Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma

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URI http://shark.lib.kagawa-u.ac.jp/kuir/metadata/28748
Title
Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma
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Description

Abstract
BACKGROUND:

Human multiple myeloma (MM) is an incurable hematological malignancy for which novel therapeutic agents are needed. Calmodulin (CaM) antagonists have been reported to induce apoptosis and inhibit tumor cell invasion and metastasis in various tumor models. However, the antitumor effects of CaM antagonists on MM are poorly understood. In this study, we investigated the antitumor effects of naphthalenesulfonamide derivative selective CaM antagonists W-7 and W-13 on MM cell lines both in vitro and in vivo.
METHODS:

The proliferative ability was analyzed by the WST-8 assay. Cell cycle was evaluated by flow cytometry after staining of cells with PI. Apoptosis was quantified by flow cytometry after double-staining of cells by Annexin-V/PI. Molecular changes of cell cycle and apoptosis were determined by Western blot. Intracellular calcium levels and mitochondrial membrane potentials were determined using Fluo-4/AM dye and JC-10 dye, respectively. Moreover, we examined the in vivo anti-MM effects of CaM antagonists using a murine xenograft model of the human MM cell line.
RESULTS:

Treatment with W-7 and W-13 resulted in the dose-dependent inhibition of cell proliferation in various MM cell lines. W-7 and W-13 induced G1 phase cell cycle arrest by downregulating cyclins and upregulating p21cip1. In addition, W-7 and W-13 induced apoptosis via caspase activation; this occurred partly through the elevation of intracellular calcium levels and mitochondrial membrane potential depolarization and through inhibition of the STAT3 phosphorylation and subsequent downregulation of Mcl-1 protein. In tumor xenograft mouse models, tumor growth rates in CaM antagonist-treated groups were significantly reduced compared with those in the vehicle-treated groups.
CONCLUSIONS:

Our results demonstrate that CaM antagonists induce cell cycle arrest, induce apoptosis via caspase activation, and inhibit tumor growth in a murine MM model and raise the possibility that inhibition of CaM might be a useful therapeutic strategy for the treatment of MM.

Keywords:
Calmodulin; Multiple myeloma; Cell cycle; Apoptosis;

(医博甲630)

Author
著者 横倉 繁行
著者(ヨミ) ヨコクラ シゲユキ
著者(別表記) Yokokura Shigeyuki
Publication Title
BMC Cancer
Publication Title Alternative
BMC Cancer .
Volume
14
Start Page
882
Publisher
BMC (part of Springer Nature)
Published Date
2014-11-26
ISSN
1471-2407
NCID
AA12034763
PMID
25424011
DOI
10.1186/1471-2407-14-882
Resource Type
Thesis or Dissertation
Language
eng
Relation
PMCID: PMC4258255
Resource URL
https://doi.org/10.1186/1471-2407-14-882
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258255/
Rights
Copyright © Yokokura et al.; licensee BioMed Central Ltd. 2014
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
"This is the Publisher's version of the following article: Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma; BMC Cancer; Volume 14 (2014) 882; doi: 10.1186/1471-2407-14-882, which has been published in final form at https://doi.org/10.1186/1471-2407-14-882 . "
Text Version
ETD
Grant ID
博甲第630号
Grant Date
2016-03-24
Degree Name
博士(医学)
Grantor
香川大学
Set
香川大学
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