ONC201, the anticancer drug, targets and activates mitochondrial ATP-dependent caseinolytic peptidase P (ClpP), a serine protease located in the mitochondrial matrix. Given the promise of ONC201 in cancer treatment, we evaluated its effects on the breast ductal carcinoma cell line (BT474). We showed that the transient single-dose treatment of BT474 cells by 10 µM ONC201 for a period of less than 48 h induced a reversible growth arrest and a transient activation of an integrated stress response indicated by an increased expression of CHOP, ATF4, and GDF-15, and a reduced number of mtDNA nucleoids. A prolonged exposure to the drug (>48 h), however, initiated an irreversible loss of mtDNA, persistent activation of integrated stress response proteins, as well as cell cycle arrest, inhibition of proliferation, and suppression of the intrinsic apoptosis pathway. Since Natural Killer (NK) cells are quickly gaining momentum in cellular anti-cancer therapies, we evaluated the effect of ONC201 on the activity of the peripheral blood derived NK cells. We showed that following the ONC 201 exposure BT474 cells demonstrated enhanced sensitivity toward human NK cells that mediated killing. Together our data revealed that the effects of a single dose of ONC201 are dependent on the duration of exposure, specifically, while short-term exposure led to reversible changes; long-term exposure resulted in irreversible transformation of cells associated with the senescent phenotype. Our data further demonstrated that when used in combination with NK cells, ONC201 created a synergistic anti-cancer effect, thus suggesting its possible benefit in NK-cell based cellular immunotherapies for cancer treatment.

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This study explored the effect of mesenchymal stem cells (MSC) conditioned medium (CM) on the severity of systemic inflammatory response caused by acetaminophen administration. The long-term effects of the toxin on the liver tissue were analysed. The effect of a fraction of the conditioned medium on the functional activity of isolated neutrophils was investigated using a model of sterile inflammation. The study showed that the >30 kDa CM fraction possesses the maximum protective effect. Proteins of this fraction reduce the severity of the systemic inflammatory reaction and the extent of liver tissue fibrosis after the toxin injection in the long term. By using the sterile inflammation model, CM was shown to reduce the complex activity of NADPH oxidase, which leads to a decrease in the total reactive oxygen species production. The CM derived from the cultivation of stem cells reduces the severity of the systemic inflammatory response through suppression of the functional activity of neutrophils.

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