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2013 ; 86
(3
): 361-77
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Destruxins: fungal-derived cyclohexadepsipeptides with multifaceted anticancer
and antiangiogenic activities
#MMPMID23747344
Dornetshuber-Fleiss R
; Heffeter P
; Mohr T
; Hazemi P
; Kryeziu K
; Seger C
; Berger W
; Lemmens-Gruber R
Biochem Pharmacol
2013[Aug]; 86
(3
): 361-77
PMID23747344
show ga
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.