Purpose: Docetaxel (dox), a noted radiosensitizer, is one of the few chemotherapy drugs approved for castration-resistant prostate cancer (CRPC), though only a fraction of CRPCs respond to it. CAV-1, a critical regulator of radioresistance, has been known to modulate dox and radiation effects. Combining dox with radiotherapy may create a synergistic anticancer effect through CAV-1 and improve CRPC patients' response to therapy. Here, we investigate the effectiveness and molecular characteristics of dox and radiation combination therapy in vitro.Materials and Methods: We used live/dead assays to determine the IC50 of dox for PC3, DU-145, and TRAMP-C1 cells. Colony formation assay was used to determine the radioresponse of the same cells treated with radiation with/without IC50 dox (4, 8, 12 Gy). We performed gene expression analysis on public transcriptomic data collected from human-derived prostate cancer cell lines (C4-2, PC3, DU-145, LNCaP) treated with dox for 8, 16, and 72 hours. Cell cycle arrest and protein expression were assessed using flow cytometry and western blot, respectively.Results: Compared to radiation alone, combination therapy with dox significantly increased CRPC death in PC3 (1.48-fold, p < 0.0001), DU-145 (1.64-fold, p < 0.05), and TRAMP-C1 (1.13-fold, p < 0.05) at 4 Gy of radiation. Gene expression of CRPC treated with dox revealed downregulated genes related to cell cycle regulation and upregulated genes related to immune activation and oxidative stress. Confirming the results, G2/M cell cycle arrest was significantly increased after treatment with dox and radiation. CAV-1 protein expression was decreased after dox treatment in a dose-dependent manner; furthermore, CAV-1 copy number was strongly associated with poor response to therapy in CRPC patients.Conclusions: Our results suggest that dox sensitizes CRPC cells to radiation by downregulating CAV-1. Dox + radiation combination therapy may be effective at treating CRPC, especially subtypes associated with high CAV-1 expression, and should be studied further.
International journal of radiation biology. 2023 Sep 25 [Epub ahead of print]
Kevin J Tu, Sanjit K Roy, Zachery Keepers, Manas R Gartia, Hem D Shukla, Nrusingh C Biswal
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland., Department of Mechanical Engineering, Louisiana State University, Baton Rouge, LA.