Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells.

Abstract

PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5-Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies.

• Authors: Sheng Tai, Yin Sun, Nan Liu, Boxiao Ding, Elaine Hsia, Sunita Bhuta, Ryan K Thor, Robert Damoiseaux, Chaozhao Liang, Jiaoti Huang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 6 Pg. 1320-31 (Jun 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22491797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2012 AACR

Chemical References

• ATG12 protein, human
• ATG5 protein, human
• Acetanilides
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 12
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• Microtubule-Associated Proteins
• Small Ubiquitin-Related Modifier Proteins
• propachlor
• Everolimus
• Sirolimus

Topics

• Acetanilides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy
• Autophagy-Related Protein 12
• Autophagy-Related Protein 5
• Beclin-1
• Cell Line, Tumor
• Drug Synergism
• Everolimus
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, SCID
• Microtubule-Associated Proteins (genetics, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Sirolimus (analogs & derivatives, pharmacology)
• Small Ubiquitin-Related Modifier Proteins (genetics, metabolism)