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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.

SUBMITTER: Tai S 

PROVIDER: S-EPMC3374015 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Tai Sheng S   Sun Yin Y   Liu Nan N   Ding Boxiao B   Hsia Elaine E   Bhuta Sunita S   Thor Ryan K RK   Damoiseaux Robert R   Liang Chaozhao C   Huang Jiaoti J  

Molecular cancer therapeutics 20120405 6

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  ...[more]

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