Aspirin in the Treatment of Mesothelioma

by | Apr 22, 2016 | 2015, Lung Health, Mesothelioma

Written by Joyce Smith, BS. Aspirin protects against malignant mesothelioma by inhibiting the carcinogenic effects of the inflammatory molecule High Motility Group Box1 (HMGB1).

Malignant mesothelioma (MM) is an aggressive cancer that has its origin in the mesothelial cells of pleura, peritoneal and pericardial cavities. Approximately 3200 people are diagnosed annually and die annually from this disease [1]. Major risk factors include a genetic predisposition, radiation exposure, and viral infections such as SV40, which can act alone or as cofactors in combination with exposure to asbestos and erionite mineral fibers [1, 2].

Asbestos fibers lodge in the pleura and cause necrosis of mesothelial cells. These cells release an inflammatory molecule called High Motility Group Box1 (HMGB1). In the cell this protein HMGB1 is both a nuclear and a cytoplasmic protein that is associated with proliferation and metastasis of many types of tumors – breast, colon, pancreas, and melanomas [3, 4]. Outside of the cell it masquerades as a cytokine, promoting angiogenesis and initiating inflammation. For example when asbestos fibers damage mesothelial cells, HMGB1 is released into the extracellular space and triggers a vicious cycle of chronic cell death and inflammation that over a period of years can lead to MM [5].

Aspirin (acetylsalicylic acid, ASA) is a popular non-steroidal anti-inflammatory drug that has been shown to reduce the incidence, metastatic potential, and morbidity of many inflammatory-induced cancers [6]. Researchers hypothesize that ASA may, because of its anti-inflammatory properties, negate the carcinogenic effects of HMGB1. They test this hypothesis in vivo and in vitro.

In Vivo Results:

Treatment of mice with ASA, at serum concentrations that are comparable to therapeutic doses in humans, significantly reduced MM tumor growth in vivo compared to controls.

  • Immunodeficient mice were injected with HMGB1-secreting human MM cell lines intraperitoneally; then, 4 days later when tumors became palpable, were given orally 25mg/kg of ASA per day until gastrointestinal (GI) bleeding occurred. A 25mg/kg dose is equivalent to 80 – 110 mg/day in humans [7]. Therapeutic doses (the amount used daily to treat different therapies for humans) range from 325 mg to 1.5 g/day. Tumor growth was significantly reduced in the ASA treated mice compared to control. (P<0.0001).
  • The experiment was repeated with lower ASA doses for a longer duration of time (48 days). Once again there was a significant reduction in tumor growth in the ASA treated mice (P<0.0001).
  • Since there was no GI bleeding this time, the experiment was continued beyond 48 days. Mean survival was 76 days for the control group; 87.5 days in the ASA 25mg/kg group and 91 days in the ASA 50 mg/kg group (P<0.0001)

Treatment of mice with BoxA, a specific inhibitor of HMGB1 [8], reduced MM tumor growth and significantly improved their survival compared to control.

  • To determine whether aspirin’s inhibition of HMBB1 worked alone to reduce tumor activity or whether other benefits of aspirin were required, researchers treated mice injected with HMGB1-secreting human MM cells with Box A.
  • Tumor growth was significantly slower in these mice than in controls (P<0.0001). Median survival was 142 days compared to 76.5 days in control (P<0.0001).

In Vitro Results:

Researchers went on to demonstrate that ASA suppresses the migration, invasion, wound healing, and colony formation of HMGB1-secreting MM cells but not those of non-HMGB1 secreting MM cells (P<0.05).

Conclusion:

Researchers successfully demonstrate that ASA protects against MM by inhibiting the carcinogenic effects of HMGB1 at “physiologically relevant concentrations.”

This study was done on mice in the early stages of tumor growth. Researchers propose that better results with aspirin and BoxA can be achieved when aspirin is administered during the early stages of tumor development or as a preventative measure. They also recommend aspirin for individuals at high risk for MM such as those with asbestos or erionite exposure or with a genetic predisposition for MM. They believe their results are relevant not only to MM “but also to other inflammation-related malignancies such as melanoma, breast, GI, prostate, and pancreatic cancers, whose growth and development also appear to be supported by high levels of HMGB1 [9, 10].

Source: Yang, Haining, et al. “Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.” Cell death & disease 6.6 (2015): e1786.

© 2015 Macmillan Publishers Limited All rights reserved 2041-4889/15

 Posted November 11, 2015.

*Prescription drugs can save lives but may also cause unwanted side effects. Thus not all drugs are considered safe. Consult with your medical healthcare provider for more information on a specific drug of interest.

References:

  1. Carbone, M., et al., Malignant mesothelioma: facts, myths, and hypotheses. Journal of cellular physiology, 2012. 227(1): p. 44-58.
  2. Carbone, M., et al., BAP1 and cancer. Nature Reviews Cancer, 2013. 13(3): p. 153-159.
  3. Chung, H.W., et al., Serum high mobility group box‐1 is a powerful diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma. Cancer science, 2012. 103(9): p. 1714-1721.
  4. Lee, H., et al., Diagnostic significance of serum HMGB1 in colorectal carcinomas. PloS one, 2012. 7(4): p. e34318.
  5. Yang, H., et al., Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. Cell death & disease, 2015. 6(6): p. e1786.
  6. Weissmann G., Aspirin. Scientific American, 1991. 265:p. 84-90..
  7. Reuter BK, Zhang XJ, Miller MJ., Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis. BMC Cancer, 2002. 2: 19.
  8. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE et al., Reversing estalished sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA, 2004. 101: 296-301.
  9. Jube S, Rivera CS, Bianchi ME, Powers A, Wang E, Pagano I et al. Cancer cell selection of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res, 2012. 72: 3290-3301.
  10. Ellerman JE, Brown CK, deVera M, Zeh HJ, Billiar T, Rubartelli A, et al. Masquerader: high motility group box-1 and cancer. Clin Cancer Res, 2007. 13: 2836-2848.