Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase-3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT/Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

Background: Cytoreductive radical prostatectomy (RP), transurethral resection of the prostate, and radiation therapy were the main local treatments for oligometastatic prostate cancer (PCa). An optimal local treatment for metastases PCa was not consensus. The purpose of this study was to evaluate the effect on these local treatments for patients with metastases PCa.Methods: All relevant studies were systematically searched through PubMed, Web of Science through November 1, 2021. Studies were screened by inclusion and exclusion criteria. Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) were evaluated by this meta-analysis.Results: Eleven studies were identified that met the inclusion criteria. 644 patients received cytoreductive surgery, 8556 patients received no surgery or radiation therapy (RT), and 461 patients received RP + androgen deprivation therapy compared with 746 patients who received RT. Pooled data indicated that cytoreductive surgery significantly prolonged the PFS (OR = 0.65, 95% CI 0.53-0.80, P < .0001), CSS and OS (OR = 0.49, 95% CI 0.43-0.56, P < .00001; and OR = 0.80, 95% CI 0.72-0.88, P < .00001; respectively). Comparing cytoreductive surgery with RT, CSS, and OS were similar (OR = 0.82, 95% CI 0.67-1.01, P = .06; and OR = 0.93, 95% CI 0.79-1.09, P = .39; respectively).Conclusions: Cytoreductive radical prostatectomy significantly prolonged the PFS for metastatic PCa. Although OS was considered a-not-so significant difference between cytoreductive surgery and non-local therapy, non-local treatment was not recommended.Abbreviations: ADT = androgen deprivation therapy, CSS = cancer-specific survival, mHSPC = metastatic hormone-sensitive prostate cancer, OR = odds ratio, OS = overall survival, PCa = prostate cancer, PFS = progression-free survival, RP = radical prostatectomy, SEER = Surveillance Epidemiology and End Results, TURP = transurethral resection of the prostate.