Curcumin: A Double Hit on Malignant Mesothelioma

Menée sur des cellules murines ou humaines de mésothéliome malin, cette étude met en évidence des mécanismes par lesquels la curcumine induit la pyroptose des cellules tumorales et réprime l'expression de gènes impliqués dans des processus inflammatoires

Résumé en anglais

Inflammation is a key mediator in the development of malignant mesothelioma (MM) which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anti-carcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of MM cells. Using in vitro models with mouse and human MM cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of High Mobility Group Box1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the Nuclear Factor kappaB (NF-κB) pathway. Furthermore, curcumin's cytotoxicity in MM cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR Array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR) and IL-1β. Our data indicates that curcumin has a double effect on MM cells through induction of pyroptosis while subsequently protecting against inflammation.