Castration-resistant
prostate cancer (CRPC) is an advanced form of
prostate cancer associated with poor survival rates. The high proliferation and
metastasis rates have made CRPC one of the most challenging types of
cancer for medical practitioners and researchers. In this study, the anti-
cancer properties and inhibition of CRPC progression by S. neglecta extract and its active constituents were determined using two CRPC cell lines, DU145 and PC3. The
ethyl acetate fraction of S. neglecta (SnEA) was obtained using a
solvent-partitioned extraction technique. The active constituents of SnEA were then determined using the HPLC technique, which showed that SnEA mainly contained
syringic acid,
pyrogallol, and
p-coumaric acid phenolic compounds. After the determination of cytotoxic properties using the SRB assay, it was found that
pyrogallol, but not the other two major compounds of SnEA, displayed promising anti-
cancer properties in both CRPC cell lines. SnEA and
pyrogallol were then further investigated for their anti-proliferation and apoptotic induction properties using
propidium iodide and
Annexin V staining. The results showed that SnEA and
pyrogallol inhibited both DU145 and PC3 cell proliferation by inducing cell cycle arrest in the G0/G1 phase and significantly decreased the expression of cell cycle regulator
proteins (
cyclin D1,
cyclin E1, CDK-2, and CDK-4, p < 0.001). SnEA and
pyrogallol treatments also promoted apoptosis in both types of CRPC cells through significantly downregulating
anti-apoptotic proteins (
survivin, Bcl-2, and Bcl-xl, p < 0.001) and upregulating apoptotic
proteins (cleaved-
caspase-9, cleaved-
caspase-3 and cleaved-PARP-1, p < 0.001). Mechanistic study demonstrated that SnEA and
pyrogallol inactivated the Akt signaling pathway leading to enhancement of the active form of GSK-3β in CRPC cell lines. Therefore, the phosphorylation of β-
catenin was increased, which caused degradation of the
protein, resulting in a downregulation of β-
catenin (unphosphorylated form) transcriptional factor activity. The current results reflect the potential impact of S. neglecta extract and
pyrogallol on the management of
castration-resistant
prostate cancer.