Anti-Cancer Potential of Synthetic Oleanolic Acid Derivatives and Their Conjugates with NSAIDs.

Wanda Baer-Dubowska,Violetta Krajka-Kuźniak,Maria Narożna

doi:10.3390/molecules26164957

Wanda Baer-Dubowska, Violetta Krajka-Kuźniak + Show 1 more

Open Access

https://doi.org/10.3390/molecules26164957

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Abstract

Naturally occurring pentacyclic triterpenoid oleanolic acid (OA) serves as a good scaffold for additional modifications to achieve synthetic derivatives. Therefore, a large number of triterpenoids have been synthetically modified in order to increase their bioactivity and their protective or therapeutic effects. Moreover, attempts were performed to conjugate synthetic triterpenoids with non-steroidal anti-inflammatory drugs (NSAIDs) or other functional groups. Among hundreds of synthesized triterpenoids, still the most promising is 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which reached clinical trials level of investigations. The new group of synthetic triterpenoids are OA oximes. The most active among them is 3-hydroxyiminoolean-12-en-28-oic acid morpholide, which additionally improves the anti-cancer activity of standard NSAIDs. While targeting the Nrf2 and NF-κB signaling pathways is the main mechanism of synthetic OA derivatives′ anti-inflammatory and anti-cancer activity, most of these compounds exhibit multifunctional activity, and affect cross-talk within the cellular signaling network. This short review updates the earlier data and describes the new OA derivatives and their conjugates in the context of modification of signaling pathways involved in inflammation and cell survival and subsequently in cancer development.

Highlights

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid, widely occurring in the plant kingdom, which includes edible and medicinal plants.The richest source of oleanolic acid (OA) are the leaves of the olive plant
This approach fits in a new trend called anakoinosis [26], the name of which derives from the ancient Greek term for “communication.” The concept of anakoinosis is an alternative to conventional chemotherapy, which is usually based on a single target, or focused on a single area of the tumor
Taking into consideration the role of NF-κB and Nrf2 in inflammation and, subsequently, cancer development, attempts have been made to use docking to elucidate the interaction of some OA derivatives with these transcription factors

Summary

Introduction

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid, widely occurring in the plant kingdom, which includes edible and medicinal plants. STAT3 signaling is a major intrinsic pathway for cancer inflammation due to its frequent activation in malignant cells, with a key role in regulating numerous genes crucial in inflammation-induced cancer and the tumor microenvironment In this regard, aberrant STAT3 promotes uncontrolled cellular growth and survival through dysregulation of gene expression, including cyclin D1, c-Myc, Bcl-xL, Mcl-1, and thereby contributing to cells surviving. The interconnection of signaling pathways such as Nrf, NF-κB, and STAT3, and aberrations in their activation mechanisms, make it possible to use them as a target in cancer cells for potential chemotherapeutic and/or chemopreventive compounds This approach fits in a new trend called anakoinosis [26], the name of which derives from the ancient Greek term for “communication.” The concept of anakoinosis is an alternative to conventional chemotherapy, which is usually based on a single target, or focused on a single area of the tumor. Multifunctional synthetic triterpenoids seem to be good candidates for such alternative chemotherapeutics or chemopreventive agents

Overview of Oleanolic Acid Derivatives—Chemical Approach

Docking Studies-Targeting Nrf2 and NF-κB

Biological Activity of Selected Synthetic OA Derivatives Which May Affect

Findings

Conclusions