Destruxins: Fungal-derived cyclohexadepsipeptides with multifaceted anticancer and antiangiogenic activities

Abstract

Destruxins (Dtx) are secondary metabolites of the entomopathogenic fungus Metarhizium anisopliae. Recently, Dtx came into focus of interest as anticancer therapeutics. However, data on human and especially on cancer cells are fragmentary. In order to successfully establish novel anticancer therapeutics, a broad knowledge on the cellular and molecular mechanisms underlying their activity is essential. Consequently, this study aimed to investigate the impact of the most common Dtx derivatives A, B and E on human cancer cell growth and survival with a focus on colon cancer cell models. Summarizing, the experimental data showed that (i) Dtx A and B exert potent antiproliferative activity in the micromolar and Dtx E in the nanomolar range in KB-3-1, A549, CaCo-2, and especially in HCT116 colon cancer cells, (ii) all three Dtx derivatives cause imbalance of cell cycle distribution, (iii) their cytostatic/cytotoxic effects are widely p53-independent but reduced by p21- and bax-deletion, respectively, (iv) cytotoxicity is based on intrinsic apoptosis induction and associated with phosphoinositide-3-kinase (PI3K)/Akt pathway inhibition, (v) anticancer activity of Dtx E but not Dtx A and B involves disturbance of the intracellular redox balance, (vi) Dtx inhibit the migration and tube formation of human endothelial cells indicating antiangiogenic potential, and (vii) all three Dtx derivatives possess ionophoric properties not differing in conductivity, ion selectivity and single channel kinetics. Thus, Dtx represent feasible, multifunctional anticancer drug candidates for preclinical development especially against colorectal cancer.

Selective apoptotic cell death effects of oral cancer cells treated with destruxin B

“…The activity of DB against cancer cells have been suggested or studied on murine leukemia, epidermal carcinoma, non-Hodgkin lymphoma, and non-small cell lung cancer cells [7-9,11,12]. We also report that DB has potential as a new therapeutic agent against human colorectal cancer and non-small cell lung cancer [10,13].…”

New Cyclohexadepsipeptides from an Entomogenous Fungus Fusarium proliferatum and Their Cytotoxicity and Autophagy‐Inducing Activity

“…Destruxins (Dtx) A, B, and E from the entomopathogenic fungus Metarhizium anisopliae presented strong antiproliferative activity against HCT116 colon cancer cells. The molecular mechanism investigation indicated that the cytotoxicity of three Dtx derivatives depends on intrinsic apoptosis induction and associated with phosphoinositide‐3‐kinase (PI3K)/Akt pathway . Beauvericin as a well‐known mycotoxin exerted antiproliferative activity against H4IIE hepatoma cells via the induction of apoptosis that was accompanied by an inhibition of NF‐ k B‐activity and modulation of MAP‐kinases .…”

Supercritical Fluid Chromatography as an Alternative Tool for the Qualitative and Quantitative Analysis of Metarhizium brunneum Metabolites from Culture Broth

“…anisopliae, Clavicipitaceae) [9][10][11], which plays an important role as a biological control agent [12,13]. It is widely accepted that dtxs exhibit a wide variety of biological activities [12,[14][15][16][17][18], although they are best known for their insecticidal and phytotoxic activities [12,15]. However, there are concerns that the use of Metarhizium spp.…”