Research Papers:
Combination of Arsenic trioxide and Everolimus Rad001 synergistically induces both autophagy and apoptosis in prostate cancer cells
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Sheng Tai1,2, Lingfan Xu1,2, Ming Xu1,2, Ligang Zhang1,2, Yangyang Zhang1,2, Kaipin Zhang1,2, Li Zhang1,2, Chaozhao Liang1,2
1The Department of Urology, The First Affiliated Hospital of Anhui Medical University, China
2The Department of Urology, The Urological Institute of Anhui Medical University, China
Correspondence to:
Sheng Tai, email: taishengwk@163.com
Chaozhao Liang, email: Liang__chaozhao@163.com
Keywords: Rad001, ATO, synergism, autophagy, prostate cancer
Received: August 05, 2016 Accepted: December 27, 2016 Published: January 04, 2017
ABSTRACT
The inhibitor of PI3K-AKT-mTOR pathway, such as Rad001, has not shown therapeutic efficacy as a single agent in prostate cancer. Arsenic trioxide induces the autophagic pathway in prostate cancer cells. We identified Arsenic trioxide can synergize with Rad001 to induce cytotoxicity of prostate cancer cells. Moreover, we identified synergistic induction of autophagy and apoptosis as the underlying mechanism. This enhanced autophagic cell death is accompanied by increased Beclin1 mRNA stability as well as upregulation of ATG5-ATG12 conjugate, Beclin1, and LC3-2. Rad001 and ATO also can synergistically inhibit tumors in prostate cancer xenograft animal model. These results identify and validate a novel mechanism to enhance and expand the existing targeted therapeutic agent to treat prostate cancer.