Impairment of Nucleolin Activity and Phosphorylation by a Trachylobane Diterpene from Psiadia punctulata in Cancer Cells

Abstract

Human nucleolin (hNcl) is a multifunctional protein involved in the progression of various cancers and plays a key role in other pathologies. Therefore, there is still unsatisfied demand for hNcl modulators. Recently, we demonstrated that the plant ent-kaurane diterpene oridonin inhibits hNcl but, unfortunately, this compound is quite toxic for healthy cells. Trachylobane diterpene 6,19-dihydroxy-ent-trachiloban-17-oic acid (compound 12) extracted from Psiadia punctulata (DC.) Vatke (Asteraceae) emerged as a ligand of hNcl from a cellular thermal shift assay (CETSA)-based screening of a small library of diterpenes. Effective interaction between this compound and the protein was demonstrated to occur both in vitro and inside two different types of cancer cells. Based on the experimental and computational data, a model of the hNcl/compound 12 complex was built. Because of this binding, hNcl mRNA chaperone activity was significantly reduced, and the level of phosphorylation of the protein was affected. At the biological level, cancer cell incubation with compound 12 produced a cell cycle block in the subG0/G1 phase and induced early apoptosis, whereas no cytotoxicity towards healthy cells was observed. Overall, these results suggested that 6,19-dihydroxy-ent-trachiloban-17-oic could represent a selective antitumoral agent and a promising lead for designing innovative hNcl inhibitors also usable for therapeutic purposes.

Exploring the Anticancer Potential of Premna resinosa (Hochst.) Leaf Surface Extract: Discovering New Diterpenes as Heat Shock Protein 70 (Hsp70) Binding Agents

“…The objective of this study is to isolate specialized metabolites from the fresh leaf exudate of P. resinosa, as several studies have highlighted the potential anticancer properties of plant exudates [12][13][14][15][16]. Previous research has focused on investigating the polar fractions of this species, elucidating their anti-angiogenic effect through the presence of iridoid glycosides such as bundlejoside A5 and saccatoside [6].…”

“…In the present study, we explore the less polar metabolites extracted from the leaf surface. In the literature, numerous plants with anticancer activity have been reported to possess multiple mechanisms of action due to the diversity of phytoconstituents in different organs of the same plants [16,17]. It is worth noting that even the same phytoconstituent could exhibit multiple mechanisms of action, as exemplified by curcumin and resveratrol [18].…”