Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma

Our plain-English summary of Inflammation as a chemoprevention target in asbestos-induced malignant mesothelioma, by Y. Kadariya, E. Sementino, U. Shrestha, et al (Carcinogenesis, 2022).

The study

• Authors: Y. Kadariya, E. Sementino, U. Shrestha, G. Gorman, J.M. White, E.A. Ross, M.L. Clapper, N. Neamati, M.S. Miller, J.R. Testa
• Journal: Carcinogenesis
• Published: 2022;43(12):1137-1148
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.

© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

In plain English

This animal experiment tested whether anti-inflammatory drugs could delay asbestos-induced malignant mesothelioma (MM) in Nf2+/-;Cdkn2a+/- mice given 800 µg intraperitoneal UICC crocidolite every 21 days, four injections (3.2 mg total per mouse). In the first experiment, median survival was 23.0 weeks in the 25 vehicle (citrate buffer) controls, 27.1 weeks with sulindac (24 mice) and 33.9 weeks with anakinra (25 mice), both P less than 0.0001. In the second experiment, median survival was 19.4 weeks in 28 vehicle-treated mice, 23.0 weeks with SC144 75 mg/kg (28 mice, P less than 0.001) and 23.8 weeks with SC144 150 mg/kg (29 mice, P less than 0.0001). Ki67 proliferation index was lower in tumours from SC144-treated mice (P = 0.013), and P-Stat3 staining was weaker. In cultured mouse MM cells SC144 lowered P-Stat3 and abolished cyclin D1 and survivin; in human LP9 mesothelial cells it blocked IL-6-induced STAT3 activation; in human MM cell lines it reduced STAT3 activity and cyclin D1 and inhibited viability and colony formation. The authors stated that no mesotheliomas were actually prevented; MM occurred in 23/24 sulindac, 23/25 anakinra, 25/28 and 26/29 SC144 mice.

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: Animal (mouse) chemoprevention experiment in a genetically engineered asbestos-induced mesothelioma model, with accompanying in vitro cell experiments
• Who was studied: Nf2+/-;Cdkn2a+/- mice on an FVB/N background, aged 8-10 weeks, roughly equal numbers of both sexes; study I had 25 mice per arm (control, sulindac, anakinra), study II had 22-29 mice per group (no asbestos control, asbestos vehicle, SC144 75 and 150 mg/kg); plus mouse and human mesothelial and MM cell cultures
• Exposure: Intraperitoneal UICC grade crocidolite asbestos, 800 µg per dose every 21 days, four doses (3.2 mg total per mouse); treatments tested were SC144 (75 or 150 mg/kg oral), sulindac (150 ppm in chow) and anakinra (5 mg/kg i.p.)
• Main results:
  • Asbestos-exposed mice given sulindac had a median survival of 27.1 weeks and those given anakinra 33.9 weeks, versus 23.0 weeks in the vehicle (citrate buffer) controls; MM developed in 25/25 controls, 23/24 sulindac and 23/25 anakinra mice
  • In the SC144 experiment, median survival was 19.4 weeks in the vehicle-treated mice, 23.0 weeks with 75 mg/kg SC144 and 23.8 weeks with 150 mg/kg SC144; MM occurred in 25/28 and 26/29 SC144-treated mice
  • Mesotheliomas from SC144-treated mice had a lower mean Ki67 cell proliferation index than those from vehicle-treated mice
  • P-Stat3 was strongly expressed in tumours from vehicle-treated mice but diminished in tumours from SC144-treated mice, with total Stat3 reduced in the 150 mg/kg group
  • In cultured mouse MM cells (MM 166, MM 174, MM 364) treated with 10, 20 or 40 µM SC144 for 72 h, P-Stat3 fell with increasing dose and cyclin D1 and survivin expression was abrogated
  • In human LP9 non-malignant mesothelial cells, SC144 inhibited IL-6-induced STAT3 activation and expression of cyclin D1 and survivin
  • In human MM cell lines, SC144 reduced STAT3 activity and cyclin D1 expression dose-dependently and inhibited cell viability and colony formation dose-dependently
  • In mouse non-malignant mesothelial cells from Nf2+/-;Cdkn2a+/- mice, SC144 inhibited activation of Stat3 by IL-6
  • The authors reported no toxicity signals: mice given SC144 showed no weight loss or other evidence of toxicity
• The authors' conclusion: The authors concluded that treatment with several anti-inflammatory agents delayed the onset of asbestos-induced MM in this mouse model, that SC144 hit its intended gp130-IL-6R target by blocking Stat3 signalling, and that the results provide proof-of-principle for this class of inhibitor, with newer analogs holding promise for future trials in people at high risk of MM
• Limitations the authors state:
  • The authors stated that no mesotheliomas were actually prevented and attributed this to the model being too aggressive
  • The data cannot distinguish between delayed onset of MM and slower tumour progression in the treated mice
  • Median survival of the two control groups differed (23 weeks versus 19.4 weeks); the authors suggested the oral gavage of a thick vehicle placed the SC144 control mice under greater stress
  • SC144's limited half-life and once-daily dosing may have limited the efficacy observed
  • The authors noted the survival difference between treatment groups was unexpectedly small given the marked Ki67 difference

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Malignant Mesothelioma, Cytokine, Tumorigenesis, Glycoprotein, Carcinogenesis, CDKN2A, Mesothelial Cells.

Related studies

• Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells — R.A. Pietrofesa, S. Chatterjee, et al. (2022)
• CREB-induced inflammation is important for malignant mesothelioma growth — C.M. Westbom, A. Shukla, et al. (2014)
• A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy — R.W. Davis, E. Papasavvas, et al. (2018)
• Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan — R. Badger, K. Park, et al. (2021)
• Analysis of microRNA expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets — E.G. Ramírez-Salazar, L.C. Salinas-Silva, et al. (2014)
• Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma — Y. Kadariya, C.W. Menges, et al. (2016)

Browse more research in Carcinogenesis, or return to medical research.