Next Article in Journal
Isolation and Characterization of Anti-Adenoviral Secondary Metabolites from Marine Actinobacteria
Next Article in Special Issue
Aplysin Sensitizes Cancer Cells to TRAIL by Suppressing P38 MAPK/Survivin Pathway
Previous Article in Journal
A Chemoinformatics Approach to the Discovery of Lead-Like Molecules from Marine and Microbial Sources En Route to Antitumor and Antibiotic Drugs
Previous Article in Special Issue
Continuous Drug Release by Sea Anemone Nematostella vectensis Stinging Microcapsules
Open AccessArticle

Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production

1
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France
2
CBP (Centre de Bio-Pathologie), Banque de Tissus, CHRU (Centre Hospitalier Régional Universitaire), Lille 59037, France
*
Author to whom correspondence should be addressed.
Mar. Drugs 2014, 12(2), 779-798; https://doi.org/10.3390/md12020779
Received: 27 November 2013 / Revised: 13 December 2013 / Accepted: 7 January 2014 / Published: 27 January 2014
(This article belongs to the Special Issue Mechanism of Action Analysis for Marine Compounds)
Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents. View Full-Text
Keywords: oxidative stress response; mitochondria; DNA damage; cellular senescence oxidative stress response; mitochondria; DNA damage; cellular senescence
Show Figures

Figure 1

MDPI and ACS Style

Ballot, C.; Martoriati, A.; Jendoubi, M.; Buche, S.; Formstecher, P.; Mortier, L.; Kluza, J.; Marchetti, P. Another Facet to the Anticancer Response to Lamellarin D: Induction of Cellular Senescence through Inhibition of Topoisomerase I and Intracellular Ros Production. Mar. Drugs 2014, 12, 779-798.

Show more citation formats Show less citations formats

Article Access Map by Country/Region

1
Only visits after 24 November 2015 are recorded.
Back to TopTop