In separate experiments, CellEvent Caspase 3/7 reagent (Life Technologies) was used to evaluate compound ability to trigger apoptosis signaling.
A methoxy group was mandatory at position 6, whereas either H or methoxy was allowed at vicinal position 5. Interestingly, extended SAR studies of xanthones demonstrated that the compounds' ability to trigger MRP1-mediated GSH efflux is not directly linked to MDR-selective toxicity, because several compounds induced a strong GSH efflux but were not selectively cytotoxic.
The average current amplitude of compound EPSCs necessary to trigger a spike at threshold level was maximal (mean = 3.3, s.e.m. = 0.04 nA; n = 10) for EPSCs with fast kinetics (τrise/τdecay 0.1/1 ms), and gradually decreased when the EPSCs became slower (Figure 3E).
In these models therapy is administered before induction of sepsis; as a consequence their findings signify the importance of the administered compound to inhibit triggering of the inflammatory cascade [ 1].
Furthermore, these compounds were able to trigger the secretion of higher levels of pro-inflammatory cytokine (TNF-α) than the well-studied NOD2 agonist, Murabutide.
Selected compounds were able to trigger apoptosis in sensitive cell lines, for example via activation of caspase-3/7, demonstrating that indole-based oxadiazoles possess in vitro antitumour and pro-apoptotic activity.
All 3 compounds were found to trigger expression of the metabolic genes CYP3A4, UGT1A1, and MDR1.
Also, individual compounds were found to trigger specific pathways within the nongenomic signaling network leading to different end points.
Some natural compounds are able to trigger the apoptosis signalling system in cancer cells disturbing their proliferation [ 3, 4], though their molecular mechanisms of action are not always well understood.
In search for strategy to study several natural and synthetic compounds in chemotherapy we (Bodo et al, 2005) and others (Fimognari et al, 2006) recently referred activities of ITCs as 'sensitizers' followed by conventional chemotherapeutic compounds as 'inducers', to trigger inhibition of proliferation and their synergy to stimulate apoptosis in cancer cells.
