Modulation of Tumour-Related Signaling Pathways by Natural Pentacyclic Triterpenoids and their Semisynthetic Derivatives

Abstract

Pentacyclic triterpenoids are a large class of natural isoprenoids that are widely biosynthesized in higher plants. These compounds are potent anticancer agents that exhibit antiproliferative, antiangiogenic, antiinflammatory and proapoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not yet been established. To date, a huge number of semisynthetic derivatives have been synthesized in different laboratories on the basis of triterpenoid scaffolds, and many have been assayed for their biological activities. The present review focuses on natural triterpenoids of the oleanane-, ursane- and lupane-types and their semisynthetic derivatives. Here, we summarize the diverse cellular and molecular targets of these compounds and the signal pathways involved in the performance of their antitumour actions. Among the most relevant mechanisms involved are cell cycle arrest, apoptosis and autophagy triggered by the effect of triterpenoids on TGF-β and HER cell surface receptors and the downstream PI3KAkt- mTOR and IKK/NF-kB signaling axis, STAT3 pathway and MAPK cascades.

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis

“…As we focus our attention on the mechanisms underlying precisely the pro-apoptogenic activity of SM, we decided to use 1 μM of the compound as the working concentration. Moreover, according to our recent review [4], similar concentrations were used in the majority of works investigated the mechanisms of antitumor effects of other cyano enone-bearing triterpenoids that can give opportunity to compare our results with these data. Previously we showed that SM at 1 μM induced apoptotic changes in KB-3-1 cells within 18 h of the treatment [11].…”

“…Pentacyclic triterpenoids (PTs) are one of the most extensively investigated classes of natural compounds. In a wide range of works it was shown that PTs display antiproliferative activity against a huge range of tumor cells, causing cell cycle arrest, the triggering of apoptosis and autophagy and inhibiting the growth and metastasis of tumors on different murine transplantable, xenograft and carcinogen-induced tumor models in vivo [4]. In recent decades, increasing research efforts were devoted to the development of chemical derivatives of PTs, with the goal of obtaining more pronounced biological activity and selectivity of action.…”

“…In recent decades, increasing research efforts were devoted to the development of chemical derivatives of PTs, with the goal of obtaining more pronounced biological activity and selectivity of action. Some of the most successful examples of semisynthetic triterpenoids are the oleanolic acid derivative CDDO-Me and its analogs (Figure 1A), bearing cyano enone functionality in ring A [4]. Such compounds were shown to be not only cytotoxic for tumor cells, but also can modify tumor microenvironment by inducing phase 2 detoxifying enzymes’ expression [5], inhibiting inflammation response [5, 6] and triggering repolarization of tumor associated macrophages to M1 phenotype [7], thus displaying a complex effect on tumor growth.…”

“…Analysis of published data, performed by us, revealed poor understanding of mechanisms underlying the antitumor effect of PTs in CC cells (Supplementary Table 1). This fact can be explained by the multitarget mode of action of PTs in tumor cells and the high complexity of cellular signaling [4]. In order to deeply understand the intracellular perturbations caused by triterpenoids and reveal their primary targets, a complex view of the processes induced by the compounds in cells is highly needed.…”

Modular Characteristics and Mechanism of Action of Herbs for Endometriosis Treatment in Chinese Medicine: A Data Mining and Network Pharmacology–Based Identification

“…Natural pentacyclic triterpenoids and their semisynthetic derivatives are involved in cell cycle arrest, apoptosis, and autophagy, triggered by the effects of triterpenoids on TGF-b and HER cell surface receptors. They also induce the PI3KAkt-mTOR and IKK/NF-kB signaling pathways, and the STAT3 and MAPK pathways (Markov et al, 2017). Luteolin, could inhibit the development of endometriosis by regulating the expression of PI3K/Akt signaling, the MAPK signaling pathway, and CCNE1 protein in human VK2/E6E7 and End1/E6E7 cell lines and in the endometriosis mouse model (Yi et al, 2018).…”