Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

Abstract

Purpose of Review This article summarises recent research on modifications of the structure or formula of usnic acid (UA), a lichen secondary metabolite, in order to obtain derivatives with higher bioavailability, potency and selectivity against cancer cells and presents the current knowledge on the mechanisms of action of such compounds. Recent Findings Numerous approaches have been undertaken to improve bioactivity of UA concerning its use as an anticancer drug. Among them, the synthesis of UA salts or complexation with 2-hydroxypropyl-β-cyclodextrin to improve its solubility and the encapsulation using different carriers (including various nanomaterials) to stabilise UA in biological fluids and improve their penetrance to, and release in, cancer cells were applied.. Synthetic modification of the UA structure has been explored to obtain more active and cancer-specific derivatives. Recent work indicates that some modifications of the C or A ring of UA selectively increase its antiproliferative potential against cancer cells. Moreover, specific changes in the UA structure allow to obtain derivatives which inhibit enzymes important for the cancer cells' survival, such as mTOR, Pim, TDP1 or PARP. Some of them have been shown to enhance anticancer activity of the already approved chemotherapeutics, such as topotecan. Others, when used in an animal cancer xenograft model, were superior to UA in retardation of tumour growth and less toxic that the parent compound. Summary UA is a promising lead compound for synthesis of anticancer drugs. Further work on its modifications, mechanisms of activity and validation in animal models is critical for development of effective therapeutics.

Unraveling the Pharmacological Potential of Lichen Extracts in the Context of Cancer and Inflammation With a Broad Screening Approach

“…Furthermore, the correlation analysis also found that usnic acid might be responsible from the reduced tumor cell viability, apoptosis, and cell cycle inhibition. In contrast to protocetraric acid, usnic acid as lead compound of F. caperata , has various well-known activities ( Cocchietto et al., 2002 ; Ingolfsdottir, 2002 ; Guzow-Krzemińska et al., 2019 ). In line with our findings, it was already shown that usnic acid induce a G1-Block in the gastric cancer cell line BGC823, in A549 lung carcinoma cells ( Singh et al., 2013 ), in the breast cancer cell line MCF-7, and in the prostate adenocarcinoma cell line LNCap ( Eryilmaz et al., 2018 ; Geng et al., 2018 ).…”

The Isoxazole Derivative of Usnic Acid Induces an ER Stress Response in Breast Cancer Cells That Leads to Paraptosis-like Cell Death

“…Moreover, these studies revealed the importance of β-triketone moiety for UA activity [22,23]. Since then, different approaches have been undertaken to improve its bioactivity, including synthetic modifications of UA's structure [24].…”

Lichen-Derived Compounds and Extracts as Biologically Active Substances with Anticancer and Neuroprotective Properties

“…For instance, the co-treatment of lobarstin, a secondary metabolite isolated from Stereocaulon alpinum, enhanced toxicity of temozolomide when used in GBM T98G cells [19]. In another study, the ketamine derivatives of (+)-usnic acid had significant cytotoxicity against human GBM-astrocytoma cell line U87MG, and a novel N-heterocyclic derivative of (+)-usnic acid was found to be even more active than temozolomide [20]. These findings justify further studies exploring the possible applications of lichenochemicals in brain tumor treatment.…”