Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering

Abstract

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as N-acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity.

Ozone mediates tumor-selective cell death caused by air plasma-activated medium independently of NOx

“…More importantly, it acts on cancer cells preferentially [28]. Notably, our data indicate that ODM .…”

“…The copyright holder for this preprint this version posted March 18, 2023. ; https://doi.org/10.1101/2023.03.17.533239 doi: bioRxiv preprint Air plasma and APAM were prepared as reported previously [28]. Briefly, the plasma was generated from the ambient air using a Piezobrush TM PZ2 model plasma jet (relyon, Germany) equipped with a piezo element.…”

“…The mitochondrial morphology and positioning and tubulin were analyzed as previously described [28]. Briefly, cells FBS/DMEM were seeded at a 5 x 10 4 /mL density in a 35 mm Poly-Lysine-coated glass bottom dish, as described above, and treated with agents at 37 °C for 2 or 18 h in a 5% CO 2 incubator.…”

“…APAM can induce apoptosis and nonapoptotic cell death in OC cells depending on the cell line and concentration [28]. Therefore, we examined whether ODM had similar effects.…”

“…PNMC participates in cancer adaptation to hypoxia through mitochondrial reactive oxygen species (ROS) production and Hypoxia-inducible factor-1α, the master transcription factor of hypoxic signaling [26]. Recently, we reported another type of mitochondrial distribution associated with cancer cell death [28]. In this case, mitochondria become fragmented and gather one side of the perinuclear sites.…”