The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma

Our plain-English summary of The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma, by L. Oguh-Olayinka, V. Agarwal, D. Ranatunge, et al (Pathology Oncology Research, 2020).

The study

• Authors: L. Oguh-Olayinka, V. Agarwal, D. Ranatunge, A. Campbell, S. Laufer, L. Cawkwell, M.J. Lind
• Journal: Pathology Oncology Research
• Published: 2020;26(2):985-995
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study from Hull, UK, examined two enzymes, 5-LOX and 12-LOX, in malignant pleural mesothelioma. It did not study asbestos exposure. The authors stained archived tumour samples from 83 patients diagnosed between 1992 and 2000, plus 8 benign pleural samples. They also tested enzyme-blocking drugs on three mesothelioma cell lines grown in the laboratory. 12-LOX was found in 69 of 83 tumour samples (83%) and 5-LOX in 56 of 77 scored samples (73%). Neither was linked to survival overall. In the sarcomatoid subtype only, 5-LOX-positive cases had longer median survival (4.2 versus 1 month). Tumours positive for both COX-2 and 5-LOX also had longer median survival than tumours negative for both (8.7 versus 2.2 months). The authors called these preliminary findings that need more cases. Baicalein was effective in all three cell lines: after 72 hours, the concentration that halved cell viability (IC50) ranged from 9.6 to 20.7 micromolar. Zileuton and licofelone showed no effect at low concentrations. The authors concluded that the enzymes may be treatment targets. They said human studies are needed to learn whether the baicalein concentrations used can be reached in patients.

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: immunohistochemistry on archival (retrospective) tumour tissue, plus in vitro drug experiments on cell lines
• Who was studied: Archival malignant pleural mesothelioma tissue from 83 patients (76 of 83 male) diagnosed 1992 to 2000 at Hull Royal Infirmary, UK; 8 benign pleural samples from male patients treated for spontaneous pneumothorax; mesothelioma cell lines NCI-H2452, NCI-H2052 and MSTO-211H, and lung cancer cell line A549
• Exposure: Asbestos exposure was not studied. The cell lines were treated for 72 hours with lipoxygenase pathway inhibitors (baicalein, MK-886, zileuton, licofelone) and the COX-2 inhibitor celecoxib, alone and as a celecoxib plus baicalein combination
• Main results:
  • Mesothelioma tissue: 12-LOX positive in 69/83 (83%); 5-LOX positive in 56/77 (73%) of scored samples
  • 12-LOX expression was not associated with survival (p = 0.455)
  • Overall, 5-LOX was not associated with survival (p = 0.640). In the sarcomatoid subtype only, 5-LOX-positive cases had median survival of 4.2 months versus 1 month in 5-LOX-negative cases (p = 0.028)
  • Co-expression of 5-LOX with 12-LOX in 46/78 (58%) of mesothelioma samples; not statistically significant and not associated with survival
  • Co-expression of COX-2 with 5-LOX in 41/77 (53%) of samples, associated with longer median survival than cases negative for both (8.7 versus 2.2 months; p = 0.011). The COX-2 data were previously published for this cohort
  • Benign pleura: 12-LOX was seen in non-reactive and reactive samples; 5-LOX only in samples with reactive mesothelial cells
  • Baicalein was effective in all 3 mesothelioma cell lines at low concentrations; after 72 hours of treatment, the IC50 values for cell viability ranged from 9.6 to 20.7 micromolar across the three lines
  • Zileuton and licofelone showed no effect at low concentrations in any mesothelioma cell line; MK-886 had an effect at low concentrations in 2 of 3
  • Combining celecoxib with baicalein: baicalein alone appeared mainly responsible for the effect, with drug synergy in only 1 cell line
• The authors' conclusion: The authors concluded that 5-LOX and 12-LOX are expressed at high frequency in mesothelioma samples and may represent therapeutic targets, and that baicalein may be effective as a novel treatment, pending human pharmacokinetic studies
• Limitations the authors state:
  • The survival associations are preliminary and need confirmation in a larger number of cases
  • The benign samples came from patients with an underlying condition that may cause reactive mesothelial cells through inflammation
  • The inhibitors have been reported to act on tumour cells independently of lipoxygenase inhibition
  • It is not known whether the baicalein concentrations used in the laboratory are achievable in humans; no maximum tolerated dose has been established

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Chemotherapy, Carcinogenesis, Mesothelioma, Immunohistochemistry.

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