Current therapeutic regimens are insufficient for treating advanced and metastatic prostate cancer. Compelling evidence suggest existence of concomitant aberrations in both activation of Androgen Receptor (AR) and Protein Kinase-B (AKT) signaling pathway in advanced castration resistant prostate cancer (CRPC). Hence, simultaneous inhibition of both AR and AKT appears to be an effective strategy for the prevention and treatment of CRPC.
We are interested in identifying small molecules from natural plant origin, which targets both AR and AKT signaling for the prevention and treatment of CRPC. Ellagic acid/ellagitannins, abundantly present in the pomegranate and berries, are actively metabolized by the intestinal microflora to Urolithin-A (UA). Oral administration of UA has been equivocally shown to be highly bioavailable in the prostate gland, and is non-toxic.
In our in vitro studies, UA treatment inhibited the growth of both AR-expressing (LNCaP, C42B) and AR-negative (PC-3) prostate cancer cell lines. The molecular analyses suggested that UA transcriptionally regulated AR function and its downstream events in these cell lines. In addition, dihydrotestosterone (DHT) induced AR signaling was attenuated by UA.
While dissecting the effect of UA on AKT signaling, we found UA inhibited pAKT (Ser 473) expression and its pro-survival target genes. Phenotypic analysis confirmed UA reduces the motility and invasive potential of prostate cancer cells by inhibiting the expression of genes that are implicated in the epithelial-to-mesenchymal transition (EMT) (e.g., β-catenin, vimentin, Snail, and Slug).
We also demonstrated the in vivo efficacy of UA against CRPC. Oral administration of UA (50 mg/kg body weight) inhibited prostate tumor growth in xenografts from PC-3 and C4-2B cells. Moreover, histopathological evaluation of the xenografts revealed a marked reduction in the tumor cell density, loss of anisocytosis and anisokaryosis, and lower mitosis in animals that received UA as compared to the control group. Studies are underway to analyze the plasma and tissue levels of UA and our ongoing immunohistochemistry studies may validate the in vitro findings and confirms whether AKT/AR are the target of UA.
Together, these results suggest that targeting and thus, overriding both AR and AKT mediated pro-survival signaling could be an effective strategy for preventing the progression of CRPC.
Citation Format: Manicka V. Vadhanam, Trinath P. Das, Suman Suman, Lakshmanan Annamalai, Chendil Damodaran. Urolithin A (UA) inhibits both androgen receptor and AKT signaling and prevents the progression of castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4651. doi:10.1158/1538-7445.AM2015-4651