The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer

Abstract

BIRM is an anticancer herbal formulation from Ecuador. Previous study established its antitumor and antimetastatic activity against prostate cancer models. The activity of BIRM against human prostate cancer (PCa) cells was investigated to uncover its mechanism of antitumor activity. In androgen receptor (AR)-expressing PCa cells BIRM was 2.5-fold (250%) more cytotoxic in presence of androgen (DHT) compared to cells grown in the absence of DHT. In AR-positive cells (LAPC-4 and LNCaP) BIRM caused a dose and time-dependent down-regulation of AR and increased apoptosis. Exposing cells to BIRM did not affect the synthesis of AR and AR promoter activity but increased degradation of AR via proteasome-pathway. BIRM caused destabilization of HSP90-AR association in LAPC-4 cells. It induced apoptosis in PCa cells by activation of caspase-8 via death receptor and FADD-mediated pathways. A synthetic inhibitor of Caspase-8 cleavage (IETD-CHO) aborted BIRM–induced apoptosis. The effect of BIRM on AKT-mediated survival pathway in both AR+ and AR- negative (PC-3 and DU145) showed decreased levels of p-AKTser 473 in all PCa cell lines. BIRM dosed by oral gavage in mice bearing PC-3ML tumors showed selective efficacy on tumor growth; before tumors are established but limited efficacy when treated on existing tumors. Moreover, BIRM inhibited the LNCaP tumor generated by orthotropic implantation into dorsal prostate of nude mice. Partial purification of BIRM by liquid-liquid extraction and further fractionation by HPLC showed 4-fold increased specific activity on PCa cells. These results demonstrate a mechanistic basis of anti-tumor activity of the herbal extract BIRM.

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

“…A potent derivate, DIM (3, 3′‐diindolylmethane) from indole‐3‐carbitol (I3C) have been shown to downregulate AR and AKT signaling which resulted in inhibition of growth in both cell culture and animal models . Similarly, a herbal formulation from Ecuador, BIRM effectively suppressed AR signaling in AR + (LAPC‐4 and LNCaP) cell lines and orthotopic models of CaP . Studies suggested that curcumin analogs suppress DHT‐induced AR activation in AR + CaP cells …”

“…29 Similarly, a herbal formulation from Ecuador, BIRM effectively suppressed AR signaling in AR + (LAPC-4 and LNCaP) cell lines and orthotopic models of CaP. 30 Studies suggested that curcumin analogs suppress DHT-induced AR activation in AR + CaP cells. 31 UroA has been shown to be effective against various carcinomas, and mechanistic studies have reported two primary mechanisms: cell cycle arrest and induction of apoptosis.…”

Potential Therapeutic Effects of Underground Parts ofKalanchoe gastonis-bonnierion Benign Prostatic Hyperplasia

“…Thus, the effects of KGB on BPH seem very interesting, since this disease is largely characterized by an imbalance between the proliferation and apoptosis [4, 7, 8, 11]. Furthermore, it was recently shown that KGB underground parts were able to abrogate the androgen signaling in prostate malignant cell lineages, besides inducing the apoptosis via caspase 8 activation, thus reinforcing the therapeutic potential of KGB in prostatic diseases [39].…”

Anti-Prostate Cancer Activity of Plant-Derived Bioactive Compounds: a Review

“…Methanolic extract of Kalanchoe gastonis-bonnieri roots contains uronic acid. The induction of caspase-8-mediated apoptosis was observed in DU145, LNCaP, and PC-3 cells exposed to this extract results in [22]. Evasion of apoptosis is one of the classic features of cancer cells.…”