The Impact of Tumor Microenvironmental Acidity on Bicalutamide Sensitivity in Prostate Cancer Cells Publisher



Golmohammadi P ; Haghani I ; Menbari Oskouie I ; Mashhadi R ; Rezaeian A ; Aghamir SMK
Source: Prostate Cancer Published:2026

Abstract

Background: Prostate cancer is the second most commonly diagnosed cancer worldwide. Although androgen deprivation therapy initially demonstrates clinical benefit, disease relapse with more aggressive phenotypes frequently occurs. The acidic tumor microenvironment in solid tumors may alter drug responsiveness. This study investigates how extracellular pH influences the cytotoxic effects of bicalutamide in human prostate cancer cell lines. Methods: PC3 and LNCaP cells were exposed to bicalutamide at varying concentrations at pH 7.4 and pH 6.8. IC50 values were determined using the MTT assay. Cell migration, apoptosis, and cell cycle distribution were evaluated by wound-healing assay, annexin V/PI staining, and DNA content analysis, respectively. The expression of BAX, BCL2, E-cadherin, N-cadherin, SNAI1, AR, and VEGF-C was quantified by qPCR. Results: Bicalutamide (140 μg/mL) reduced PC3 cell viability to 39.62% at pH 7.4 compared with 51.36% at pH 6.8. In LNCaP cells, viability declined to 33.64% at pH 7.4% and 56.09% at pH 6.8. Treated PC3 cells exhibited significantly greater migration at pH 6.8 (p < 0.01). Early apoptosis in treated LNCaP cells was significantly reduced at pH 6.8 (p < 0.001). Both cell lines demonstrated enhanced S phase accumulation and reduced G1-phase distribution at pH 6.8. The BAX/BCL2 ratio was significantly decreased at pH 6.8, indicating the suppression of proapoptotic signaling. Additionally, genes associated with epithelial–mesenchymal transition (EMT) were upregulated, and VEGF-C and AR expression increased at pH 6.8 (p < 0.05). Conclusion: The efficacy of bicalutamide in prostate cancer cells is significantly influenced by extracellular pH. The drug exerts stronger cytotoxic, antimigratory, and proapoptotic effects at physiological pH (7.4) compared with acidic conditions (6.8). Copyright © 2026 Pedram Golmohammadi et al. Prostate Cancer published by John Wiley & Sons Ltd.