Plasma-stimulated medium kills TRAIL-resistant human malignant cells by promoting caspase-independent cell death via membrane potential and calcium dynamics modulation

Tokunaga,Tomohiko; Ando,Takashi; Suzuki-Karasaki,Miki; Ito,Tomohisa; Onoe-Takahashi,Asuka; Ochiai,Toyoko; Soma,Masayoshi; Suzuki-Karasaki,Yoshihiro

doi:10.3892/ijo.2018.4251

Plasma-stimulated medium kills TRAIL-resistant human malignant cells by promoting caspase-independent cell death via membrane potential and calcium dynamics modulation

Authors:
- Tomohiko Tokunaga
- Takashi Ando
- Miki Suzuki-Karasaki
- Tomohisa Ito
- Asuka Onoe-Takahashi
- Toyoko Ochiai
- Masayoshi Soma
- Yoshihiro Suzuki-Karasaki
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Affiliations: Division of General Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan, Department of Orthopedic Surgery, Yamanashi University School of Medicine, Chuo, Yamanashi 409-3898, Japan, Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan, Department of Orthopedic Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan, Department of Dermatology, Nihon University Hospital, Tokyo 101-8309, Japan
Published online on: January 23, 2018 https://doi.org/10.3892/ijo.2018.4251
Pages: 697-708
Copyright: © Tokunaga et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cold plasma-stimulated medium (PSM) have been shown to exhibit tumor-selective cytotoxicity and have emerged as promising new tools for cancer treatment. However, to date, at least to the best of our knowledge, no data are available as to which substance is more potent in killing cancer cells. Thus, in this study, we systematically compared their abilities to kill human malignant cells from different origins. We found that PSM dose-dependently killed TRAIL-resistant melanoma, osteosarcoma and neuroblastoma cells. Moreover, PSM had little cytotoxicity toward osteoblasts. PSM was more potent than TRAIL in inducing caspase-3/7 activation, mitochondrial network aberration and caspase-independent cell death. We also found that PSM was more potent in inducing plasma membrane depolarization (PMD) and disrupting endoplasmic-mitochondrial Ca2+ homeostasis. Moreover, persistent PMD was caused by different membrane-depolarizing agents; the use of the anti-type II diabetes drug, glibenclamide, alone caused mitochondrial fragmentation and enhanced TRAIL-induced Ca2+ modulation, mitochondrial network abnormalities and caspase-independent cell killing. These results demonstrate that PSM has a therapeutic advantage over TRAIL owing to its greater capacity to evoke caspase-independent cell death via mitochondrial network aberration by disrupting membrane potential and Ca2+ homeostasis. These findings may provide a strong rationale for developing PSM as a novel approach for the treatment of TRAIL-resistant malignant cells.

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