Prostate cancer (PC) is the second most common cancer in men worldwide. Despite recent advances in diagnosis and treatment, castration-resistant prostate cancer (CRPC) remains a significant medical challenge. Prostate cancer cells can develop mechanisms to resist androgen deprivation therapy, such as AR overexpression, AR mutations, alterations in AR coregulators, increased steroidogenic signaling pathways, outlaw pathways, and bypass pathways. Various treatment options for CRPC exist, including androgen deprivation therapy, chemotherapy, immunotherapy, localized or systemic therapeutic radiation, and PARP inhibitors. However, more research is needed to combat CRPC effectively. Further investigation into the underlying mechanisms of the disease and the development of new therapeutic strategies will be crucial in improving patient outcomes. The present work summarizes the current knowledge regarding the underlying mechanisms that promote CRPC, including both AR-dependent and independent pathways. Additionally, we provide an overview of the currently approved therapeutic options for CRPC, with special emphasis on chemotherapy, radiation therapy, immunotherapy, PARP inhibitors, and potential combination strategies.

Despite significant advances in antisense oligonucleotide (ASO) chemistry and nanocarrier design, therapeutic efficacy is often limited by inefficient cellular uptake and sequestration within endosomal–lysosomal compartments. Here, we show that ionizing radiation can be leveraged to overcome these barriers and enhance antisense nanomedicine delivery in castration-resistant prostate cancer (CRPC). CRPC cells (PC-3, C4-2) exhibited greater resistance to irradiation than castration-sensitive prostate cancer cells (LNCaP) and upregulated heat shock protein 27 (HSP27) in response to radiation, indicating an adaptive stress response. HSP27 downregulation by HSP27 mRNA -targeting ASO restored radiation-induced apoptotic signaling. To improve intracellular delivery, we developed lipid-modified ASOs (LASOs) targeting HSP27 mRNA that self-assemble into nanomicelles and enter cells via macropinocytosis. Although LASOs showed enhanced cellular uptake, they were predominantly sequestered within endosome–lysosome compartments, limiting their therapeutic activity. Strikingly, irradiation promoted endosomal-lysosomal escape of LASO nanomicelles, facilitating cytoplasmic delivery, robust HSP27 suppression, ultimately leading to increased anti-cancer effects, including an approximately 75% reduction in CRPC cell viability and delayed CRPC 3D spheroid growth. Collectively, these findings reveal a bidirectional therapeutic synergy in which HSP27 silencing resensitizes CRPC cells to radiation while irradiation enhances LASO intracellular trafficking. This study establishes irradiation as a trigger for intracellular drug release and provides a synergistic strategy integrating radiotherapy with antisense nanomedicine to overcome delivery barriers and restore therapeutic efficacy in CRPC.

Management of advanced solid cancers remains challenging, particularly after the development of therapeutic resistance. Here, we synthesized a library of phosphonium-substituted 5-fluorouracil (5-FU) derivatives and evaluated their anticancer activity across multiple tumor models. Among fourteen compounds, EB-18 emerged as the lead candidate, displaying sub-micromolar cytotoxicity in both androgen receptor (AR)-negative PC-3 and AR-positive C4-2 castration-resistant prostate cancer (CRPC) cells and activity across several other malignant solid-tumor cell lines. EB-18 inhibited proliferation, migration, and three-dimensional spheroid growth and induced cell-cycle perturbation and apoptosis. Mechanistic studies in vitro showed that EB-18 disrupted HSP27-associated survival signaling, promoted ubiquitination and proteasome-dependent degradation of DDX5, and suppressed AKT/mTOR signaling. In addition, EB-18 also increased γ-H2AX and reduced Ku70/Ku80 expression, consistent with perturbation of the DNA damage response. AR downregulation was additionally observed in AR-positive C4-2 cells. EB-18 retained activity in patient-derived organoids and multidrug-resistant CRPC cells and significantly inhibited tumor growth in PC-3 xenografts. Collectively, these findings identify EB-18 as a promising anticancer candidate with activity in treatment-resistant CRPC and provide a rationale for further pharmacological, mechanistic, and translational evaluation. Graphical Abstract EB-18, a novel 5-FU derivative, demonstrates superior anticancer activity compared with 5-FU and clinically used chemotherapies (Docetaxel, Cabazitaxel, and Mitoxantrone) across multiple preclinical models, including 2D/3D CRPC cell models, prostate cancer patient-derived organoids, PC-3 xenografts, and multidrug-resistant PC-3 cells, supporting its potential to overcome acquired drug resistance. Mechanistically, EB-18 exerts multifaceted antitumor effects by disrupting the HSP27/DDX5 axis and DNA damage-response machinery, promoting DNA damage and apoptosis, while suppressing AKT/mTOR prosurvival signaling. In AR-positive CRPC cells, EB-18 additionally reduces AR expression. Together, these effects inhibit cancer cell proliferation and survival and support EB-18 as a promising therapeutic candidate for treatment-resistant cancer.