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The investigation of lipoxygenases as therapeutic targets in malignant pleural mesothelioma

Oguh-Olayinka, Lily; Agarwal, Vijay; Ranatunge, Dulani; Campbell, Anne; Laufer, Stefan; Cawkwell, Lynn; Lind, Michael J

Authors

Lily Oguh-Olayinka

Vijay Agarwal

Dulani Ranatunge

Anne Campbell

Stefan Laufer

Professor Michael Lind M.J.Lind@hull.ac.uk
Foundation Professor of Oncology/ Head of the Joint Centre for Cancer Studies

Abstract

Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclo-oxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogen-esis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72 h treatment with the lipoxygenase pathway inhibitors baicalein, licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6 μM to 20.7 μM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable.

Journal Article Type Article
Journal Pathology & Oncology Research
Print ISSN 1219-4956
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Institution Citation Oguh-Olayinka, L., Agarwal, V., Ranatunge, D., Campbell, A., Laufer, S., Cawkwell, L., & Lind, M. J. (in press). The investigation of lipoxygenases as therapeutic targets in malignant pleural mesothelioma. Pathology and Oncology Research, https://doi.org/10.1007/s12253-019-00652-x
DOI https://doi.org/10.1007/s12253-019-00652-x
Keywords Arachidonic acid; Cyclooxygenase; Immunohistochemistry; Lipoxygenase; Mesothelioma
Publisher URL https://link.springer.com/article/10.1007/s12253-019-00652-x

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© The Author(s) 2019
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.




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