Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression

Our plain-English summary of Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression, by H. Yang, L. Pellegrini, A. Napolitano, et al (Cell Death & Disease, 2015).

The study

• Authors: H. Yang, L. Pellegrini, A. Napolitano, C. Giorgi, S. Jube, A. Preti, C.J. Jennings, F. De Marchis, E.G. Flores, D. Larson, I. Pagano, M. Tanji, A. Powers, S. Kanodia, G. Gaudino, S. Pastorino, H.I. Pass, P. Pinton, M.E. Bianchi, M. Carbone
• Journal: Cell Death & Disease
• Published: 2015;6(6):e1786
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.

In plain English

This laboratory study used human malignant mesothelioma (MM) cell lines and mice; its experiments involved neither people nor asbestos exposure. Reviewing Physicians' Health Study data (17 MM cases among 22 067 physicians), the authors reported a relative risk of 0.7 (95% confidence interval 0.3–1.9) for aspirin versus placebo, not statistically significant. It tested whether aspirin (ASA), salicylic acid (SA) and the HMGB1 blocker BoxA slowed MM. In one mouse experiment (seven per group), daily ASA significantly slowed tumor growth, but treated mice died of gastrointestinal bleeding. In a second experiment (20 per group, modified schedule), median survival was 76 days (controls), 87.5 days (25 mg/kg) and 91 days (50 mg/kg), without bleeding. With BoxA (10 mice per group), median survival was 142 days versus 76.5 days for controls. In cells, ASA and SA reduced colony growth, movement and invasion of high HMGB1-secreting MM cells but not a low-secreting line. This appeared independent of COX-2. The authors concluded that aspirin's antitumor activity works at least partly through inhibiting HMGB1. They noted the experiments did not address large symptomatic tumors.

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 and animal experiments in which human MM cells were grown in immunodeficient mice (xenografts) randomly assigned to treatment and control groups. The authors also reviewed information from the Physicians' Health Study, a human study of aspirin versus placebo.
• Who was studied: Human MM cell lines REN, HMESO and PHI (high HMGB1-secreting) and PPM-MILL (low HMGB1-secreting control). Mouse embryonic fibroblasts, including fibroblasts lacking the COX-2 gene. Female SCID mice injected intraperitoneally with REN cells: 14 mice in the first ASA experiment, 60 in the second and 20 in the BoxA experiment. Separately, the authors reviewed information from the Physicians' Health Study, in which 22 067 physicians were followed for 24 years with 17 reported MM cases.
• Exposure: The exposures were treatments, not asbestos. In mice, aspirin (acetylsalicylic acid) was given by oral gavage at 25 or 50 mg/kg, and BoxA (a specific HMGB1 antagonist) was injected intraperitoneally at 400 μg three times a week for 10 weeks. In cell culture, ASA and salicylic acid were used at 0.1 μM to 1 mM. In the Physicians' Health Study, the comparison was ASA 325 mg on alternate days versus placebo.
• Main results:
  • Physicians' Health Study information reviewed by the authors: an intention-to-treat analysis comparing ASA (325 mg on alternate days) with placebo gave a relative risk of MM of 0.7 (95% confidence interval 0.3–1.9). The authors stated that the small number of MM cases gave insufficient power for a statistically significant analysis.
  • First mouse experiment (7 ASA-treated and 7 control mice, ASA 25 mg/kg daily): ASA significantly suppressed MM tumor growth compared with controls (slope comparison test, P less than 0.0001).
  • In the first experiment, ASA-treated mice lost weight and died of gastrointestinal bleeding.
  • Second mouse experiment (60 mice, 20 per group; ASA daily for 2 weeks, then three times a week): median survival was 76 days in controls, 87.5 days with ASA 25 mg/kg and 91 days with ASA 50 mg/kg. The increase in survival was statistically significant for both ASA groups (log-rank test, P less than 0.0001).
  • In the second experiment, there was no difference in body weight between control and treated groups and no evidence of gastrointestinal bleeding.
  • In soft agar, ASA and SA at concentrations as low as 100 μM significantly inhibited colony formation by high HMGB1-secreting MM cells. No effect was seen on the low HMGB1-secreting line PPM-Mill.
  • In REN MM cells, ASA and SA inhibited HMGB1-induced cell motility, migration and invasion at concentrations as low as 0.1 μM after 48 hours.
  • SA inhibited HMGB1-induced migration of mouse fibroblasts in a dose-dependent manner, both in fibroblasts lacking the COX-2 gene and in normal fibroblasts, with an IC50 of about 3–4 μM.
  • In cells, ASA and BoxA combined did not have synergic or additive effects.
  • BoxA experiment (20 mice, 10 per group): BoxA-treated mice had a median survival of 142 days, compared with 76.5 days in controls, whose longest survival was 96 days. The difference was statistically significant (log-rank test, P less than 0.0001).
  • One BoxA-treated mouse survived 413 days. It died of a T-cell lymphoma, and no residual human MM cells were found in it.
• The authors' conclusion: The authors concluded that at least some of aspirin's antitumor activity is mediated through inhibition of HMGB1 activity. They proposed, without testing it in people, that aspirin and BoxA may work better early in tumor growth or in a preventive setting, for example in people with a history of asbestos or erionite exposure or carriers of germline BAP1 mutations.
• Limitations the authors state:
  • The Physicians' Health Study had too few MM cases for a statistically significant analysis.
  • Mice were treated during the early stages of tumor growth. The experiments were not designed to address possible effects on symptomatic MM with large tumor masses.
  • BoxA is not yet available for clinical use.
  • The precise mechanism by which aspirin inhibits HMGB1 remains to be determined.

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: Mesothelioma, High Mobility Group Box 1 (HMGB1), Inflammation, Carcinogenic.

Related studies

• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)
• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma — S. Jube, Z.S. Rivera, et al. (2012)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells — I. Zanellato, I. Bonarrigo, et al. (2013)
• HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients — A. Napolitano, D.J. Antoine, et al. (2016)

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