RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Preparações de Plantas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Equador , Humanos , Kalanchoe/química , Masculino , Camundongos Nus , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Caribbean tropical tree, Pimenta dioica has been used for a variety of human endeavors, such as in perfumery industry, food spice, as a natural pesticide, and in folk medicine. Discovered in Jamaica during the voyages of Christopher Columbus, the dried unripe berries of P. dioica also known as Allspice can be found in all continents with unique names in over 50 languages. Systematic investigation of aromatic constituents of Pimenta leaves and its unripe berries, Allspice, have resulted in discovery of many and novel aromatic compounds, mostly glycosides and polyphenols that show antibacterial, hypotensive, anti-neuralgic and analgesic properties. Recent studies have shown two of the known compounds isolated from Allspice, Eugenol and Gallic acid have selective antiproliferative and anti-tumor properties on human cancer cells and their animal models. New characterization of novel compounds such as Ericifolin from the aqueous extract of Allspice berries show potent anti-prostate cancer and anti-breast cancer properties that can be verified in vitro as well as in vivo. Considering its purity, mostly available as "organically grown" berries, availability at low cost, wide acceptance in culinary delights of many cultures world-wide, Allspice may have an additional space in most households, in their medicine cabinets.