Curcumin: a double hit on malignant mesothelioma

Our plain-English summary of Curcumin: a double hit on malignant mesothelioma, by J.M. Miller, J.K. Thompson, M.B. MacPherson, et al (Cancer Prevention Research, 2014).

The study

• Authors: J.M. Miller, J.K. Thompson, M.B. MacPherson, S.L. Beuschel, C.M. Westbom, M. Sayan, A. Shukla
• Journal: Cancer Prevention Research
• Published: 2014;7(3):330-40
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (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 NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma 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 indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

In plain English

This laboratory study tested curcumin, a compound in turmeric, on mouse and human malignant mesothelioma cells in culture and in mice with implanted mesothelioma tumors. In culture, curcumin reduced the growth of mouse and human mesothelioma cells. The effect depended on dose and time. Curcumin activated an enzyme called caspase-1 and caused a type of inflammatory cell death the authors identified as pyroptosis. IL-1 beta and IL-18, two inflammatory signals, were undetectable in mouse cell cultures, and curcumin did not significantly change their levels in human cells. Blocking caspase-1 beforehand significantly reduced curcumin's killing effect on human mesothelioma cells. Curcumin increased reactive oxygen species, and an antioxidant (NAC) reduced several of curcumin's effects. In human mesothelial cells, curcumin given before crocidolite asbestos increased two inflammation-related gene signals compared with asbestos alone. In mice, curcumin did not reduce tumor burden. It showed no synergistic effect with the drug cisplatin in the allograft (mouse-cell) model. The authors concluded that curcumin kills mesothelioma cells through pyroptosis and warrants further study. They added that its poor bioavailability must first be overcome.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell-culture (in vitro) experiments plus mouse tumor (allograft and xenograft) experiments
• Who was studied: Mouse malignant mesothelioma cells (#40); human malignant mesothelioma cell lines HMESO, H2595 and H2461; human mesothelial LP9/TERT-1 cells. In vivo: male C57/BL6 mice (allograft model) and male Fox Chase SCID mice (xenograft model) were injected in the peritoneal cavity with mesothelioma cells, with 4 to 8 mice per treatment group
• Exposure: Curcumin at 0 to 50 micromoles per liter (40 in most experiments), given to cells for 24 to 72 hours. Crocidolite asbestos was used with LP9 mesothelial cells. In mice, curcumin was given orally or by intraperitoneal injection, alone or with cisplatin 2 mg/kg. The antioxidant NAC and a caspase-1 inhibitor were used as pretreatments
• Main results:
  • In mouse malignant mesothelioma cells, curcumin at 40 and 50 micromoles per liter for 48 and 72 hours significantly inhibited cell growth compared with control
  • In human malignant mesothelioma cells, curcumin at 30 to 50 micromoles per liter caused significant cytotoxicity at all time points
  • In mouse malignant mesothelioma cells, ELISA showed undetectable IL-1 beta and IL-18 in both control and curcumin-treated cells
  • In HMESO cells, curcumin increased caspase-1 activity but did not significantly change processed IL-1 beta and IL-18 levels
  • Pretreating HMESO cells with a caspase-1 inhibitor significantly reduced curcumin's inhibitory effect on cell numbers
  • In mouse mesothelioma cells, reducing NLRP3 or ASC with siRNA did not affect curcumin's activation of caspase-1
  • Curcumin given for 6 hours increased reactive oxygen species in HMESO cells compared with control cells, and NAC pretreatment inhibited this increase
  • A PCR array in HMESO cells showed that curcumin significantly reduced expression of inflammasome-related genes in the inflammation, NF-kappa B, toll-like receptor and IL-1 pathways. HSP90AA1, IL-12, IL-6 and MEFV were upregulated
  • In LP9 mesothelial cells, curcumin pretreatment followed by crocidolite asbestos increased NLRP3 and pro-IL-1 beta mRNA compared with control and asbestos-only cells. It had no added effect on caspase-1 activation
  • In mice, curcumin given at various doses and by different routes did not reduce mesothelioma tumor burden. It had no synergistic effect with cisplatin in the allograft model
• The authors' conclusion: The authors concluded that curcumin kills malignant mesothelioma cells through pyroptosis, in a process that involves reactive oxygen species and does not depend on the NLRP3 inflammasome. They also concluded that curcumin has anti-inflammatory effects and warrants further investigation as a therapy. They said improved analogs or better delivery are needed because of its limited bioavailability
• Limitations the authors state:
  • The mouse experiments did not match the cell-culture results. The authors said this was likely due to curcumin's low solubility and poor bioavailability
  • The molecular pathway by which curcumin activates caspase-1 remains unclear
  • Ruling out the NLRC4 and NLRP1 inflammasomes would require further siRNA experiments
  • How curcumin modulates the effects of asbestos in mesothelial cells remains unclear

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Inflammation, Prognosis, Cytokine, High Mobility Group Box 1 (HMGB1).

Related studies

• Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis — Y. Wang, A.K. Rishi, et al. (2011)
• Differential activation of the inflammasome in THP-1 cells exposed to chrysotile asbestos and Libby "six-mix" amphiboles and subsequent activation of BEAS-2B cells — M. Li, M.E. Gunter, et al. (2012)
• Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma — C. Zhang, Y. Hao, et al. (2018)
• Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma — C. Westbom, J.K. Thompson, et al. (2015)
• Curcumin induces autophagy in ACC-MESO-1 cells — Y. Yamauchi, Y. Izumi, et al. (2012)
• Vimentin regulates activation of the NLRP3 inflammasome — G. dos Santos, M.R. Rogel, et al. (2015)

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