Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells

Abstract

Androgen receptor (AR) is the major 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 is only effective for a period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selective inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR–coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.

Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis

“…Unlike the currently used anti-androgens that reduce or prevent androgen binding to AR, the newly developed anti-AR compound, ASC-J9, has the unique capability to degrade AR protein in selective cells. On the other hand, CTS also could suppress the AR activity by inhibition of N-terminal and C-terminal interaction or change the histone methylation pattern to reduce the AR transcriptional activity (12,28).…”

“…trast, we found that the newly developed AR degradation enhancers, ASC-J9 (8 -11) and cryptotanshinone (CTS) (12), could simultaneously suppress PCa cell growth and invasion, which might help us to develop a new therapy to better battle the metastatic PCa at the castration-resistant stage.…”

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

“…In the present study, we investigated the anticancer activity of CPT in colorectal cancer. The concentration of CPT used in the current study was based on that of a previous study in mice where a 25 mg/kg dose of CPT (human equivalent dose of 2.34 mg/kg) was used and found to be well tolerated with no reported toxicity [39]. In Fig.…”

Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling

“…Recently, CPT was reported to inhibit the androgen receptor activity and suppress prostate cancer growth in androgen-dependent manner, but the reason for that is not due to the direct bind to androgen receptor and is attributed to its functional inhibition of LSD1-mediated demethylation of H3K9. 19,20 Thanshinone I has been reported to induce apoptosis of breast cancer cells, 27 so it is possible that Thanshinone I also could inhibit ER transcriptional activity due to the similarity of the chemical structures of Thanshinone I and CPT. However, we found that anshinones I less effectively inhibited E2-induced transcriptional activity and expression of the ER target gene (pS2, and Cat D) in the presence of E2, compared with CPT, which is consistent with the same inhibitory effect of anshinones I on ERpositive as well as ER-negative cancer cells.…”

“…[14][15][16][17] Recently, CPT has also been reported to have obvious antitumor activity in a variety of cancer cells, including prostate carcinoma, hepatocarcinoma, rhabdomyosarcoma and melanoma cells. [18][19][20][21][22][23] In breast carcinoma cells, CPT has been shown to inhibit MCF7 cell proliferation by suppressing mTOR mediated CyclinD1 expression and Rb phosphorylation that lead to MCF7 cell apoptosis by inducing stress in the endoplasmic reticulum (ER). 24,25 However, it is not known whether CPT has any effects on estrogen-stimulated ER signaling and estrogen /ER mediated cancer cell growth.…”