Abstract
Prostate cancer (PCa) is the second most prevalent malignancy in men, and therapeutic options become severely limited once androgen deprivation therapy (ADT) fails. This study evaluated the antitumor activity of Annonacin, a natural acetogenin, alone or in combination with docetaxel (DTX) in PCa. The antitumor effects and underlying mechanisms of Annonacin and/or DTX were investigated in DU145 cells and a xenograft mouse model by assessing proliferation, migration, apoptosis, colony formation, DNA damage and FAK expression and distribution. Through an integrated strategy combining network pharmacology and a series of in vitro assays, the findings demonstrated that Annonacin exerts significant antitumor activity by inducing DNA damage and downregulating FAK expression and localisation. Co-treatment with DTX further enhanced these effects, with combination index (CI) values < 1, indicating strong synergism. In vivo, the combination therapy achieved more than 74% tumour growth inhibition (p < 0.0001), accompanied by increased tumour cell death, reduced Ki-67 expression and elevated γ-H2AX levels. Collectively, these findings demonstrate that Annonacin exerts potent antitumor activity and synergistically enhances DTX efficacy by promoting DNA damage and suppressing FAK signalling, supporting its potential as a promising adjuvant candidate for PCa treatment.