Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling.

Abstract

The anti-tumor activity of rapamycin is compromised by the feedback-loop-relevant hyperactive PI3K and ERK-MAPK pathway signaling. In breast cancer cells treated with rapamycin, we observed a moderate increase of AKT phosphorylation (P-AKT) in a rapamycin resistant cell line, MDA-MB-231, as well as a slight increase of P-AKT in a rapamycin sensitive cell line, MCF-7. We found that resveratrol, a natural phytoalexin, suppressed the phosphorylation and activation of the PI3K/AKT pathway in all the three breast cancer cell lines that we tested. It also had a weak inhibitory effect on the activation of the mTOR/p70S6K pathway in two cell lines expressing wildtype PTEN, MCF-7 and MDA-MB-231. The combined use of resveratrol and rapamycin resulted in modest additive inhibitory effects on the growth of breast cancer cells, mainly through suppressing rapamycin-induced AKT activation. We, therefore, reveal a novel combination whereby resveratrol potentiates the growth inhibitory effect of rapamycin, with the added benefit of preventing eventual resistance to rapamycin, likely by suppressing AKT signaling. We also present data herein that PTEN is an important contributor to resveratrol's growth suppressive effects and its potentiation of rapamycin in this therapeutic scenario, as resveratrol's suppression of rapamycin-mediated induction of P-AKT is both PTEN-dependent and -independent. Thus, the resveratrol-rapamycin combination may have therapeutic value in treating breast cancer and perhaps other processes where mTOR is activated.

• Authors: Xin He, Yu Wang, Jinhong Zhu, Mohammed Orloff, Charis Eng
• Journal: Cancer letters (Cancer Lett) Vol. 301 Issue 2 Pg. 168-76 (Feb 28 2011) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 21168265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Membrane Proteins
• Stilbenes
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• TPTE protein, human
• PTEN Phosphohydrolase
• Resveratrol
• Sirolimus

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Immunoblotting
• Inhibitory Concentration 50
• Membrane Proteins (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Resveratrol
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• Stilbenes (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)