The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells
Defeng Xu1, Tzu-Hua Lin, Caixia Zhang
1Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York, USA.
Background:
Androgen receptor (AR) is the main therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy (ADT) is only effective for a short period of time. Here we tested PTS33, a new sodium derivative of cryptotanshinone, which can effectively inhibit the DHT-induced AR transactivation and PCa cell growth, and then explored the effects of PTS33 on inhibiting the expressions of AR target genes and proteins.
Methods:
PCa cells, LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with PTS33 and luciferase assay was used to evaluate the ability of each to regulate AR transactivation. RT-PCR was used to evaluate the mRNA levels of AR target genes such as PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR, PSA, estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and progesterone receptor (PR) protein expression. Cell growth and IC50 were determined by MTT assay after 48 hr treatment.
Results:
Our data showed that PTS33 selectively inhibits AR activities, but PTS33 does not repress the activities of other nuclear receptors, including ERα, GR, and PR. At a low concentration, 2 µM of PTS33 effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Furthermore, our data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 can also inhibit estrogen/Δ5-androstenediol induced AR activities. The mechanistic studies indicate that PTS33 can inhibit AR function by suppression of AR protein expression, the AR N-C interaction, and AR-coregulator interaction.
Conclusions:
PTS33 has shown a good efficacy to inhibit AR transactivation, block AR regulated gene expression, and reduce cell growth in AR positive PCa cells. The structure of PTS33 could be used as a base for development of novel AR signaling inhibitors to treat PCa.
Insights
PTS33, a novel cryptotanshinone derivative, effectively inhibits androgen receptor (AR) activity and prostate cancer (PCa) cell growth. This compound shows promise for developing new AR signaling inhibitors for PCa treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor (AR) is a key target in prostate cancer (PCa) treatment.
- Current androgen depletion therapy (ADT) has limited long-term efficacy.
- PTS33, a cryptotanshinone derivative, is investigated for its anti-cancer properties.
Purpose of the Study:
- To evaluate PTS33's efficacy in inhibiting AR transactivation and PCa cell growth.
- To explore PTS33's effects on AR target gene and protein expression.
- To investigate the mechanisms by which PTS33 inhibits AR function.
Main Methods:
- Treatment of various PCa cell lines (LNCaP, CWR22Rv1, C4-2, PC-3, DU145) with PTS33.
- Luciferase assays for AR transactivation.
- RT-PCR for AR target gene mRNA levels (PSA, TMPRSS2, TMEPA1).
- Western blot for protein expression (AR, PSA, ERα, GR, PR).
- MTT assays for cell growth and IC50 determination.
Main Results:
- PTS33 selectively inhibits AR activity without affecting other nuclear receptors (ERα, GR, PR).
- PTS33 suppresses AR-positive PCa cell growth at low concentrations (2 µM).
- PTS33 modulates AR transactivation and downregulates AR target genes in LNCaP and C4-2 cells.
- PTS33 inhibits AR protein expression, AR N-C interaction, and AR-coregulator interaction.
Conclusions:
- PTS33 effectively inhibits AR transactivation, AR-regulated gene expression, and PCa cell growth.
- The structure of PTS33 serves as a basis for developing novel AR signaling inhibitors.
- PTS33 demonstrates potential as a therapeutic agent for AR-positive prostate cancer.
