Mechanistic Pathways and Molecular Targets of Plant-Derived Anticancer ent-Kaurane Diterpenes

Abstract

Since the first discovery in 1961, more than 1300 ent-kaurane diterpenoids have been isolated and identified from different plant sources, mainly the genus Isodon. Chemically, they consist of a perhydrophenanthrene subunit and a cyclopentane ring. A large number of reports describe the anticancer potential and mechanism of action of ent-kaurane compounds in a series of cancer cell lines. Oridonin is one of the prime anticancer ent-kaurane diterpenoids that is currently in a phase-I clinical trial in China. In this review, we have extensively summarized the anticancer activities of ent-kaurane diterpenoids according to their plant sources, mechanistic pathways, and biological targets. Literature analysis found that anticancer effect of ent-kauranes are mainly mediated through regulation of apoptosis, cell cycle arrest, autophagy, and metastasis. Induction of apoptosis is associated with modulation of BCL-2, BAX, PARP, cytochrome c, and cleaved caspase-3, -8, and -9, while cell cycle arrest is controlled by cyclin D1, c-Myc, p21, p53, and CDK-2 and -4. The most common metastatic target proteins of ent-kauranes are MMP-2, MMP-9, VEGF, and VEGFR whereas LC-II and mTOR are key regulators to induce autophagy.

Nucleophosmin in Its Interaction with Ligands

“…Another natural compound that has shown efficacy against NPM1c+ is Oridonin [130]. This is a plant-derived tetracycline diterpenoid that holds anticancer and antiproliferative activities in a number of tumors, inducing apoptosis in cancer cell lines of diverse origin [131]. Oridonin treatments of OCI-AML3 cells dose-dependently inhibited viability and caused NPM1c+ translocation to the nucleus, likely due to CRM1 (Chromosomal Region Maintenance 1) nuclear accumulation, together with unchanged total NPM1 protein levels.…”

Bioactive Ent-Kaurane Diterpenes Oridonin and Irudonin Prevent Cancer Cells Migration by Interacting with the Actin Cytoskeleton Controller Ezrin

“…In this context, it is worthwhile to mention that MMP-2, MMP-9, VEGF and VEGFR have been recently identified as the most common metastatic target proteins of ent-kauranes [ 3 ], although the mechanism of action through which they regulate these protein targets remains largely unknown. However, in many cancer cell lines, the MMP-2 and MMP-9 expression at both transcriptional and translational levels was regulated by PI3-K/AKT signalling pathway [ 27 , 28 , 29 ].…”

“…Several plant-derived bioactive compounds have anticancer properties [ 1 , 2 ]. Among them, 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 ].…”

“…Among them, 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 ]. Oridonin (Ori) is a widely investigated compound derived from Isondon rubescens , a Chinese herb retaining various pharmacological features such as anti-inflammatory, anti-bacterial, and anticancer properties [ 4 ].…”

“…Oridonin (Ori) is a widely investigated compound derived from Isondon rubescens , a Chinese herb retaining various pharmacological features such as anti-inflammatory, anti-bacterial, and anticancer properties [ 4 ]. Therefore, Ori was one of the first diterpenoids undergoing clinical trial [ 3 , 4 , 5 , 6 , 7 ]. Several studies have reported that Ori prevents cell growth and invasion by inhibiting distinct signalling pathways in a wide range of cancer cells.…”