Anticancer properties and mechanism of action of the quassinoid ailanthone

Abstract

Ailanthone (AIT) is a quassinoid natural product isolated from the worldwide‐distributed plant Ailanthus altissima. The drug displays multiple pharmacological properties, in particular significant antitumor effects against a variety of cancer cell lines in vitro. Potent in vivo activities have been evidenced in mice bearing hepatocellular carcinoma, nonsmall cell lung cancer and castration‐resistant prostate cancer. This review focusses on the mechanism of action of AIT, notably to highlight the capacity of the drug to activate DNA damage responses, to inhibit the Hsp90 co‐chaperone p23 and to modulate the expression of several microRNA. The interconnexion between these effects is discussed. The unique capacity of AIT to downregulate oncogenic miR‐21 and to upregulate the tumor suppressor miRNAs miR‐126, miR‐148a, miR‐195, and miR‐449a is presented. AIT exploits several microRNAs to exert its anticancer effects in distinct tumor types. AIT is one of the rare antitumor natural products that binds to and strongly inhibits cochaperone p23, opening interesting perspectives to treat cancers. However, the toxicity profile of the molecule may limit its development as an anticancer drug, unless it can be properly formulated to prevent AIT‐induced gastro‐intestinal damages in particular. The antitumor properties of AIT and analogs are underlined, with the aim to encourage further pharmacological studies with this underexplored natural product and related quassinoids. Highlights Ailanthone (AIT) is an anticancer quassinoid isolated from Ailanthus altissima It inhibits proliferation and induces cell death of many cancer cell types The drug activates DNA damage response and targets p23 cochaperone Up or downregulation of several microRNA by AIT contributes to the anticancer activity Analogs or specific formulations must be developed to prevent the toxicity of AIT

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…As HSP90 inhibitors show a very broad spectrum of action [101], degradation of AhR can be optimized by targeting the co-chaperone protein p23. Down-regulation of the p23 protein triggers ubiquitination of AhR [102] and specific inhibition of p23 (ailanthone) shows important anticancer effects in vitro [103].…”

The Anthelmintic Quassinoids Ailanthone and Bruceine a Induce Infertility in the Model Organism Caenorhabditis elegans by an Apoptosis-like Mechanism Induced in Gonadal and Spermathecal Tissues

“…On the other side, a pharmaceutical development of quassinoids as deworming drugs in livestock or in human medicine has also to be aware of the potential toxicity of these diterpenes on the host. Especially DNA damage and the subsequent induction of apoptosis by ailanthone has to be taken into account [ 11 , 30 ], and systematic toxicological studies have to be performed to clarify the risk–benefit ratio. Preclinical toxicology and toxicokinetic data in mice indicated dose-dependent (2.5 to 10 mg/kg) organ toxicity, with stomach and intestinal tissues being the main target organs [ 31 ].…”

“…The family Simaroubaceae is altogether known for a variety of genera investigated for their medicinal properties (e.g., the genus Eurycoma for antimicrobial, anti-plasmodial or anti-fungal properties [ 7 ], the genus Picrasma for anti-inflammatory, anti-cancer or anti-viral effects [ 8 ] or the genus Quassia for anti-plasmodial effects [ 9 ]). In general, quassinoids are a class of terpenoid-like natural products and are commonly known for a diversity of promising biological activities [ 10 , 11 , 12 , 13 ]. These degraded triterpenes can be structurally diversified by having either a C-18, C-19, C-20, C-22, or a C-25 skeleton [ 14 ], and the majority of quassinoids exerting interesting bioactivities typically contains a δ-lactone and a methylenoxy bridge between C-8 and C-11 (e.g., ailanthone, Figure 1 ( 1 )) or C-8 and C-13 (e.g., bruceine A, Figure 1 ( 2 )) [ 15 ].…”

Two Novel Quassinoid Glycosides with Antiviral Activity from the Samara of Ailanthus altissima

“…The quassinoids previously obtained from the samara of A. altissima can generally be classified as the C-6 or C-15 substituted derivatives of chaparrione and ailanthone, as well as their monoglycosides [13]. Ailanthone is the best known bioactive secondary metabolite isolated from A. altissima, which displays multiple pharmacological properties, in particular significant antitumor effects against a variety of cancer cell lines in vitro [29,30]. Two more C 20 quassinoid glycosides were reported based on our current findings, among which chuglycoside J wears a keto group in C-12, which, in the case of quassinoids from A. altissima, usually appears as a hydroxy substituted group, while chuglycoside K was the only one diglycoside we obtained from the extract of the samara of A. altissima.…”