Background: The lethality of prostate cancer is mainly due to metastasis. Inhibition of
metastasis is expected to be a promising approach for prostate cancer therapy. Phosphatidylinositol
3-kinase (PI3K)/Akt pathway is reported to be closely involved in cell growth, migration, etc.
Objective: The study investigated the antimetastatic activities of pan-PI3K inhibitor ZSTK474 on
Methods: 1. The In vitro effect of ZSTK474 on the migration, invasion and adhesion of DU145
cells was determined with Transwell migration assay and wound healing assay, Tranwell invasion
assay and adhesion assay, respectively. 2. In vitro effect of ZSTK474 on the signal proteins in
DU145 cells was determined with Western blot analysis and ELISA. 3. Moreover, the In vivo antimetastatic
effect of ZSTK474 was evaluated with MicroCT and histology analysis.
Results: ZSTK474 potently attenuated the capability of migration, invasion and adhesion of DU145
cells, negatively regulated Girdin, Integrinβ1 and matrix metalloproteinases (MMPs). In addition,
the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor
(VEGF), which are known to be related to angiogenesis and metastasis, was also inhibited. Oral
administration of ZSTK474 (200 mg/kg) ameliorated in vivo bone metastasis of DU145 cells, with
improved bone structure and bone mineral density (BMD). Tissue staining indicated a reduction in
metastatic DU145 cells and osteoclasts in the bones of ZSTK474-treated mice, compared with the
Conclusion: Our result demonstrated the antimetastatic activity of ZSTK474 on prostate cancer
DU145 cells, suggesting the potential application in prostate cancer patients.