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Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis.

ABSTRACT: Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. In this paper, we report the production of mammospheres from three lines of TNBC cells and demonstrate that both parthenolide (PN) and its soluble analog dimethylaminoparthenolide (DMAPT) suppressed this production and induced cytotoxic effects in breast cancer stem-like cells, derived from dissociation of mammospheres. In particular, the drugs exerted a remarkable inhibitory effect on viability of stem-like cells. Such an effect was suppressed by N-acetylcysteine, suggesting a role of reactive oxygen species (ROS) generation in the cytotoxic effect. Instead z-VAD, a general inhibitor of caspase activity, was ineffective. Analysis of ROS generation, performed using fluorescent probes, showed that both the drugs stimulated in the first hours of treatment a very high production of hydrogen peroxide. This event was, at least in part, a consequence of activation of NADPH oxidases (NOXs), as it was reduced by apocynin and diphenylene iodinium, two inhibitors of NOXs. Moreover, both the drugs caused downregulation of Nrf2 (nuclear factor erythroid 2-related factor 2), which is a critical regulator of the intracellular antioxidant response. Prolonging the treatment with PN or DMAPT we observed between 12 and 24 h that the levels of both superoxide anion and hROS increased in concomitance with the downregulation of manganese superoxide dismutase and catalase. In addition, during this phase dissipation of mitochondrial membrane potential occurred together with necrosis of stem-like cells. Finally, our results suggested that the effect on ROS generation found in the first hours of treatment was, in part, responsible for the cytotoxic events observed in the successive phase. In conclusion, PN and DMAPT markedly inhibited viability of stem-like cells derived from three lines of TNBCs by inducing ROS generation, mitochondrial dysfunction and cell necrosis.

SUBMITTER: Carlisi D

PROVIDER: S-EPMC4855673 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Project description:This study investigated the effects of acute stress on breast meat quality, redox status, and mitochondrial function in pectoralis major (PM) muscle of broilers. A total of 168 broiler chickens (42-d-old, Ross 308) were randomly divided into control (CON) and preslaughter transport (T) treatments. A broiler was an experimental unit. Each treatment consisted of 84 broilers, and they were put in 12 crates with 7 broilers each. Broilers in the T group were transported according to a designed protocol, and the CON broilers were kept in crates under normal living conditions before slaughtering. Based on the meat quality traits assessed at postmortem 24 h, all PM muscles of the transported broilers were further classified into normal (T-NOR) and pale, soft, and exudative (PSE)-like (T-PSE) groups for the determination of redox status in PM muscle and isolated mitochondria, energy metabolites, mitochondrial electron transport chain complexes activities, as well as mitochondrial function-modulating genes expression. Compared with CON, the extent of lipid peroxidation as well as protein oxidation were significantly increased in both PM muscles and mitochondria in T-PSE (P < 0.05), whereas not in T-NOR. Higher activities of glutathione peroxidase, total superoxide dismutase, and Cu-Zn superoxide dismutase were observed in PM muscle of T-NOR broilers when compared with CON (P < 0.05). Preslaughter transport increased the generation of reactive oxygen species, as well as enhanced antioxidant capacity in PM mitochondria of broilers (P < 0.05). Compared with CON, the ATP content, activities of complexes I and III, as well as relative mitochondrial membrane potential and swelling were significantly decreased in T-PSE (P < 0.05), whereas no significant changes in either ATP content or complex I activity were observed in T-NOR. Preslaughter transport enhanced the mRNA expression of regulators involved in the glutathione system, thioredoxin 2 system, and mitochondrial biosynthesis in PM muscle of broilers (P < 0.05). Moreover, we noticed a more evident enhancement effect in T-NOR than in T-PSE (P < 0.05). Overall, this work indicates that acute stress-induced redox imbalance and mitochondrial dysfunction have significant implications for the development of PSE-like meat.

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Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis.

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