Combination of Arsenic trioxide and Everolimus (Rad001) synergistically induces both autophagy and apoptosis in prostate cancer cells.

Sheng Tai,Ming Xu,Kaipin Zhang,Li Zhang,Chaozhao Liang,Ligang Zhang,Lingfan Xu,Yangyang Zhang

doi:10.18632/oncotarget.14493

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.

Highlights

Prostate cancer (PCa) is the most common cause of cancer-related death in the United States [1,2,3]
The colony formation ability in prostate cancer LNCaP and PC3 cells treated with two compounds was significant inhibited at the 14th day, compared with one compound treatment (Figure 2B), suggesting the prostate cancer cells tumorigenesis may be synergistically inhibited with the combination of Arsenic trioxide (ATO) and Rad001 treatment
For PC3 cells, the ED50 for ATO and Rad001 were 24.45 μM and 0.70 μM, respectively. For both PC3 and LNCaP prostate cancer cell lines, the combination of ATO and Rad001 treatment resulted in more reduction of cell luminescent units (Z-axis), compared with either ATO or Rad001 alone treatment (Figure 3B)

Summary

Introduction

Prostate cancer (PCa) is the most common cause of cancer-related death in the United States [1,2,3]. The early stages PCa may be cured by certain therapeutic strategies such as radical surgery or radiation, but the therapeutic effect for advanced and metastatic PCa is poor [4, 5]. It has been reported that the PI3KAKT-mTOR pathway is vital of importance for the PCa progression [8, 9]. The Rad (Figure 1A) is one of the mTOR, the PI3K-AKT-mTOR pathway, specific inhibitors, which may exert a negative effect on the PCa progression. Its therapeutic effect in the PCa is poor, which may be attributable to activation of other bypass signaling pathways [10]. Its severe side effects, hepatic toxicity, cardiac toxicity, granulocytopenia, etc, may confine it therapeutic effect in clinical practice

Methods

Results

Conclusion