Ferrocifen derivatives that induce senescence in cancer cells: selected examples

• Two ferrocenyl complexes induce marked anti-cancer effects in the micromolar range
• These anti-cancer effects are related to senescence induction
• No pathways usually involved in senescence induction are triggered by DP1 or P5
• Treated cells display typical senescence characteristics including SASP
• In vitro senescence induction leads to increased survival in a mouse cancer model

Platinum coordination complexes represent an important class of anti-tumor agents. Due to recognized drawbacks, research into other types of metallodrugs has been diversified with the aim of finding new chemical entities with alternative mechanisms of action to overcome classical chemoresistance. P5 and DP1, two closely related ferrocenyl complexes bearing a similar ferrocenyl-ene-phenyl motif and displaying marked differences in their conformations and oxidation state versatility, were assayed in cancer cell models characterized by various sensitivities to pro-apoptotic stimuli. P5 and DP1 exert growth inhibitory effects between 0.5 and 10 μM against glioma and melanoma cells including pluripotent stem-like cells. These effects are due, at least partly, to senescence induction with typical SA-β-galactosidase staining and senescence-associated secretory phenotype (SASP) as measured by the secretion of IL-1α, IL-1β, IL-6, IL-8 and TNF-α. Regulation of these cytokines' secretion may be related to AP-1 and other transcription factors unrelated to senescence. An in vivo graft of B16F10 cells after in vitro pre-incubation with DP1 or P5 led to increased survival in mice. In conclusion, P5 and DP1 ferrocenyl complexes induce senescence in various cancer cell models associated with distinct sensitivity to pro-apoptotic stimuli.

Figure optionsDownload as PowerPoint slideSynopsisThis study reports that synthetic ferrocenyl complexes can overcome apoptosis resistance by inducing irreversible senescence associated with a typical secretory phenotype. However and interestingly this senescence occurs via an unclassical pathway.