The Marine Natural Compound Dragmacidin D Selectively Induces Apoptosis in Triple-Negative Breast Cancer Spheroids

Cancer cells grown in 3D spheroid cultures are considered more predictive for clinical
efficacy. The marine natural product dragmacidin D induces apoptosis in MDA-MB-231 and MDAMB-
468 triple-negative breast cancer (TNBC) spheroids within 24 h of treatment while showing no
cytotoxicity against the same cells grown in monolayers and treated for 72 h. The IC50 for cytotoxicity
based on caspase 3/7 cleavage in the spheroid assay was 8 ± 1 µM in MDA-MB-231 cells and
16± 0.6 µM in MDA-MB-468 cells at 24 h. No cytotoxicity was seen at all in 2D, even at the highest
concentration tested. Thus, the IC50 for cytotoxicity in the MTT assay (2D) in these cells was found to
be >75 µM at 72 h. Dragmacidin D exhibited synergy when used in conjunction with paclitaxel, a
current treatment for TNBC. Studies into the signaling changes using a reverse-phase protein array
showed that treatment with dragmacidin D caused significant decreases in histones. Differential
protein expression was used to hypothesize that its potential mechanism of action involves acting
as a protein synthesis inhibitor or a ribonucleotide reductase inhibitor. Further testing is necessary
to validate this hypothesis. Dragmacidin D also caused a slight decrease in an invasion assay in
the MDA-MB-231 cells, although this failed to be statistically significant. Dragmacidin D shows
intriguing selectivity for spheroids and has the potential to be a treatment option for triple-negative
breast cancer, which merits further research into understanding this activity.