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Mar Drugs
2013 Dec 24;121:54-68. doi: 10.3390/md12010054.
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Palmitic acid and ergosta-7,22-dien-3-ol contribute to the apoptotic effect and cell cycle arrest of an extract from Marthasterias glacialis L. in neuroblastoma cells.
Pereira DM
,
Correia-da-Silva G
,
Valentão P
,
Teixeira N
,
Andrade PB
.
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We describe the effect of a chemically characterized lipophilic extract obtained from Marthasterias glacialis L. against human breast cancer (MCF-7) and human neuroblastoma (SH-SY5Y) cell lines. Evaluation of DNA synthesis revealed that both cell lines were markedly affected in a concentration-dependent way, the SH-SY5Y cell line being more susceptible. Cell cycle arrest was observed, an effect induced by the sterol, ergosta-7,22-dien-3-ol, present in the extract. Morphological evaluation of treated cells showed the advent of lipid droplets and chromatin condensation compatible with apoptosis, which was confirmed by the evaluation of caspase-3 and -9 activities. Palmitic acid was the main compound responsible for this apoptotic effect by a ceramide-independent mechanism that involved endoplasmic reticulum (ER)-stress with upregulation of CCAAT/-enhancer-binding protein homologous protein (CHOP).
Figure 1. Rate of DNA synthesis in MCF-7 and SH-SY5Y cells treated with the extract (78–625 µg/mL for 24 or 48 h) by the 3H-thymidine incorporation assay. The results correspond to the mean ± standard deviation of three independent experiments performed in triplicate.
Figure 2. Morphological assessment of MCF-7 cells (control vs. treatment, 48 h of incubation). Giemsa and Hoechst 33342 stainings show chromatin condensation (red and white arrows, respectively) following incubation with the extract. Cytoplasmic vesicles, visible in Giemsa staining, proved to harbor lipophilic compounds, as shown with Oil Red O staining and transmission electron microscopy (yellow arrows).
Figure 3. Morphological assessment of SH-SY5Y cells (control vs. treatment, 24 h of incubation). Giemsa and Hoechst 33342 stainings show chromatin condensation and fragmentation (red and white arrows). The advent of lipophilic cytosolic vesicles is demonstrated by the Oil Red O staining.
Figure 8. Effect of the extract (Ext, 156 µg/mL) and palmitic acid (PA, 20 µM) on the expression of CHOP by Western blot.
Figure 9. Proposed mechanism for the effect of the purified extract from M. glacialis. The anti-proliferative effect is caused by ergosta-7,22-dien-3-ol, which triggers cell cycle arrest. Palmitic acid is not involved in ceramide biosynthesis; instead, it causes ER-stress, as depicted by the increase in CHOP expression levels. This protein then triggers apoptosis by interacting with mitochondrial proteins. SPT: Serine palmitoyl transferase; CERase: Ceramidase; SM: Sphingomyelin; SM synthase: Sphingomyelin synthase; CS: Ceramide synthase; SMase: Sphingomyelinase; ER: Endoplasmic reticulum.
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