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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3588

Title: Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro.
Other Titles: 高純度natural killer細胞及びtemozolomide併用によるヒト膠芽腫細胞に対する抗腫瘍効果の研究
Authors: Tanaka, Yoshitaka
Nakazawa, Tsutomu
Nakamura, Mitsutoshi
Nishimura, Fumihiko
Matsuda, Ryosuke
Omoto, Koji
Shida, Yoichi
Murakami, Toshiharu
Nakagawa, Ichiro
Motoyama, Yasushi
Morita, Hiromichi
Tsujimura, Takahiro
Nakase, Hiroyuki
Issue Date: 6-Mar-2019
Publisher: Public Library of Science
Citation: PloS one Vol.14 No.3 Article No.e0212455 (2019 Mar)
Abstract: Glioblastoma is the leading malignant glioma with a poor prognosis. This study aimed to investigate the antitumor effects of natural killer cells in combination with temozolomide as the standard chemotherapeutic agent for glioblastoma. Using a simple, feeder-less, and chemically defined culture method, we expanded human peripheral blood mononuclear cells and assessed the receptor expression, natural killer cell activity, and regulatory T cell frequency in expanded cells. Next, using the standard human glioblastoma cell lines (temozolomide-sensitive U87MG, temozolomide-resistant T98G, and LN-18), we assessed the ligand expressions of receptors on natural killer cells. Furthermore, the antitumor effects of the combination of the expanded natural killer cells and temozolomide were assessed using growth inhibition assays, apoptosis detection assays, and senescence-associated β-galactosidase activity assays in the glioblastoma cell lines. Novel culture systems were sufficient to attain highly purified (>98%), expanded (>440-fold) CD3-/CD56+ peripheral blood-derived natural killer cells. We designated the expanded population as genuine induced natural killer cells. Genuine induced natural killer cells exhibited a high natural killer activity and low regulatory T cell frequency compared with lymphokine-activated killer cells. Growth inhibition assays revealed that genuine induced natural killer cells inhibited the glioblastoma cell line growth but enhanced temozolomide-induced inhibition effects in U87MG. Apoptosis detection assays revealed that genuine induced natural killer cells induced apoptosis in the glioblastoma cell lines. Furthermore, senescence-associated β-galactosidase activity assays revealed that temozolomide induced senescence in U87MG. Genuine induced natural killer cells induce apoptosis in temozolomide-sensitive and temozolomide-resistant glioblastoma cells and enhances temozolomide-induced antitumor effects in different mechanisms. Hence, the combination of genuine induced natural killer cells and temozolomide may prove to be a promising immunochemotherapeutic approach in patients with glioblastoma if the antitumor effects in vivo can be demonstrated.
Description: 博士(医学)・甲第715号・平成31年6月26日
Copyright: © 2019 Tanaka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/10564/3588
ISSN: 19326203
Academic Degrees and number: 24601A715
Degree-granting date: 2019-06-26
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2019年度

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