Statins Do Not Alter the Incidence of Mesothelioma in Asbestos Exposed Mice or Humans

Abstract

Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44–2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61–1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos.

Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

“…The exclusive effects of statins on MPM with dysregulated Hippo pathway may explain the earlier observation that statins do not affect the incidence of mesotheliomas in asbestosexposed mice or humans. 51 Statins have also been shown to be highly effective against therapy-resistant solid tumor cells, 52 and in MPM, statins enhance the efficacy of doxorubicin, likely by reducing the ability of MPM cells to develop resistance to doxorubicin treatment. 53 Targeting SRC and FAK tyrosine kinase.…”

Asbestos‐induced mesothelial injury and carcinogenesis: Involvement of iron and reactive oxygen species

“…119 On the other hand, vitamin A, D, E and selenium supplementations did not prevent the development of crocidolite-induced murine MM. 120 The cancer immunotherapy that blocks programmed death-ligand 1 (PD-L1) is clinically put into practice as a new therapeutic strategy for MM patients. In immunodeficient NOD-scid IL2Rg null (NSG) mice, tumor growth of B 16 (murine melanoma cell line) was suppressed by the combination of anti-PD-L1 and anti-CTLA-4 therapy, which was significantly canceled by liprostain-1.…”

Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma

“…Statins have also been found to be effective against MM in vivo when combined with doxorubicin chemotherapy, likely by reducing the ability of the MM cells to acquire resistance to doxorubicin treatment [ 108 ]. In contrast, both a mouse model and human cohort study of 1738 patients with a history of asbestos exposure reported that statins do not moderate mesothelioma development or progression [ 109 ]. Although the putative preventive and therapeutic effects of statins in the treatment of various cancers, including mesothelioma, require further investigation, their effects on the mevalonate pathway have been confirmed to control YAP1/TAZ activity [ 110 ], such that statin treatment inhibits both YAP1/TAZ nuclear localization and transcriptional responses [ 110 ].…”