Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma

Our plain-English summary of Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma, by C. Westbom, J.K. Thompson, A. Leggett, et al (PloS One, 2015).

The study

• Authors: C. Westbom, J.K. Thompson, A. Leggett, M. MacPherson, S. Beuschel, H. Pass, P. Vacek, A. Shukla
• Journal: PloS One
• Published: 2015;10(12):e0145404
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.

In plain English

This laboratory study examined the 'inflammasome', part of the cell's inflammation machinery, in malignant mesothelioma (MM). It did not test asbestos. It tested two chemotherapy drugs, doxorubicin and cisplatin. All seven human MM cell lines examined had lower levels of NLRP3 (an inflammasome component) mRNA than LP9, an immortalized human mesothelial cell line. Three of 4 MM tumors had lower NLRP3 than their matching normal tissue. Both drugs raised NLRP3 in 3 of 4 MM cell lines. In the two lines studied further, both drugs increased caspase-1 activation and release of inflammatory molecules such as IL-1β. Blocking caspase-1 significantly reduced doxorubicin-induced cell death in one line (H2373) but not in the other (Hmeso). In mice injected with human MM cells (5 per group), cisplatin alone significantly reduced tumors. Cisplatin plus Anakinra, an IL-1 receptor blocker, reduced them more; only one of 5 mice in that group had a small tumor. The authors concluded the combination could be a possible strategy. They called their report a very small first step needing confirmation, and noted the mice lacked a normal immune system.

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 using human cell lines and tumor tissue, plus an animal experiment (human MM cells grown in the abdomen of SCID mice)
• Who was studied: Seven human MM cell lines (Hmeso, H2373, H2595, H2461, H2818, H2596, HP-1), compared with LP9, an immortalized human peritoneal mesothelial cell line. Also 4 MM tumors with their normal counterparts, three MM tissue arrays (each with 10–15 MM tumor sections from different patients), and 8-week-old male Fox Chase SCID mice (5 per group) at the University of Vermont.
• Exposure: Chemotherapy drugs doxorubicin (mainly 5 μM) and cisplatin (mainly 100 μM) in cells. In mice: cisplatin (2 mg/kg, intraperitoneal, once a week for 2 weeks), the IL-1 receptor antagonist Anakinra (92 mg/kg twice daily for 3 weeks), both together, or saline. Asbestos was not tested in this study. It appears only in the background as a cause of MM and as the subject of the authors' earlier work.
• Main results:
  • All 7 MM cell lines had lower NLRP3 mRNA than LP9, an immortalized human mesothelial cell line. NLRP3 protein, examined in selected MM lines, was very low or absent compared with LP9.
  • In MM tumors, 3 of 4 had low NLRP3 compared with their matching normal tissue.
  • In MM cell lines, both drugs increased NLRP3 mRNA in 3 of 4 lines tested.
  • In both Hmeso and H2373 cells, both drugs increased caspase-1 activation and raised IL-1β, IL-18, FGF2 and HMGB1 in the culture medium.
  • In H2373 cells, blocking caspase-1 significantly reduced cell death caused by doxorubicin. It did not contribute significantly to drug-induced death of Hmeso cells, and the trend with cisplatin in H2373 cells was not statistically significant.
  • In cultured Hmeso cells, Anakinra at the concentration used had no significant effect on any inflammasome measure studied (data not shown).
  • In mice, cisplatin alone significantly reduced tumors, and cisplatin plus Anakinra was more effective than cisplatin alone. Only one of 5 mice in the combination group had a small tumor.
  • No significant weight loss was seen in mice given Anakinra alone or Anakinra plus cisplatin, compared with untreated controls (data not shown).
  • In abdominal fluid from mice, neutrophil counts were significantly lower in the cisplatin and combination groups. MCP-1, FGF2, IL-8 and VEGF were lower in the cisplatin and combination groups than in controls. IL-1β was decreased by cisplatin and by Anakinra but increased by the combination.
• The authors' conclusion: The authors concluded that chemotherapy drugs can activate NLRP3 inflammasomes in MM, accompanied by increased release of pro-inflammatory cytokines. They suggested that combining chemotherapy with an IL-1 receptor antagonist could be a possible strategy for inhibiting MM tumor growth, while calling their report a very small first step requiring further studies.
• Limitations the authors state:
  • The mice were immunocompromised, so the role of adaptive immune cells is unknown.
  • Only one fibrosarcomatoid MM cell line was available, making it difficult to verify differences between cell types.
  • Almost no tumor tissue remained in the combination group, so no tumor tissue analysis could be done.
  • The intraperitoneal mouse model allowed only one time-point measurement of tumor and abdominal fluid.
  • Larger and more detailed animal studies are needed to confirm the findings.

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, Mesothelial Cells, Doxorubicin, Cisplatin.

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