*3.2. Tanshinone and AR*

Androgen is very important for PCa. It is reported that testosterone, after binding to hormone ligands, is transferred to the nucleus and combined with androgen response elements (ARE) located in the promoter region of genes involved in cell proliferation and escape from apoptosis to promote the growth and development of PCa cells. It can also promote the growth and development of PCa by activating other extracellular signaling pathways that crosstalk with androgen signaling pathways [113,114]. Androgen deprivation therapy (ADT) is widely used as a first-line treatment method for metastatic androgen-dependent PCa. However, accept the ADT after treatment of PCa, often in about two years into a more aggressive PCa (CRPC) [4]. Previous views that CRPC does not depend on the nourishment effect of androgens; however, recent laboratory evidence suggests that CRPC still relies on androgen to nourish them either by synthesizing more bioactive androgen through themselves and the adrenal cortex or by increasing the expression of ARs and inducing them to mutate into a more active form to tolerate low androgen levels induced by castration therapy [115–117]. Therefore, inhibition of androgen nourishing effects is of great significance for the treatment of PCa.

Interestingly, Tanshinone inhibits androgen signaling through a variety of mechanisms. Cryptotanshinone has been reported to have a chemical structure similar to dihydrotestosterone (DHT), the most effective androgen for AR activation, and can bind to AR receptors as a competitive antagonist of DHT, thereby inhibiting DHT-mediated AR trans-activation [46]. Tanshinone also has a significant regulatory effect on the expression and activity of AR. According to current published reports, Tanshinone can not only directly inhibit the expression of AR [34,40], but also increase the monomethyl and dimethylation of lysine 9 (H3K9) of histone H3 by targeting the lysine-specific demethylase 1 (LSD1) complex. In addition, AR activity and expression can be inhibited by inhibiting AR N and C terminal dimerization and the formation of an AR-regulator complex [46,55], and reducing the availability of AR by overexpressing heat shock protein (Hsp90) can be changed [30], and it also has a regulatory effect on ARE [46]. Tanshinone, by regulating ARE, can inhibit the transcriptional regulation of AR signaling to its target genes. In addition, Tanshinone also regulates AR receptor mutations. In a study by Liu et al., Tanshinone IIA and its derivatives not only significantly inhibited AR expression but also acted as effective inhibitors of AR receptor mutations, thereby inhibiting AR receptor mutations [41]. Furthermore, it also has a certain regulatory effect on androgen secretion. Previous studies have shown that Tanshinone can not only regulate the expression of key enzymes related to androgen biosynthesis but also regulate extracellular signal-regulated kinase (ERK)/C-FOS/17, 20-lyase (CYP17), leading to androgen biosynthesis levels being down [118,119]. However, it is worth noting that, in addition to having similar pharmacological effects, Tanshinone has other advantages over existing anti-male drugs. As reported, Tanshinone derivatives can significantly inhibit AR trans-activation mediated by 17-estradiol (E2) and androgen-5–Δene-3, 7-diol (Δ5-androstenediol or Adiol) [55]. E2 and Adiol are natural hormones in PCa cells. Because current adt-related drugs do not target these two natural hormones, and because they have the characteristics of converting to testosterone and even acting as effective activators of the AR signaling pathway, they are significantly associated with drug resistance and castration resistance in PCa [120,121]. Secondly, in a clinical trial, LinTH et al. found that although the use of enzaluamide and bicaluamide could lead to the reduction of the primary tumor and PSA, the invasion of PCa cells was significantly enhanced, while the use of Tanshinone could not only achieve the reduction of the primary tumor and PSA but also inhibit PCa cell invasion to a certain extent [53]. Similarly, for other steroid receptors present in PCa, Tanshinone has been reported to inhibit prostatic stromal and epithelial proliferation by down-regulating estrogen receptorα (ERα) [122]. Interestingly, ER is limited to basal cells and stromal cells of the prostate epithelium [123]. It is associated with mitogen-activated protein kinase (MAPK) activity and maintenance of the phosphoinositol 3-kinase (PI3K) signaling pathway in PCa [124].

In short, the occurrence and progression of prostate cancer are inextricably linked to the nourishing effect of androgens. Even if it is CCRP, inhibiting the nourishing effect of androgen in prostate cancer is still the primary purpose of endocrine therapy for prostate cancer. Therefore, as previously described, Tanshinone has a significant inhibitory effect not only on androgen biosynthesis but also on the expression and synthesis of various proteins and genes related to the androgen pathway. Tanshinone has been shown to be more effective than some anti-androgenic drugs because, when compared to these anti-androgenic drugs, Tanshinone not only achieves the same effect but also inhibits prostate cancer cell metastasis. In fact, compared with traditional antiandrogenic drugs, the inhibition of the androgenmediated signaling pathway by Tanshinone is multi-pathway and multi-target. These data once again confirm the possibility of Tanshinone as an anti-prostate drug.
