Oncology Research 19(10-11) Abstracts

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Oncology Research, Vol. 19, pp. 445–453, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504011X13123323849717
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Review

The Potential of Protein Disulfide Isomerase as a Therapeutic Drug Target

Maola M. G. Khan,*† Siro Simizu,*‡ Makoto Kawatani,* and Hiroyuki Osada*†

*Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, Saitama, Japan
†Graduate School of Science and Engineering, Saitama University, Saitama, Japan
‡Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan

Protein disulfide isomerase (PDI) is a multifunctional protein of the thioredoxin superfamily. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction; it also has chaperone and antichaperone activities. Although PDI localizes primarily to the endoplasmic reticulum (ER), it is secreted and expressed on the cell surface. In the ER, PDI is primarily involved in protein folding, whereas on the cell surface, it reduces disulfide bonds. The functions of PDI depend on its localization and the redox state of its active site cysteines. The ER-based functions of PDI are linked to cancer invasion and migration. Surface-associated PDI facilitates the entry of viruses, such as HIV-1, and toxins, such as diphtheria and cholera. Thus, based on its involvement in pathological events, PDI is considered a potential drug target. However, a significant challenge in the therapeutic targeting of PDI is discovering function-specific inhibitors for it. To this end, a wide range of therapeutic agents, such as antibiotics, thiol blockers, estrogenic compounds, and arsenical compounds, have been used, although few are bona fide specific inhibitors. In this review, we will describe the potential of PDI as a therapeutic drug target.

Key words: Protein disulfide isomerase; Juniferdin; Inhibitor; Bacitracin

Address correspondence to Hiroyuki Osada, Ph.D., Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel: 81-48-467-9542; Fax: 81-48-462-4669; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 455–461, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13285365944256
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Coenzyme Q10 Decreases Basic Fibroblast Growth Factor (bFGF)-Induced Angiogenesis by Blocking ERK Activation

Jae-Sun Choi,* Shi-Young Park,† Eui-Yeun Yi,† Yung-Jin Kim,† and Joo-Won Jeong*‡

*Department of Biomedical Science, Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
†Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Korea
‡Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea

Coenzyme Q10 (CoQ10) is an essential factor of the mitochondrial respiratory chain and has effective antioxidant properties. Therefore, CoQ10 has been used in a variety of clinical applications and used as a nutritional supplement to treat several human diseases. Here, we tested the effects of CoQ10 on angiogenesis stimulated by basic fibroblast growth factor (bFGF). CoQ10 significantly inhibited bFGF-induced angiogenesis in a mouse Matrigel plug and the sprouting of endothelial cells in rat aortic rings. In addition, CoQ10 decreased the ability of tube formation, migration, and invasion in endothelial cells. When CoQ10 was used to inhibit angiogenesis in endothelial cells, the expression of vascular endothelial growth factor (VEGF) and the phosphorylation of ERK were decreased. Taken together, these results indicate that CoQ10 is able to act as an antiangiogenic regulator, and its inhibitory activity is mediated by blocking an ERK-dependent pathway. This study suggests that CoQ10 may be used a therapeutic agent to decrease neovascularization in several diseases, including solid tumors.

Key words: Coenzyme Q10 (CoQ10); Basic fibroblast growth factor (bFGF); Angiogenesis; ERK

Address correspondence to Joo-Won Jeong at his current address: Department of Anatomy and Neurobiology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea. Tel: 82-2-961-9103; Fax: 82-2-968-1506; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 463–469, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13285365944292
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Targeted Repression of Overexpressed CD30 Downregulates NF-κB and ERK1/2 Pathway in Hodgkin Lymphoma Cell Lines

Mariko Watanabe,* Kazumi Nakano,† Tomiteru Togano,* Makoto Nakashima,*† Masaaki Higashihara,* Marshall E. Kadin,‡ Toshiki Watanabe,† and Ryouichi Horie*

*Department of Hematology, School of Medicine, Kitasato University, Kanagawa, Japan
†Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
‡Department of Dermatology and Skin Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA

We previously reported that CD30 is induced during lymphocyte transformation and that overexpressed CD30 can transduce ligand-independent signals in Hodgkin lymphoma (HL) cells. However, its biological consequence is not fully addressed. In this study, we examined the effects of targeted repression of overexpressed CD30 on cell signaling and proliferation using small-interfering RNAs (siRNAs) in HL cell lines. Repression of CD30 inhibited cellular proliferation through reduced activation of IκB kinase (IKK) and extracellular signal-regulated kinase (ERK) 1/2 in both B- and T-HL cell lines. These HL cell lines bear one or more defects in negative regulators of nuclear factor (NF)-κB signaling, including A20, cylindromatosis tumor suppressor protein (CYLD), and IκBα, and when CD30 is repressed, they show reduced activation of the canonical NF-κB pathway. This suggests that CD30 governs NF-κB and ERK1/2 signaling pathways, and is involved in the proliferation of HL cells. Defective mutations in negative regulators of NF-κB signaling appear to promote CD30-initiated basal NF-κB activation. These results indicate that CD30 is involved in the tumorigenic process of HL, and that it may be useful as a therapeutic target for the treatment of HL.

