Phytol Suppresses Androgen Receptor Nuclear Localization and Doubles Survival in Nude Mice Bearing...

Androgen receptor (AR) plays a pivotal role in the development and progression of prostate cancer by regulating the expression of androgen-responsive genes. AR must translocate into the nucleus to exert its gene-regulatory functions. Disruption in AR nuclear localization or its cytoplasmic retention hampers its ability to activate target genes, thus impeding prostate cancer progression. Taraxacum officinale (dandelion) is a medicinal herb with potent anticancer properties, rich in antioxidants, flavonoids, and nutrients, dandelion serves as a promising herbal nutraceutical and superfood for cancer prevention. The study aimed to explore plant-based molecules from Taraxacum officinale (dandelion) capable of modulating AR nuclear localization in recurrent prostate cancer cells in vitro and in vivo. 400 plants were collected and 25,000 extracts were prepared using solvents of varying polarity (Indian Patent Grant No. 499495) and were screened for abrogation of Nuclear-cytoplasmic localization of AR. Phytochemical screening led to the isolation of Phytol (3,7,11,15-tetramethylhexadec-2-en-1-ol) (TaxO) from the hexane extract of Taraxacum officinale L leaves. The effects of TaxO was evaluated in vitro using the castration-resistant prostate cancer cell line C4-2, androgen-responsive cell line LNCaP, and AR-negative cell line PC3. Expression of AR and androgen-responsive genes, including EAF2, PSA, and CALR, were analyzed via RT-PCR. Inhibition of cellular proliferation and migration was assessed in vitro. Comparative transcriptomic analysis (RNA-Seq) was conducted to elucidate the mechanistic differences between treated and control groups. Molecular docking studies were conducted to evaluate interactions between TaxO and the AR ligand-binding domain. Finally, in vivo efficacy was examined using C4-2, LNCaP and PC3 xenograft mouse models, including immunohistochemistry (IHC) for AR, Ki67, CD31, and PSA. PK/PD analysis was carried out to assess the safety profile of TaxO. TaxO abrogated nuclear localization of GFP-tagged AR. TaxO significantly downregulated AR-responsive gene expression, EAF2, ELL2, PSA, and CALR and inhibited cell proliferation and migration of C4-2 and LNCaP cells. Transcriptomic profiling revealed major alterations in oncogenic signaling pathways post-TaxO treatment. Molecular docking confirmed strong binding between TaxO and the AR ligand-binding domain, driven by van der Waals forces and hydrogen bonding. In the xenograft model, TaxO markedly reduced tumor volume and doubled the life expectancy of mice harboring C4-2 and LNCaP prostate cancer cells. IHC revealed downregulation of AR and PSA levels and showed a reduction in Ki67 and CD31 index. However, PC3 cells were not affected by TaxO implicating that TaxO inhibits cancer cell growth through the AR-mediated pathway. The study demonstrates that TaxO, a phytochemical (Phytol) isolated from the hexane extract of Taraxacum officinale leaves, effectively modulates androgen receptor (AR) nuclear localization, thereby inhibiting prostate cancer progression. In vitro, TaxO significantly downregulated AR and androgen-responsive gene expression (EAF2, ELL2, PSA, CALR), reduced cell proliferation and migration in AR-positive C4-2 and LNCaP cell lines but showed no effect on AR-negative PC3 cells, indicating an AR-mediated mechanism. Transcriptomic analysis revealed disruptions in oncogenic signaling pathways, while molecular docking confirmed TaxO's strong binding to the AR ligand-binding domain. In vivo, TaxO reduced tumor volume, downregulated AR, PSA, Ki67, and CD31 protein expression, and doubled life expectancy in C4-2 and LNCaP xenograft mouse models. Pharmacokinetic and pharmacodynamic analyses further supported TaxO's favorable safety profile. These findings highlight TaxO as a promising plant-based therapeutic candidate for targeting AR-driven prostate cancer, warranting further clinical investigation.