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

Abstract

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 MDA-MB-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.

Mechanisms of the Antineoplastic Effects of New Fluoroquinolones in 2D and 3D Human Breast and Bladder Cancer Cell Lines

“…Interestingly, all FQ derivatives promoted apoptosis in RT112 spheroids and, surprisingly, except for 7d , also in MCF7 cell spheroids. We do not know the reasons why apoptosis was observed in spheroid-grown but not in 2D-cultured MCF7 cells; however, a similar behavior was reported by Guzman and coworkers in other breast cancer cell lines [ 60 ]. Unlike their derivatives, CIP and NOR did not induce substantial changes in spheroid growth and morphology.…”

Transition-Metal-Catalyzed Transformations for the Synthesis of Marine Drugs

“…Among these natural products, Dragmacidin D 1 is a powerful inhibitor of serine–threonine protein phosphatases. It also induces cytotoxicity in the murine leukemia cell line and in the human lung adenocarcinoma cell line [ 36 ]. The biological properties of this compound have prompted the development of synthetic routes to Dragmacidin D and precursors.…”