Abstract
The ent-kaurane diterpene oridonin was reported to inhibit cell migration and invasion in several experimental models. However, the process by which this molecule exerts its anti-metastatic action has not been yet elucidated. In this article, we have investigated the anti-metastatic activity of Oridonin and of one homolog, Irudonin, with the aim to shed light on the molecular mechanisms underlying the biological activity of these ent-kaurane diterpenes. Cell-based experiments revealed that both compounds are able to affect differentiation and cytoskeleton organization in mouse differentiating myoblasts, but also to impair migration, invasion and colony formation ability of two different metastatic cell lines. Using a compound-centric proteomic approach, we identified some potential targets of the two bioactive compounds among cytoskeletal proteins. Among them, Ezrin, a protein involved in the actin cytoskeleton organization, was further investigated. Our results confirmed the pivotal role of Ezrin in regulating cell migration and invasion, and indicate this protein as a potential target for new anti-cancer therapeutic approaches. The interesting activity profile, the good selectivity towards cancer cells, and the lower toxicity with respect to Oridonin, all suggest that Irudonin is a very promising anti-metastatic agent.
Highlights
Several plant-derived bioactive compounds have anticancer properties [1,2]
Further evidences have shown that Ori was able to inhibit, in vitro, invasion of breast cancer cells either by reducing Matrix Metalloproteinases (MMP)-9 and MMP-2 expression, or by regulating the integrin β1/FAK pathway [9]
Our result showed an increase in the Tm of Ezrin following the incubation with both compounds, passing from about 51 ◦C in the cells incubated with the vehicle to 53 ◦C and 54 ◦C in the cells treated with Ori or Iru, respectively (Figure 4C,D)
Summary
Ent-kaurane diterpenoids have certainly attracted particular attention among investigators because of their biological activity and safety profile [3]. Those compounds belong to a subclass of tetracyclic diterpenes containing a kaurane scaffold, with configurational inversion at all chiral centres, known as ent-kaurane diterpenes [3]. Further evidences have shown that Ori was able to inhibit, in vitro, invasion of breast cancer cells either by reducing MMP-9 and MMP-2 expression, or by regulating the integrin β1/FAK pathway [9]. In human breast cancer cells, Ori inhibits cell proliferation, migration, and invasion via a negative modulation of the Notch pathway, and reduces tumor mass in a nude mouse model [10]
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