RT Journal Article
SR Electronic
T1 Synergistic anticancer effect of plasma-activated infusion and salinomycin by targeting autophagy and mitochondrial morphology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.14.340208
DO 10.1101/2020.10.14.340208
A1 Takashi Ando
A1 Manami Suzuki-Karasaki
A1 Miki Suzuki-Karasaki
A1 Jiro Ichikawa
A1 Toyoko Ochiai
A1 Yukihiro Yoshida
A1 Hirotaka Haro
A1 Yoshihiro Suzuki-Karasaki
YR 2020
UL http://biorxiv.org/content/early/2020/10/15/2020.10.14.340208.abstract
AB Non-thermal atmospheric plasma (NTAP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines showed much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anti-cancer stem cell agent, mutually operated as adjuvants. Combined administration of PAI and Sal was much more effective than single agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 in a rapid and transient manner. PAI also suppressed the ambient autophagic flux by activating the mammalian target of rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.Competing Interest StatementMa.S.K. (Manami Suzuki-Karasaki), Mi.S.K. (Miki Suzuki-Karasaki), and Y.S.K. are employees of the Non-Profit Institute Plasma ChemiBio Laboratory. The remaining authors have no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.