title: Mechanisms underlying the anticancer activities of the angucycline landomycin E.
abstract: Anthracyline antibiotics, produced by Streptomyces sp., still rank among the most efficient anticancer drugs in clinical use. Aim of this study was to gain deeper insight into the anticancer properties of the anthracycline-related angucycline landomycin E (LE). The impact of LE on nuclear morphology was assessed by 4',6-diamidino-2-phenylindole (DAPI) staining in the human carcinoma cell model KB-3-1. LE treatment led to the appearance of typical morphological signs of programmed cell death like cell shrinkage, chromatin condensation and formation of apoptotic bodies. Apoptotic cell death induced by LE was further characterised by caspase (substrate) cleavage and intense mitochondrial membrane depolarisation (JC-1 and rhodamine 123 staining) already after 1h drug incubation. Moreover, incubation with LE led to reduced intracellular ATP pools suggesting LE-induced apoptotic cell death as a consequence of rapid mitochondrial damage. Furthermore, LE treatment led to profound generation of intracellular oxidative stress, indicated by radical scavenger pre-treatment and dichlorofluorescin diacetate (DCF-DA) staining experiments. Since chemoresistance is a common problem in cancer therapy, we also investigated the influence of ABCB1 (P-glycoprotein, P-gp), ABCC1 (multidrug resistance-related protein, MRP1) and ABCG2 (breast cancer resistance protein, BCRP) overexpression on the anticancer activity of LE. Compared to anthracyclines, cytotoxic activity of LE was only weakly reduced by P-gp and MRP1 overexpression. Moreover, BCRP expression had no influence on LE anticancer activity. In summary, LE exerts anticancer activity via potent induction of apoptosis and has promising anticancer activity even against multidrug resistant (MDR) cells. Taken together, these data suggest further development of LE as a new anticancer drug.
authors: Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine.
authors: Alla
authors: A
authors: Korynevska
authors: Petra
authors: P
authors: Heffeter
authors: Bohdan
authors: B
authors: Matselyukh
authors: Leonilla
authors: L
authors: Elbling
authors: Michael
authors: M
authors: Micksche
authors: Rostyslav
authors: R
authors: Stoika
authors: Walter
authors: W
authors: Berger
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D018384:Oxidative Stress
chemical_list: D000617:Aminoglycosides; D000970:Antineoplastic Agents; C113593:landomycin E