Curcumin: A Double Hit on Malignant Mesothelioma

Abstract

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.

HMGB1 in health and disease

“…Inflammasomes have recently been shown to play an important role in mediating HMGB1 release from activated immune cells (Barlan et al, 2011; Craven et al, 2009; Lamkanfi et al, 2010; Lippai et al, 2013; Willingham et al, 2009; Willingham et al, 2007) or cancer cells (Miller et al, 2014). Thus, inflammasome-deficient mice or inflammasome inhibitor can inhibit HMGB1 release and protects mice against sepsis or I/R injury (Kamo et al, 2013; Xiang et al, 2011; Zhu et al, 2011b).…”

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…They showed that knockdown of TXNIP reduced inflammasome activation following asbestos treatment, indicating the important role of TXNIP in mediating inflammasome activation [111]. A recent study shows that curcumin, a polyphenol derived from turmeric was able to induce pyroptosis of mouse MM cells through activation of caspase-1 in the NALP3 inflammasome and the effect was ROS dependent [112].…”

Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome

“…After ensuring the integrity of the RNA samples, 500 ng of RNA was used for cDNA synthesis to be used in the Human EMT pathway RT 2 Profiler PCR Array as described previously. 13 Data obtained were then analyzed using the online SA Biosciences data analysis template.…”

“…Ninety percent confluent LP9 cells were transiently transfected with On-Target Smart Pool siNLRP3 [ThermoScientific (Life Technologies), Grand Island, NY] or nontargeted control (siControl) constructs 32 hours before asbestos exposure to study the effects of reduced NLRP3 protein levels on MFT as previously described. 13 Additional experiments were performed with 4 single small interfering NLRP3 (siNLRP3) and nontarget controls [ThermoScientific (Life Technologies), Grand Island, NY] as described above. …”