Hepatocellular carcinoma (HCC), which accounts for more than half a million deaths annually, is one of the most common malignancies worldwide. Significantly, the 5-year survival rate of patients having non-resectable tumours is below 9% (1). Further, patients are often diagnosed at an advanced stage, and have co-morbidities that limit the treatment options. Sorafenib is the first-line therapy for such patients, however, many patients discontinue its use due to severe toxicity. It is therefore imperative to identify novel therapeutic targets in HCC for the development of drugs, either as monotherapy or in combination, to reduce toxicity related to sorafenib.
The eicosanoid pathway has a well-defined role in inflammation and carcinogenesis, and one of the critical enzymes in this pathway is phospholipase A2 (PLA2), which hydrolyses the membrane phospholipids at sn-2 position to release fatty acids and lysophospholipids. Arachidonic acid is the most frequently released fatty acid, and is the precursor for bioactive lipids or eicosanoids, including prostaglandins and leukotrienes. Two of the most studied isoforms of PLA2 are secreted PLA2 group IIA (sPLA2-IIA) and cytosolic PLA2-a (cPLA2-a), which have been implicated in numerous solid malignancies (2-5), however, their role in HCC has not been well-defined. In this study, we show that pharmacological inhibition of cPLA2-a by pyrrophenone reduces the cell viability of HCC cells, and has a synergistic effect when combined with sorafenib. We also demonstrate that sPLA2-IIA is expressed by various HCC cell lines. Additionally, inhibition of sPLA2-IIA by c2, which is a novel drug currently in clinical trials at Liverpool Hospital for advanced prostate cancer patients, does not affect the cell viability by itself, however, our preliminary data suggest that c2 when combined with sorafenib, reduces the IC50 of sorafenib. In conclusion, these data suggest that pharmacological intervention to block the function of PLA2 enzymes warrant further investigation as a potential new therapeutic approach for HCC.