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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3996

Title: The Angiotensin II Receptor Blocker Losartan Sensitizes Human Liver Cancer Cells to Lenvatinib-Mediated Cytostatic and Angiostatic Effects.
Other Titles: アンジオテンシンII 受容体拮抗薬であるロサルタンは、レンバチニブによるヒト肝癌細胞への 細胞増殖抑制性および血管新生抑制効果の感性を向上させる
Authors: Takagi, Hirotetsu
Kaji, Kosuke
Nishimura, Norihisa
Ishida, Koji
Ogawa, Hiroyuki
Takaya, Hiroaki
Kawaratani, Hideto
Moriya, Kei
Namisaki, Tadashi
Akahane, Takemi
Mitoro, Akira
Yoshiji, Hitoshi
Keywords: HCC
VEGF
angiotensin-II
angiogenesis
lenvatinib
Issue Date: 5-Mar-2021
Publisher: MDPI
Citation: Cells Vol.10 No.3 Article No.575 (2021 Mar)
Abstract: Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage.
Description: 博士(医学)・甲第813号・令和4年3月15日
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
URI: http://hdl.handle.net/10564/3996
ISSN: 20734409
Academic Degrees and number: 24601A813
Degree-granting date: 2022-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2021年度

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