A novel protoapigenone analog RY10-4 induces breast cancer MCF-7 cell death through autophagy via the Akt/mTOR pathway.

Abstract

Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells is exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, Western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggesting that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed the activation of mTOR and p70S6K via the Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design a promising antitumor agent.

• Authors: Xuenong Zhang, Han Wei, Ziwei Liu, Qianying Yuan, Anhua Wei, Du Shi, Xian Yang, Jinlan Ruan
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 270 Issue 2 Pg. 122-8 (Jul 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23624174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)pyran-4-one
• Antineoplastic Agents
• Pyrones
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, ethnology, pathology)
• Cell Survival (drug effects)
• Female
• Humans
• MCF-7 Cells
• Microscopy, Electron, Transmission
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrones (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)