Key words: CD30; Hodgkin lymphoma; NF-κB; ERK1/2; A20; IκBα

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. 19, pp. 471–478, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13285365944337
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Effect of Acquired Cisplatin Resistance on Sensitivity to EGFR Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Cells

Jin Kyung Rho,* Yun Jung Choi,*† You Ri Choi,* Sun Ye Kim,* Su Jin Choi,‡ Chang-Min Choi,*§ Im Il Na,‡ and Jae Cheol Lee†§

*Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea
†University of Science & Technology, Daejeon, Korea
‡Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
§Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Korea

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are used as first-line agents for treating nonsquamous cell lung cancer with EGFR mutation, there are many patients who have to receive these drugs following platinum-based chemotherapy. This study was designed to define whether exposure to cisplatin could affect the sensitivity to EGFR TKIs because conflicting results have been presented. We established sublines that are resistant to cisplatin from EGFR wild-type cells (A549 and H460) and EGFR mutant cells (PC-9 and HCC827). The EGFR-related signals were examined by Western blotting. MTT assay and the trypan blue exclusion method were used for the in vitro study, while tumor size and the SUV of the 18FDG-PET scans were measured in animal models. The IC50 value and apoptotic fractions after exposure to EGFR TKIs, such as gefitinib, erlotinib, and BIBW 2992, were almost the same in the cisplatinresistant sublines compared to that of the parent cells. Although the baseline PTEN expression was reduced in the resistant cells, as was indicated in a previous study, the EGFR-related signals similarly responded to the EGFR TKIs. Furthermore, the reduced tumor size and SUV of the 18FDG-PET of the implanted tumor in nude mice according to erlotinib treatment were not different between the resistant sublines and the parent cells. In conclusion, the acquired resistance to cisplatin did not affect the sensitivity to EGFR TKIs in the EGFR mutant lung cancer cells, and this should abrogate any concerns about the use of EGFR TKIs following platinum-based chemotherapy.

Key words: Lung cancer; Epidermal growth factor receptor (EGFR) inhibitor; Chemoresistance; Cisplatin

Address correspondence to Jae Cheol Lee, Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 388-1 Pungnap-2 Dong, Songpa-Gu, Seoul 138-736, Korea. Tel: +82 2 30103208; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

 

Oncology Research, Vol. 19, pp. 479–486, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13285365944373
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Enhancement of IL-2-Induced Cytotoxicity by Interferon-α in Renal Cell Carcinoma

Michio Naoe,* Yoshio Ogawa,* Yuki Hasebe,* Jun Morita,* Takeshi Shichijo,* Atsushi Igarashi,* Kozo Fuji,* Sanju Iwamoto,† Toru Suzuki,‡ and Shuji Terao§

*Division of Urology, Showa University, Tokyo, Japan
†Division of Biochemistry, Showa University, Tokyo, Japan
‡Division of Urology, Hyogo College of Medicine, Hyogo, Japan
§Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan

Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL-2) and interferon-α (IFN-α) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-α, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF-related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-α  were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-á negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-α  therapy against mRCC.

Key words: Renal cell cancer (RCC); Interferon-α  (IFN-α); Interleukin-2 (IL-2); Natural killer (NK) cell; Treg cell

Address correspondence to Michio Naoe, Department of Urology, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, Japan. Tel: +81-3-3784-8560; Fax: +81-3-3784-1400; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 487–500, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13286534482476
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Separation of Circulating Cancer Cells by Unique Microfluidic Chip in Colorectal Cancer

H. X. Du,* Z. G. Wang,* Z. L. Yang,* D. Chen,† J. D. Chen,† and R. J. Hu†

*Department of General Surgery, the Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, China
†National Key Laboratory of Science and Technology on Nano/Micro Fabrication Technology, Research Institute of Micro/Nano Science and Technology, Shanghai Jiao Tong University, Shanghai, China

Circulating tumor cells (CTCs) from peripheral blood are emerging as a useful tool for the detection of malignancy, monitoring disease progression, and measuring response to therapy. We describe a unique microfluidic chip that was capable of efficient and selective separation of CTCs from peripheral whole blood samples. The ability of microfluidic chip to capture CTCs from PBS and whole blood samples was tested. Sixty-eight peripheral blood samples from 68 colorectal cancer patients were investigated for the presence of CTCs by microchip technology. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. We also examined samples from 20 healthy individuals as controls. The calculated capture efficiency was 85.7% and decreased significantly at flow rates above 2.0 ml/h. The number of CTCs isolated ranged from 3 to 236/ml for colorectal patients [99 ± 64 (mean ± SD) CTCs/ml]. None of the 20 healthy subjects had any identifiable CTCs. We identified CTCs in 46 (67.65%) of the 68 patients: in two of nine (22.22%) Dukes A, in 10 of 24 (41.67%) Dukes B, in 21 of 22 (95.45%) Dukes C, and in all 13 Dukes D patients. The detection rate in Dukes C and D patients was much higher than in Dukes A and B patients (97.73% vs. 36.36%) (p < 0.01). A significant correlation between detection of CTCs and clinical stage (r = 0.792, p < 0.01) was found, which was higher than carcinoembryonic antigen (r = 0.285, p > 0.01), carbohydrate antigen 19-9 (r = 0.258, p > 0.01), α-fetoprotein (r = 0.096, p > 0.01), and cancer antigen 125 (r = 0.134, p > 0.01). Microfluidic chip provides a novel method for capturing CTCs. The presence of CTCs correlated with clinical stage. It is important to evaluate CK-positive and DAPI-stained tumor cells together to determine the role of CTCs in tumor behavior and disease progression.

