Anticancer Activities and Mechanism of Action of Nagilactones, a Group of Terpenoid Lactones Isolated from Podocarpus Species

Abstract

Nagilactones are tetracyclic natural products isolated from various Podocarpus species. These lactone-based compounds display a range of pharmacological effects, including antifungal, anti-atherosclerosis, anti-inflammatory and anticancer activities reviewed here. The most active derivatives, such as nagilactones C, E and F, exhibit potent anticancer activities against different cancer cell lines and tumor models. A comprehensive analysis of their mechanism of action indicates that their anticancer activity mainly derives from three complementary action: (i) a drug-induced inhibition of cell proliferation coupled with a cell cycle perturbation and induction of apoptosis, (ii) a blockade of the epithelial to mesenchymal cell transition contributing to an inhibition of cancer cell migration and invasion and (iii) a capacity to modulate the PD-L1 immune checkpoint. Different molecular effectors have been implicated in the antitumor activity, chiefly the AP-1 pathway blocked upon activation of the JNK/c-Jun axis. Nag-C is a potent inhibitor of protein synthesis binding to eukaryotic ribosomes and inhibition of different protein kinases, such as RIOK2 and JAK2, has been postulated with Nag-E. The literature survey on nagilactones highlights the therapeutic potential of these little-known terpenoids. The mechanistic analysis also provides useful information for structurally related compounds (podolactones, oidiolactones, inumakilactones) isolated from Podocarpus plants.

Keywords: Cancer; Mechanism of action; Molecular target; Natural products; Terpenoids.

Fig. 1

Chemical structure of the nagilactones. The structure of Nag-H could not be identified

Fig. 2

The three chemical types of tetracyclic nagilactones. They differ by the organization of the conjugated lactone system in the B–C ring moiety. The numbering of the totarane diterpene nucleus is indicated

Fig. 3

The various biological properties of nagilactones, principally isolated from the seeds, roots, foliage of Podocarpus nagi [67] and other Podocarpus species

Fig. 4

Structure–anticancer activity relationships in the Nag-E series. The indicated IC₅₀ values (mM) correspond to the compound concentrations required to reduce proliferation of human epithelial carcinoma A431 cells by 50%, as described by Zheng et al. [15]

Fig. 5

Schematic view of the mechanism of action of antitumor nagilactones (Nag-C–E). Binding of the drug to ribosome leads to protein synthesis inhibition. Binding to the protein kinases RIOK2 and JAK2 has been also reported, leading to inhibition of phospo-STAT3, and then to cancer cell growth inhibition and induction of apoptosis. In addition, Nag-E was found to inhibit epithelial to mesenchymal transition (EMT) of cancer cells, thereby reducing their capacity to migrate and invade tissues (inhibition of metastasis)

Fig. 6

Illustration of Nag-C bound to the 80S ribosome (PDB code U52) [50]. a The entire yeast 80S ribosome, b a focused view of Nag-C at the heart of the ribosome, blocking the peptidyl transferase center, c the molecular contacts (H-bonds and p stacking interactions) between residues of Nag-C and nucleotides of the 25S ribosomal RNA unit, d and e two views of the drug (in yellow) bound to the ribosomal site, in a cavity formed by the indicated RNA nucleotides