Maduramicin inhibits proliferation and induces apoptosis in myoblast cells.

Abstract

Maduramicin, a polyether ionophore antibiotic derived from the bacterium Actinomadura yumaensis, is currently used as a feed additive against coccidiosis in poultry worldwide. It has been clinically observed that maduramicin can cause skeletal muscle and heart cell damage, resulting in skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. However, the mechanism of its toxic action in myoblasts is not well understood. Using mouse myoblasts (C2C12) and human rhabdomyosarcoma (RD and Rh30) cells as an experimental model for myoblasts, here we found that maduramicin inhibited cell proliferation and induced cell death in a concentration-dependent manner. Further studies revealed that maduramicin induced accumulation of the cells at G0/G1 phase of the cell cycle, and induced apoptosis in the cells. Concurrently, maduramicin downregulated protein expression of cyclin D1, cyclin-dependent kinases (CDK4 and CDK6), and CDC25A, and upregulated expression of the CDK inhibitors (p21Cip1 and p27Kip1), resulting in decreased phosphorylation of Rb. Maduramicin also induced expression of BAK, BAD, DR4, TRADD and TRAIL, leading to activation of caspases 8, 9 and 3 as well as cleavage of poly ADP ribose polymerase (PARP). Taken together, our results suggest that maduramicin executes its toxicity in myoblasts at least by inhibiting cell proliferation and inducing apoptotic cell death.

• Authors: Xin Chen, Ying Gu, Karnika Singh, Chaowei Shang, Mansoureh Barzegar, Shanxiang Jiang, Shile Huang
• Journal: PloS one (PLoS One) Vol. 9 Issue 12 Pg. e115652 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25531367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Lactones
• Proto-Oncogene Proteins c-bcl-2
• Cyclin-Dependent Kinase Inhibitor p27
• maduramicin
• Poly(ADP-ribose) Polymerases
• Cyclin-Dependent Kinases
• Caspases

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Cyclins (metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Lactones (pharmacology)
• Mice
• Myoblasts (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rhabdomyosarcoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured