An isoflavone type secondary metabolite Glabrescione B

An isoflavone type secondary metabolite, Glabrescione B (GlaB), from Derris glabrescens (Benth.) J.F. Macbr. from the family Fabaceae, was found to possess the capacity to bind the Gli1 zinc finger domain and to further block DNA binding capacity [118]. Pyrvinium, an anthelmintic drug approved by the FDA, was shown to possess strong inhibitory action on the Hedgehog pathway [119]. FN1-8 was demonstrated to be active against diverse cancer cells characterized by Gli activation, including colon, pancreatic and prostate malignancies [120]. Natural compounds, namely zerumbone, physalin, staurosporinone and arcyriaflavin C, were characterized as molecules with Gli transcription inhibition activity [121]. Zerumbone, the main compound of Zingiber zerumbet (L.) Sm. (Zingiberaceae) extract, enhanced apoptosis and inhibited invasion of cancer cells, revealing antitumor effects when administrated in leukemia and breast, liver, lung and pancreatic cancers via inhibition of Gli1 and Gli2, as well as SHh signaling gene-mediated transcription [[121], [122], [123], [124], [125]]. Among the other natural Hh inhibitors there is curcumin, a very well-known agent with anti-cancer effects from the same plant family, Zingiberaceae. It is derived from the plant Curcuma longa L. and has been investigated as a cancer preventive agent in recent years [126,127]. This compound was reported to inhibit prostate cancer cell growth by inhibiting SHh signaling via downregulation of SHh pathway proteins, as well as enhancing the antitumor activity of cisplatin and γ-rays [128,129]. Moreover, genistein, one of the soy isoflavones from Glycine max (L.) Merr. (Fabaceae), was shown to display high antiproliferative action in breast, prostate, gastric, membrane transport colon and skin cancer cells [130]. Genistein inhibited prostate cancer cell growth and exerted anti-CSC effect via inhibition of SHh signaling [128,131]. Resveratrol, a polyphenolic compound obtained from Vitis vinifera L. (Vitaceae) and Polygonum cuspidatum Siebold & Zucc. (Polygonaceae), was associated with the ability to inhibit human cancer cell proliferation including chronic myeloid leukemia (CML) cells and reduce carcinogenesis in vivo through inhibition of the SHh pathway and mediation of Bcr-Abl expression [128,[132], [133], [134]]. Norcantharidin is a demethylated analog derived from cantharidin which was isolated from Mylabris phalerata Pall. and was reported to induce cell anoikis and apoptotic processes, also inhibiting the invasion, angiogenesis and metastasis processes [135,136] and combating the installation of mutidrug resistance through inhibition of SHh signaling and expression of downstream multidrug resistance genes [128]. Epigallocatechin-3-gallate (EGCG) from Camellia sinensis (L.) Kuntze (Theaceae), was reported to possess inhibitory abilities upon the SHh pathway, inducing apoptosis and suppressing proliferation in human chondrosarcoma cells [137]. In addition, EGCG was demonstrated to reduce prostate cancer cell growth via suppression of Gli1 transcript [128] and self-renewal abilities of pancreatic CSCs by inhibiting the SHh pathway components and Gli transcriptional activity [138]. Withaferin A and its derivatives from the leaves of Withania somnifera were identified as Gli1-mediated transcriptional inhibitors. The compounds displayed cytotoxic effects on Hh signaling-positive cancer cell lines including DU145, MCF7 and PANC-1 by suppressing target proteins within the Hh signaling pathway, Hh ligand receptor PTCH and anti-apoptosis protein BCL-2. In addition, Withaferin A showed inhibitory action on the formation of the Gli1-DNA complex [139]. Berberine, an isoquinoline alkaloid isolated from Berberis species, inhibits Hh signaling through modulation of Smo, most probably through direct targeting. A similar mechanism of action was found for Vitamin D3, which was found to bind Smo at the same site with cyclopamine, further inhibiting Hh signaling [117]. Even if the classical concept associates Gli inhibition with beneficial effects in cancer treatment, more insights are required on the mechanisms involved before progressing into clinical trials. Specifically, impairment of the Hh/Gli pathway could sustain the progression of disease, as this pathway is involved in repair and regeneration processes. For example, inhibition of Hh signaling in bladder cancer stroma resulted in accelerated progression of the malignancy [140]. Also, there are several other natural agents considered to have activity upon Hh signaling; these potential compounds were extensively reviewed by Bao et al. [117].