Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

• Published in: Cell biology and toxicology 2012-04, Vol.28 (2), p.103-114
• Main Authors: Stulpinas, Aurimas, Imbrasaitė, Aušra, Kalvelytė, Audronė Valerija
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Antibiotics, Antineoplastic - toxicity; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Blotting, Western; c-Jun amino-terminal kinase; c-Jun protein; Cancer; Cell activation; Cell Biology; Cell culture; Cell Culture Techniques; Cell Line; Cell survival; Cell Survival - drug effects; Chemotherapy; Cytotoxicity; Daunorubicin; Daunorubicin - toxicity; Glycogen Synthase Kinases - antagonists & inhibitors; Glycogen Synthase Kinases - metabolism; Heart; Inactivation; Life Sciences; MAP kinase; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Mortality; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Original Research; Pharmacology; Pharmacology/Toxicology; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Rabbits; Signal transduction; Signal Transduction - drug effects; Skeletal muscle; Stem cells; Stem Cells - drug effects; Stem Cells - enzymology; Stem Cells - pathology; Toxicity; Transcription factors; Transfection; Western blotting
• ISSN: 0742-2091; 1573-6822
• DOI: 10.1007/s10565-011-9210-x

Daunorubicin (as well as other anthracyclines) is known to be toxic to heart cells and other cells in organism thus limiting its applicability in human cancer therapy. To investigate possible mechanisms of daunorubicin cytotoxicity, we used stem cell lines derived from adult rabbit skeletal muscle. Recently, we have shown that daunorubicin induces apoptotic cell death in our cell model system and distinctly influences the activity of MAP kinases. Here, we demonstrate that two widely accepted antagonistic signalling pathways namely proapoptotic JNK and prosurvival PI3K/AKT participate in apoptosis. Using the Western blot method, we observed the activation of JNK and phosphorylation of its direct target c-Jun along with inactivation of AKT and its direct target GSK in the course of programmed cell death. By means of small-molecule kinase inhibitors and transfection of cells with the genes of the components of these pathways, c-Jun and AKT, we confirm that JNK signalling pathway is proapoptotic, whereas AKT is antiapoptotic in daunorubicin-induced muscle cells. These findings could contribute to new approaches which will result in less toxicity and fewer side effects that are currently associated with the use of daunorubicin in cancer therapies.