The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma

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

doi:10.1007/s12253-019-00652-x

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 cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. 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.

Highlights

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumour
We have previously shown using immunohistochemistry (IHC) that COX-2 is overexpressed in MPM and that the specific COX-2 inhibitor DuP-697 can potentiate the in vitro cytotoxic effects of pemetrexed in MPM cell lines [4, 17]
In the MPM samples the expression of the 12-LOX protein was again predominantly found in the nucleus and cytoplasm of the malignant cells, with varying intensity (Fig. 1)

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumour. Despite recent advances in chemotherapy, it isL. Malignant pleural mesothelioma (MPM) is a rare, aggressive tumour. Despite recent advances in chemotherapy, it is. In 80% of cases, MPM can be attributed to asbestos fibre exposure with a median latency of at least 32 years [1, 2]. MPM can be classified into epithelial, biphasic and sarcomatoid subtypes. The epithelial subtype is associated with longer survival when compared with sarcomatoid [3, 4]. With the administration of cisplatin/pemetrexed the median survival of MPM is still only 12 months and currently there is no widely approved second line regimen after failure of first line treatment [5,6,7,8]

Objectives

Methods

Results

Conclusion