Related Experiment Video
Updated: May 31, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy
Hifzur Rahman Siddique1, Shrawan Kumar Mishra, R Jeffery Karnes
1Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, USA.
Purpose:
Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration-resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify those agents that could target AR for both disease types. We provide mechanism-based evidence that lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of androgen receptor (AR) in vitro and in vivo.
Experimental Design:
Normal prostate epithelial cell (RWPE-1), LAPC4 (wild functional AR/ADPC), LNCaP (mutant functional/AR/ADPC), and C4-2b (mutant functional/AR/CRPC) cells were used to test the anti-AR activity of lupeol. Cells grown under androgen-rich environment and treated with lupeol were tested for proliferation, AR transcriptional activity, AR competitive ligand binding, AR-DNA binding, and AR-ARE/target gene binding. Furthermore, in silico molecular modeling for lupeol-AR binding was done. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intraperitoneally with lupeol (40 mg/kg; 3 times/wk) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, lupeol serum levels were measured.
Results:
Lupeol significantly inhibited R1881 (androgen analogue) induced (i) transcriptional activity of AR and (ii) expression of PSA. Lupeol (i) competed antagonistically with androgen for AR, (ii) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK, and IL-6, and (iii) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to antihormone therapy. High-performance liquid chromatography analysis showed that lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels.
Conclusion:
Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP.
Insights
Lupeol effectively inhibits the androgen receptor (AR), showing potential as a novel treatment for both androgen-dependent and castration-resistant prostate cancer (CaP). This natural compound demonstrates bioavailability and anti-tumor activity in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Conventional prostate cancer (CaP) therapies are often ineffective against androgen-dependent (ADPC) and castration-resistant (CRPC) phenotypes.
- Targeting the androgen receptor (AR) is crucial for developing effective treatments for all stages of CaP.
Purpose of the Study:
- To investigate lupeol as a potential AR inhibitor for both ADPC and CRPC.
- To provide mechanism-based evidence for lupeol's anti-AR activity in vitro and in vivo.
Main Methods:
- Utilized various prostate cancer cell lines (RWPE-1, LAPC4, LNCaP, C4-2b) to assess lupeol's anti-AR effects.
- Evaluated lupeol's impact on cell proliferation, AR transcriptional activity, ligand binding, and AR-DNA binding.
- Conducted in silico molecular modeling and in vivo studies in athymic mice bearing human CaP xenografts.
Main Results:
- Lupeol significantly inhibited AR transcriptional activity and PSA expression induced by an androgen analogue.
- Lupeol competitively inhibited androgen binding to AR and blocked AR binding to target genes, including PSA.
- In vivo studies demonstrated lupeol's bioavailability, inhibition of tumor growth in both ADPC and CRPC models, and reduced PSA levels.
Conclusions:
- Lupeol acts as a potent inhibitor of the androgen receptor.
- Lupeol exhibits potential as a therapeutic agent for treating human prostate cancer.
