Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors

Kang,Wonyoung; Seol,Ho   Jun; Seong,Dong-Ho; Kim,Jandi; Kim,Yonghyun; Kim,Seung  U.; Nam,Do-Hyun; Joo,Kyeung  Min

doi:10.3892/or.2013.2584

September 2013 Volume 30 Issue 3

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September 2013 Volume 30 Issue 3

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Article

Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors

Authors:
- Wonyoung Kang
- Ho Jun Seol
- Dong-Ho Seong
- Jandi Kim
- Yonghyun Kim
- Seung U. Kim
- Do-Hyun Nam
- Kyeung Min Joo
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Affiliations: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, Department of Anatomy, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea, Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, USA, Division of Neurology, Department of Medicine, University of British Columbia,Vancouver, BC, Canada
Pages: 1101-1106
|
Published online on: July 3, 2013

https://doi.org/10.3892/or.2013.2584
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Abstract

Tumor-tropic properties of neural stem cells (NSCs) provide a novel approach with which to deliver targeting therapeutic genes to brain tumors. Previously, we developed a therapeutic strategy against metastatic brain tumors using a human NSC line (F3) expressing cytosine deaminase (F3.CD). F3.CD converts systemically administered 5-fluorocytosine (5-FC), a blood-brain barrier permeable nontoxic prodrug, into the anticancer agent 5-fluorouracil (5-FU). In this study, we potentiated a therapeutic strategy of treatment with nucleosides in order to chemically facilitate the endogenous conversion of 5-FU to its toxic metabolite 5-FU ribonucleoside (5-FUR). In vitro, 5-FUR showed superior cytotoxic activity against MDA-MB-435 cancer cells when compared to 5-FU. Although adenosine had little cytotoxic activity, the addition of adenosine significantly potentiated the in vitro cytotoxicity of 5-FU. When MDA-MB‑435 cells were co-cultured with F3.CD cells, F3.CD cells and 5-FC inhibited the growth of MDA-MB-435 cells more significantly in the presence of adenosine. Facilitated 5-FUR production by F3.CD was confirmed by an HPLC analysis of the conditioned media derived from F3.CD cells treated with 5-FC and adenosine. In vivo systemic adenosine treatment also significantly potentiated the therapeutic effects of F3.CD cells and 5-FC in an MDA-MB-435 metastatic brain tumor model. Simple adenosine addition improved the antitumor activity of the NSCs carrying the therapeutic gene. Our results demonstrated an increased therapeutic potential, and thereby, clinical applicability of NSC-based gene therapy.

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1	Patchell RA: The management of brain metastases. Cancer Treat Rev. 29:533–540. 2003. View Article : Google Scholar : PubMed/NCBI
2	Seol HJ, Jin J, Seong DH, Joo KM, Kang W, Yang H, Kim J, Shin CS, Kim Y, Kim KH, Kong DS, Lee JI, Aboody KS, Lee HJ, Kim SU and Nam DH: Genetically engineered human neural stem cells with rabbit carboxyl esterase can target brain metastasis from breast cancer. Cancer Lett. 311:152–159. 2011. View Article : Google Scholar : PubMed/NCBI
3	Aboody KS, Najbauer J, Schmidt NO, Yang W, Wu JK, Zhuge Y, Przylecki W, Carroll R, Black PM and Perides G: Targeting of melanoma brain metastases using engineered neural stem/progenitor cells. Neuro Oncol. 8:119–126. 2006. View Article : Google Scholar : PubMed/NCBI
4	Schmidt NO, Przylecki W, Yang W, Ziu M, Teng Y, Kim SU, Black PM, Aboody KS and Carroll RS: Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia. 7:623–629. 2005. View Article : Google Scholar : PubMed/NCBI
5	Joo KM, Park IH, Shin JY, Jin J, Kang BG, Kim MH, Lee SJ, Jo MY, Kim SU and Nam DH: Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases. Mol Ther. 17:570–575. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ito S, Natsume A, Shimato S, Ohno M, Kato T, Chansakul P, Wakabayashi T and Kim SU: Human neural stem cells transduced with IFN-beta and cytosine deaminase genes intensify bystander effect in experimental glioma. Cancer Gene Ther. 17:299–306. 2010. View Article : Google Scholar : PubMed/NCBI
7	Lee SJ, Kim Y, Jo MY, Kim HS, Jin Y, Kim SU, Jin J, Joo KM and Nam DH: Combined treatment of tumor-tropic human neural stem cells containing the CD suicide gene effectively targets brain tumors provoking a mild immune response. Oncol Rep. 25:63–68. 2011.PubMed/NCBI
8	Kim JH, Kim JY, Kim SU and Cho KG: Therapeutic effect of genetically modified human neural stem cells encoding cytosine deaminase on experimental glioma. Biochem Biophys Res Commun. 417:534–540. 2012. View Article : Google Scholar : PubMed/NCBI
9	Christensen CL, Zandi R, Gjetting T, Cramer F and Poulsen HS: Specifically targeted gene therapy for small-cell lung cancer. Expert Rev Anticancer Ther. 9:437–452. 2009. View Article : Google Scholar : PubMed/NCBI
10	Rogulski KR, Kim JH, Kim SH and Freytag SO: Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Hum Gene Ther. 8:73–85. 1997.PubMed/NCBI
11	Christensen CL, Gjetting T, Poulsen TT, Cramer F, Roth JA and Poulsen HS: Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small-cell lung cancer-specific cytotoxicity and tumor growth delay. Clin Cancer Res. 16:2308–2319. 2010. View Article : Google Scholar
12	Lee HJ, Kim KS, Kim EJ, Choi HB, Lee KH, Park IH, Ko Y, Jeong SW and Kim SU: Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells. 25:1204–1212. 2007. View Article : Google Scholar
13	Kim SU and de Vellis J: Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 87:2183–2200. 2009. View Article : Google Scholar : PubMed/NCBI
14	Seol HJ, Yoo HY, Jin J, Joo KM, Kim HS, Yoon SJ, Choi SH, Kim Y, Pyo HR, Lim DH, Kim W, Um HD, Kim JH, Lee JI and Nam DH: The expression of DNA damage checkpoint proteins and prognostic implication in metastatic brain tumors. Oncol Res. 19:381–390. 2011. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors

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