Key words: Circulating tumor cells; Colorectal neoplasms; Microfluidic analytical techniques; Neoplasm metastasis

Address correspondence to Z. G. Wang, Department of General Surgery, the Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China. Tel: +8618930177675; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 501–509, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13286534482511
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Overexpression of LIMK1 Promotes Migration Ability of Multidrug-Resistant Osteosarcoma Cells

Hanyang Zhang,* Yan Wang,† Fengjuan Xing,† Jincheng Wang,* Yang Wang,* Hong Wang,† Yudan Yang,† and Zhongli Gao*

*Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, China
†Research Center for Gene Therapy, China-Japan Union Hospital, Jilin University, Changchun, China

Multidrug resistance (MDR) to chemotherapy is a major obstacle in the treatment of cancer and the resistance process is multifactorial. Studies on multidrug resistance mechanisms relied on the availability of cancer multidrug resistance cell lines that have been established. In this study we successfully established a multidrug resistance cell line MG63/VCR derived from human osteosarcoma cell line MG63 based on the induction by vincristine. MG63/VCR cells exhibited high resistance to vincristine and other anticancer drugs, accompanied by upregulated expression of MDR-associated genes MDR1, MRP1, and Bcl-2. Notably, we found that MG63/VCR cells exhibited higher migration ability compared to parental MG63 cells. Moreover, we demonstrated that LIMK1, a key regulator of actin cytoskeleton, was overexpressed at both mRNA and protein levels in MG63/VCR cells and the higher LIMK1 protein level was correlated with higher level of phosphorylated cofilin. In addition, knockdown of LIMK1 abolished the higher migration ability of MG63/VCR cells. These results suggest that LIMK1 overexpression contributes to the invasion and metastasis of drug-resistant osteosarcoma and reveal LIMK as a novel therapeutic target for drug resistant osteosarcoma.

Key words: Multidrug resistance; Osteosarcoma; MG63; Vincristine; LIMK1; Migration

Address correspondence to Zhongli Gao, Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun 130033, China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Yan Wang, Research Center for Gene Therapy, China-Japan Union Hospital, Jilin University, Changchun 130033, China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 511–518, 2012
0965-0407/12 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504011X13127606672887
E-ISSN 1555-3906
Copyright © 2012 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Effects of Reduced Dose Intensity of Modified FOLFOX6 in Patients With Metastatic or Recurrent Colorectal Cancer

Sakiko Mochinaga,* Tomoyo Okahashi,* Shinobu Koga,† Yukitaka Nakano,* Tomomi Yakabe,‡§ Kenji Sumi,‡ Kenji Kitahara,‡ Hirokazu Noshiro,‡ Shinya Kimura,§ and Hiroshi Fujito*

*Department of Pharmacy, Saga University Hospital, Saga, Japan
†Department of Pharmacy, Kyorin University Hospital, Tokyo, Japan
‡Department of General and Gastrointestinal Surgery, Saga University Hospital, Saga, Japan
§Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan

The current study was conducted to retrospectively investigate the effects of reducing average relative dose intensity (ARDI) in response to adverse events on time to treatment failure (TTF) and overall survival (OS) in patients with metastatic or recurrent colorectal cancer receiving modified FOLFOX6 (mFOLFOX6) therapy between January 2006 and May 2010. Patients were divided into two groups based on ARDI: those with an ARDI of 85% or more (ARDI maintained; n = 12) and those with an ARDI of less than 85% (ARDI reduced; n = 37). In the ARDI-reduced group, out of a total of 402 treatment courses conducted, 25.9% involved treatment delays and 8.2% involved dose reductions, and the incidence rate of treatment delay was significantly higher than that of dose reduction (p < 0.001). Hematological toxicity was the main reason for both treatment delays and dose reductions. Reduced ARDI by dose reduction effectively prevented any increase in the severity of neutropenia and the treatment delays in the next courses, suggesting that the dose reductions were appropriately performed. Median TTF in the ARDI-maintained and ARDI-reduced groups was 5.2 and 5.8 months, respectively (p = 0.225). Median OS was 15.5 months and 33.9 months in the ARDI-maintained and ARDI-reduced groups, respectively (p = 0.347). These findings suggested that reductions in ARDI of mFOLFOX6 therapy for metastatic or recurrent colorectal cancer due to treatment delays and dose reductions in response to adverse events do not necessarily lead to shortened TTF and OS.

Key words: Dose intensity; Modified FOLFOX6 (mFOLFOX6); Metastatic colorectal cancer

Address correspondence to Shinya Kimura, M.D., Ph.D., Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Tel: +81-952-34-2353; Fax: +81-952-34-2017; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it