFX knockdown on cell proliferation and in vitro tumorigenesis using lentivirus-mediated loss-of-function strategy. The results demonstrated that the proliferation and colony formation ability of human osteosarcoma Saos-2 and MG63 cells was impaired by ZFX small interfering RNA (siRNA)-expressing lentivirus. Moreover, loss of ZFX led to G0/G1 phase cell cycle arrest and a significant increase of cells in the sub-G1 fraction, indicating that ZFX functions as an oncogene in the malignant proliferation process in osteosarcoma. Furthermore, ZFX siRNA may have an antitumorigenic effect on osteosarcoma cells. Our findings hold important significance for RNA interference-mediated cancer gene therapy for human osteosarcoma.

Key words: Zinc finger X-chromosomal protein (ZFX); Small interfering RNA (siRNA); Osteosarcoma; Tumorigenesis

Address correspondence to Han Wu, M.D., Department of Orthopedic Surgery, China–Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, Changchun 130033, PR China. Tel/Fax: +86-431-84666805; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 571–577, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13775486749371
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Synergistic Effect of 5-Azacytidine and NF-κB Inhibitor DHMEQ on Apoptosis Induction in Myeloid Leukemia Cells

Tomiteru Togano,*† Makoto Nakashima,*† Mariko Watanabe,* Kazuo Umezawa,‡ Toshiki Watanabe,† Masaaki Higashihara,* and Ryouichi Horie*

*Department of Hematology, School of Medicine, Kitasato University, Minami-ku, Sagamihara, Kanagawa, Japan
†Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Minato-ku, Tokyo, Japan
‡School of Medicine, Aichi Medical University, Nagakute, Aichi, Japan

Constitutive NF-κB activation characterizes a subset of myeloid leukemia (ML) cells. Recent reports have indicated that DNA methyltransferase (DNMT) inhibitors are alternative candidates for the treatment of ML. However, the optimal use of DNMT as a chemotherapeutic agent against ML has yet to be established. In this report, we examined the effect of the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) and its combinational use with the DNMT inhibitor 5-azacytidine (AZA) in ML cell lines. DHMEQ alone induced cell death in ML cell lines with NF-κB activation, although the response varied among the cell lines. The addition of DHMEQ enhanced the effect of AZA on the viability and apoptosis induction of ML cell lines. The treatment of ML cell lines with AZA marginally induced NF-κB binding activity, although the treatment induced NF-κB protein. These results indicate the potential usefulness of DHMEQ and its combinational use with AZA in the treatment of ML, although the molecular effect by AZA on the NF-κB pathway awaits further study.

Key words: Leukemia; NF-κB; 5-Azacytidine (AZA); Dehydroxymethylepoxyquinomicin (DHMEQ)

Address correspondence to Ryouichi Horie, M.D., Ph.D., Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. Tel: +81-42-778-8111; Fax: +81-42-778-8441; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 579–587, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13775486749416
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Inhibition of Lymphatic Metastases by a Survivin Dominant-Negative Mutant

Guang-Chao Xu,*1 Peng Zhang,†1 Fei Leng,* Li Pan,* Zhi-Yong Li,* Dan-Dan Yu,* Yan Shan,* Qing-Zhong Yuan,* Yuan Wen,* Bo Mu,* Hua-Shan Shi,* Xiang Chen,* and Chun-Ting Wang*

*State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
†Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan, China

Metastasis is the most lethal attribute of human malignancy. High-level expression of survivin is involved in both carcinogenesis and angiogenesis in cancer. Previous studies indicate that a mutation of the threonine residue at position 34 (Thr34Ala) of survivin generates a dominant-negative mutant that induces apoptosis, inhibits angiogenesis, and suppresses highly metastatic breast carcinoma in mouse models. We investigated the efficacy of gene therapy with a survivin dominant-negative mutant and possible factors related to lymph node metastasis. The metastasis rate was compared between each group in order to find a survivin-targeted therapy against lymphangiogenesis in its earliest stages. We established lymph node metastasis models and treated animals with H22 tumors with Lip-mSurvivinT34A (Lip-mS), Lip-plasmid (Lip-P), or normal saline (NS). Eight days after the last dose, five randomly chosen mice from each group were sacrificed. We detected the apoptotic index, microvessel density (MVD), lymphatic microvessel density (LMVD), and the expression of VEGF-D with immunohistochemistry. After the remaining animals were sacrificed, we compared the tumor-infiltrated lymph nodes in each group. Administration of mSurvivinT34A plasmid complexed with cationic liposome (DOTAP/chol) resulted in the efficacious inhibition of tumor growth and lymph node metastasis within the mouse H22 tumor model. These responses were associated with tumor cell apoptosis, and angiogenesis and lymphangiogenesis inhibition. Our results suggested that Lip-mSurvivinT34A induced apoptosis and inhibited tumor angiogenesis and lymphangiogenesis, thus suppressing tumor growth and lymphatic metastasis. The mSurvivinT34A survivin mutant is a promising strategy of gene therapy to inhibit lymphatic metastasis.

Key words: Lymphatic metastasis; Survivin; Mutation; Lymphangiogenesis; Gene therapy

1These authors provided equal contribution to this work.
Address correspondence to Chun-Ting Wang, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Gaopeng Street, Keyuan Road 4, Chengdu 610041, China. Tel: +86-028-85164063; Fax: +86-028-85164060; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 589–600, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13775486749452
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Cancer Stem Cell-Like Cells Exist in Mucoepidermoid Carcinoma Cell Line MC3

Louqiang Zhang,*†‡ Yichao Xia,*† Longjiang Li,*† Yin Wang,‡ Ying Liu,*† Chunjie Li,*† and Tao Yu*†

*State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, People’s Republic of China
†Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan, People’s Republic of China
‡Department of Stomatology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China

Strong evidence for the presence of cancer stem cells (CSCs) in tumors exists. CSCs play an important role in the development, invasion, and drug resistance of carcinoma. Poorly differentiated mucoepidermoid carcinoma (MEC) is a lethal malignancy of human salivary gland tumors. However, whether there are CSCs in MEC and their phenotypes remains unclear. We isolated side population (SP) and sphere-forming cells from the MEC cell line MC3 and identified their characteristics. The results showed that sphere-forming assays could enrich stem cell-like cells, with this group of cells exhibiting high cloning efficiency, possessing strong tumorigenic ability, and highly expressing Oct4 based on PCR and immunocytochemistry assays. They also highly expressed CD44 and lowly expressed CD24 according to PCR, immunocytochemistry assays, and fluorescence-activated cell sorting analysis. Higher cloning efficiency was observed in the SP cells, but PCR revealed that the SP and non-SP cells did not statistically differ in their expression of ABCG2, Oct4, CD44, and CD24. In spite of these, the findings were not conclusive on whether SP cells are stem cell-like cells. In conclusion, CSC-like cells do exist in the MC3 cell line, and sphere-forming assays could enrich them, sphere-forming and SP cells are not the same kind of cell subpopulations, and the characteristics of SP cells need to be further investigated.

Key words: Cancer stem cells (CSCs); Mucoepidermoid carcinoma (MEC); Oct4; CD44; CD24; ABCG2

Address correspondence to Longjiang Li, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, No. 14, Sec. 3, Renminnan Road, Chengdu, Sichuan 610041, People’s Republic of China. Tel: +86-28-85501428; Fax: +86-28-85582167; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it