Inhibition of Gli/hedgehog signaling in prostate cancer cells by “cancer bush” Sutherlandia frutescens extract

Abstract

Sutherlandia frutescens is a medicinal plant traditionally used to treat various types of human diseases, including cancer. Previous studies of several botanicals link suppression of prostate cancer growth with inhibition of the Gli/hedgehog (Gli/Hh) signaling pathway. Here we hypothesized the anti-cancer effect of S. frutescens was linked to its inhibition of the Gli/Hh signaling in prostate cancer. We found a dose- and time- dependent growth inhibition in human prostate cancer cells PC3 and LNCaP, and mouse prostate cancer cells TRAMP-C2 treated with S. frutescens methanol extract (SLE). We also observed a dose-dependent inhibition of the Gli-reporter activity in Shh Light II and TRAMP-C2QGli cells treated with SLE. In addition, SLE can inhibit Gli/Hh signaling by blocking Gli1 and Ptched1 gene expression in the presence of a Gli/Hh signaling agonist (SAG). A diet supplemented with S. frutescens suppressed the formation of poorly differentiated carcinoma in prostates of TRAMP mice. Finally, we found Sutherlandioside D was the most potent compound in the crude extract that could suppress Gli-reporter in Shh Light II cells. Together this suggests that the S. frutescens extract may exert anti-cancer effect by targeting Gli/Hh signaling, and Sutherlandioside D is one of the active compounds.

The Implication of Chemotypic Variation on the Anti-Oxidant and Anti-Cancer Activities of Sutherlandia frutescens (L.) R.Br. (Fabaceae) from Different Geographic Locations

“…This is interesting as there has been a perception, since the isolation and purification of this chemical, that it could play a strong role in the cytotoxicity actions of Sutherlandia plants and it may have other pharmacological functions, hence it is monitored in products manufactured from the raw materials of this species [5]). Recently, the study of Lin et al [17] showed those fractions with sutherlandioside D to have high anti-tumorogenic effects against prosrate cancer using an in vivo setup suggesting that these anti-cancer effects are exerted through Gli/Hn signaling pathways that control cell patterning and formation plus proliferation in animal cells. A previous study identified a sutherlandioside D isomer in plants obtained from the Gansbaai area [5] but plants from the Northern Cape had sutherlandioside B and C [6].…”

“…At this stage, it is unclear which chemicals in the extract possess the highest anti-cancer action although new information related to this aspect is starting to appear in the literature as fractions with high amounts of sutherlandioside D were recently found to be more potent against prostate cancer cells [17]. It would thus be interesting to further the tests on pure samples of sutherlandins and sutherlandioside in terms of their anti-oxidant and anti-cancer inhibition effects.…”

“…Ntuli et al [16] showed anti-mutagenic effects of ethyl acetate and methanol extracts using an AMES analysis. Several authors use commercially available products of Sutherlandia to obtain plant material for pharmacological testing (see work of Leisching et al [9]; Ntuli et al [16]; Lin et al, [17]; and Van Der Walt et al [18]). However, the manufacturers of these products do not necessarily attest to the origins of the chemotypes used in the manufacturing process and neither do they indicate where the mother stock plants used for building an agricultural crop of the species actually came from.…”

Unveiling the anti-inflammatory activity of Sutherlandia frutescens using murine macrophages

“…It is entirely possible that these compounds exhibit important biological activities other than those examined here and in cells other than macrophages. For example, collaborators have recently reported dose- and time-dependent growth inhibition in human prostate cancer cells from a methanolic extract from this botanical [39]. While others have recently reported that a S. frutescens extract down-regulated PI-3 kinase and Akt phosphorylation in human colon cancer cells [40].…”

Preliminary Cytotoxic Activity of Sutherlandia frutescens and Carpobrotus edulis on Malignant glioblastoma Cells

“…[18][19][20][21][22] More so, S. frutescens has been reported to show anti-cancer activity in prostate cancer as it induced cytotoxicity in human prostate cancer cells DU-145, PC3, LNCaP and mouse prostate cancer cell, TRAMP-C2. 20,23 It also induced apoptosis and inhibited the PI3K-kinase cell survival pathway in CaCo2 colon cancer cells. 24 More recently, our laboratory also reported that S. frutescens induced cytotoxicity and apoptosis in SKNBE(2) and SH-SY5Y neuroblastoma cells via the accumulation of intracellular reactive oxygen species (ROS) and depolarization of mitochondria membrane potential (MMP).…”