title: Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells.
abstract: Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by l-ascorbate. l-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM l-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 μM) of l-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of l-ascorbate was completely abolished by a prolonged 4 h pre-incubation with l-ascorbate (500 μM). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and l-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Ito
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya 466-8550, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Plasma Nanotechnology Research Center, Nagoya University, Nagoya 464-8603, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Hori
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: toyokuni@med.nagoya-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D001205:Ascorbic Acid / Q000737:chemistry*; D001343:Autophagy; D045744:Cell Line, Tumor; D002470:Cell Survival; D003676:Deferoxamine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress; D058626:Plasma Gases; D017382:Reactive Oxygen Species / Q000737:chemistry; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D058626:Plasma Gases; D017382:Reactive Oxygen Species; D003676:Deferoxamine; D001205:Ascorbic Acid
keywords: Autophagy; Mesothelioma; Non-thermal plasma (NTP); Reactive oxygen species (ROS); l-ascorbate