Anti-Proliferative Effects of Dihydrotanshinone I on Autosomal Dominant Polycystic Kidney Disease via Immunomodulation

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder affecting individuals worldwide and is one of the leading causes of end-stage renal disease. Based on the shared pathogenic mechanisms between cancer and ADPKD, we explored the potential of repurposing dihydrotanshinone I (DHTS), a compound previously shown to possess anticancer properties, for ADPKD treatment. Using sulforhodamine B cytotoxic and real-time cell analysis, we evaluated the effects of various DHTS concentrations on WT 9-12 (ADPKD) cells for up to 72 hours. Our results revealed a concentration-dependent decrease in WT 9-12 cell viability, with minimal impact on HK-2 (normal kidney) cells. Notably, 32 μM DHTS was identified with an IC50 after 24 hours of treatment on WT 9-12 cells. Cell cycle analysis further indicated that 32 μM DHTS-induced G1 phase arrest in WT 9-12 cells. We determined that DHTS has a preference for necrosis over apoptosis in WT 9-12 cells in the apoptosis analysis. To elucidate the underlying molecular mechanisms, we employed isobaric tags for relative and absolute quantitation-based proteomic analysis to identify differentially expressed proteins and reveal their intricate interplay and the signaling pathways modulated by DHTS treatment. Some of our key findings include enhanced immune surveillance and its role in suppressing metabolic pathways that promote ADPKD progression in WT 9-12 cells prior to DHTS treatment. After DHTS exposure, these pathways appeared to be modulated, with a potential restoration of extracellular matrix regulation. However, DHTS treatment may have failed to reinstate metabolic suppression in untreated WT 9-12 cells. Overall, our results highlight the therapeutic potential of DHTS in slowing ADPKD progression, offering promise for a safer and more effective treatment approach that targets the underlying disease mechanisms rather than merely managing symptoms. SIGNIFICANCE STATEMENT: This study found that dihydrotanshinone I (DHTS) suppressed autosomal dominant polycystic kidney disease (ADPKD) cell proliferation through G1 phase cell cycle arrest and enhanced necrosis. DHTS treatment may also modulate the increased immune surveillance shown in untreated ADPKD cells. Upon understanding its implicated signaling pathways and assuring its safety on normal cells, the DHTS-induced antiproliferative effects on ADPKD cells prove the potential of DHTS as alternative treatment for ADPKD.