Another facet to the anticancer response to lamellarin D: induction of cellular senescence through inhibition of topoisomerase I and intracellular Ros production.
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.
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. caro.ballot@gmail.com.
Caroline
C
Ballot
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. alain.Martoriati@univ.lille1.fr.
Alain
A
Martoriati
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. manel.jendoubi@gmail.com.
Manel
M
Jendoubi
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. sebastien.buche@chru-lille.fr.
Sébastien
S
Buche
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. pierre.formstecher@inserm.fr.
Pierre
P
Formstecher
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. laurent.mortier@chru-lille.fr.
Laurent
L
Mortier
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. jerome.kluza@inserm.fr.
Jérome
J
Kluza
Inserm U837-JPARC, Université de Lille II, Faculté de Médecine, 1Place Verdun, Lille 59037, France. philippe.marchetti@inserm.fr.
Philippe
P
Marchetti
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D003374:Coumarins / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D003374:Coumarins; D004272:DNA, Mitochondrial; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D017382:Reactive Oxygen Species; D059003:Topoisomerase Inhibitors; C455554:lamellarin D; D004264:DNA Topoisomerases, Type I