Abstract
Landomycin A (LA) is a new antitumor antibiotic of angucycline group, possessing high antitumor activity against cancer cells of different origin, which induces early apoptosis in target cells. It was shown that under LA action the level of reactive oxygen species (ROS) in human T-leukemia cells had increased 5.6 times in comparison to control already at the 1st hour after the addition of studied antibiotic to the culture medium. At the 6th hour after incubation of cells with LA the nucleosomal DNA cleavage, chromatin condensation and nucleus fragmentation were observed, indicating apoptotic cell death. Catalase (scavenger of hydrogen peroxide), mannitol (scavenger of hydroxyl radicals) and superoxide dismutase (scavenger of superoxide radicals) reduced the level of ROS production under LA, suggesting the generation of H2O2, OH* and O2- radicals, respectively. It was revealed that catalase and mannitol effectively inhibited LA-mediated tumor cell death, increasing 2.5 times the percentage of alive cells in comparison to LA. However, superoxide dismutase had no significant inhibitory effect on cytotoxic activity of LA, indicating the minor role of superoxide anions in the implementation of antitumor activity of this antibiotic. Combination of catalase, mannitol and superoxide dismutase with LA increased 4-fold the percentage of alive cells in comparison to the action of LA. Dynamics of ROS formation confirms that the increase of ROS is a very rapid process, but at the same time it is not a direct consequence of apoptosis triggering, mediated by mitochondria.
Highlights
Chemotherapy, targeted on the level of reactive oxygen species modulating (ROS) in tumor cells, is considered the most promi sing and effective strategy in the fight against cancer [1,2,3]
It is known that normal cells are characterized by a powerful antioxidant defense system that effectively eliminates free radicals, which are the byproducts of oxidative phosphorylation in the mitochondria
Previous studies showed that landomycin A acts as a prooxidant, so the aim of this study was to clarify the role of ROS in apoptotic death of tumor cells induced by this antibiotic
Summary
Chemotherapy, targeted on the level of reactive oxygen species modulating (ROS) in tumor cells, is considered the most promi sing and effective strategy in the fight against cancer [1,2,3]. Above threshold ROS concentrations are not toxic to malignant cells, a further sudden increase in the level of free radicals in tumor cells by exog nous ROS-induced agents causes their rapid death. This special feature of malignant cells makes them promising target for anticancer drugs which induce oxidative stress in tumor cells [2]. Previous studies showed that landomycin A acts as a prooxidant, so the aim of this study was to clarify the role of ROS in apoptotic death of tumor cells induced by this antibiotic
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