Novel Anthraquinone Compounds as Anticancer Agents and their Potential Mechanism

Abstract

Anthraquinones exhibit a unique anticancer activity. Since their discovery, medicinal chemists have made several structural modifications, resulting in the design and synthesis of a large number of novel anthraquinone compounds with different biological activities. In general, anthraquinone compounds have been considered to have anticancer activity mainly through DNA damage, cycle arrest and apoptosis. However, recent studies have shown that novel anthraquinone compounds may also inhibit cancer through paraptosis, autophagy, radiosensitising, overcoming chemoresistance and other methods. This Review article provides an overview of novel anthraquinone compounds that have been developed as anticancer agents in recent years and focuses on their anticancer mechanism.

Marine Anthraquinones: Pharmacological and Toxicological Issues

“…As described in Figure 17 , the anticancer activity of marine-derived AQs mainly relies on their ability to induce DNA damage, cell-cycle arrest, and apoptosis [ 17 ]. The cytotoxic and cytostatic activity of many AQs derivatives is mediated by miRNA regulation and by the orchestration of PI3K/Akt/mTOR pathway, abnormally activated in many tumorigenesis processes.…”

“…AQs and their derivatives are increasingly attracting attention, thanks to their multiple biological activities, such as laxative [ 8 ], antifungal [ 9 ], antibacterial [ 10 ], antimalarial [ 11 ], anti-inflammatory [ 12 , 13 ], antiarthritic [ 13 ], diuretic [ 12 ], antiplatelet [ 14 , 15 ], neuroprotective [ 16 ], and anticancer activity [ 5 , 8 , 17 , 18 , 19 ]. Thus far, six natural and semi-synthetic anthracyclines were approved by the FDA (Food and Drug Administration) as anticancer drugs: daunorubicin, adriamycin, idarubicin, epirubicin, valrubicin, and mitoxantrone [ 8 ].…”

Anthraquinones as Inhibitors of SOS RAS-GEF Activity

“…Recent reports have described the identification of novel inhibitors of RAS activation by cellular GEFs (reviewed in [18,40]) but none of them belong to the anthraquinone family of compounds. Consistently, a wide spectrum of anthraquinone compounds with different biological activities have been previously used as anticancer agents [22,25,41], but none of them were described as possessing this type of specific SOS GEF inhibitory activity. Thus, our data adds a new mechanism of action to the list of anticancer actions played by different members of this family of drugs.…”

“…Here we describe the identification of several compounds capable of inhibiting the GEF activity of SOS on RAS in an in vitro GEF assay used to screen a collection of about 1000 different compounds including previously known biomedical compounds and new, untested compounds of marine origin. Strikingly, the chemical structures of all positive hits identified in our screening of both libraries shared related chemical structures belonging to the anthraquinone family, which has long been known for its anticancer activity [22].…”

“…Using assays in triplicate to confirm positive hits in our screenings, we identified two compounds from the SMR-NCATS library (Idarubicin and Epirubicin) and two compounds from Biomar MT (CL0292 and CL0294) that consistently showed inhibition of SOS GEF activity towards WT HRAS with micromolar IC50s values (Figure 1A; not shown). Although Idarubicin and Epirubicin are known to belong to the same family of anthraquinone compounds [22], the structural analysis and characterization of the Biomar MT CL0294 and CL0292 compounds revealed also similar, related anthraquinone structures (Figure 1B).…”