Abstract
The cytotoxic mechanism of the saponin QS-21 and its aglycone quillaic acid (QA) was studied on human gastric cancer cells (SNU1 and KATO III). Both compounds showed in vitro cytotoxic activity with IC50 values: 7.1 μM (QS-21) and 13.6 μM (QA) on SNU1 cells; 7.4 μM (QS-21) and 67 μM (QA) on KATO III cells. QS-21 and QA induce apoptosis on SNU1 and KATO III, as demonstrated by TUNEL, Annexin-V and Caspase Assays. Additionally, we performed in silico docking studies simulating the binding of both triterpenic compounds to key proteins involved in apoptotic pathways. The binding energies (∆Gbin) thus calculated, suggest that the pro-apoptotic protein Bid might be a plausible target involved in the apoptotic effect of both triterpenic compounds. Although QA shows some antiproliferative effects on SNU1 cells cultured in vitro, our results suggest that QS-21 is a more powerful antitumor agent, which merits further investigation regarding their properties as potential therapeutic agents for gastric cancer.
Highlights
The cytotoxic mechanism of the saponin Quillaja saponaria Molina (QS)-21 and its aglycone quillaic acid (QA) was studied on human gastric cancer cells (SNU1 and KATO III)
In order to determine the therapeutic potential of QS-21 and QA on the treatment of gastric cancer, we first tested their impact on the viability of the in vitro cell lines KATO III, SNU1 and GES-1, using the MTS test[11]
QA and QS-21 were cytotoxic to KATO III and SNU1 tumor lines in a dose dependent way (Fig. 2A, B); both compounds were barely cytotoxic on GES-1 cells, a human normal cell line employed as control (Fig. 2A, B)
Summary
The cytotoxic mechanism of the saponin QS-21 and its aglycone quillaic acid (QA) was studied on human gastric cancer cells (SNU1 and KATO III). The bark of Quillaja saponaria Molina (QS)—an evergreen tree native from Chile—is widely used as a source of physiologically active saponins based on the triterpenic aglycone quillaic acid (QA) The latter is a pentacyclic triterpenoid, i.e. olean-12-ene substituted by hydroxy groups at positions 3 and 16, an oxo group at position 23 and a carboxyl group at position 28. The purpose of this study was to determine the in vitro therapeutic potential and the cytotoxic mechanism of saponin QS-21 and its aglycone QA on two cell lines of human GC (SNU1 and KATO III). To complement the in vitro study and to attain insight on the mechanism of action of QS-21 and QA to trigger cell death, we performed molecular docking studies of these compounds with known 3D structures of the proteins involved in cell death signaling, such as Death Receptor (DR4), FAS-protein and C-Jun-N-terminal Kinase (JNK1), RAC-alpha serine/threonine-protein kinase (AKT1), pro-apoptotic protein BAX, BID, and fibroblast growth factor receptor 2 (FGFR-2); all of these proteins are key components in the extrinsic apoptotic pathway and overexpressed in solid tumors c ell[8,9,10]
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