Sorafenib and docosahexaenoic acid act in synergy to suppress cancer cell viability: a role of heme oxygenase 1

Background: Docosahexaenoic acid (DHA) is a long chain n-3 polyunsaturated fatty acid that has anticancer activity. Heme oxygenase 1 (HO-1) is a potential therapeutic target due to its cytoprotective activity in cancer cells. We recently reported that DHA induces HO-1 gene transcription in human cancer cells by augmenting the degradation of Bach1 protein, which functions as a negative regulator of HO-1. Since the degradation of Bach1 protein relies on protein phosphorylation, we hypothesized that DHA-induced HO-1 gene transcription could be attenuated by kinase inhibitors, resulting in an enhanced cytotoxicity. Sorafenib, a tyrosine kinase inhibitor, was first applied to test our hypothesis.

Methods: Human cancer cell lines and a xenograft nude mouse model were applied to test our hypothesis. Gene expression was analyzed by western blot analysis and reporter gene assay. Cell viability was analyzed using a colorimetric assay. Isobologram was applied to analyze drug action.

Results: Pretreatment of cancer cells with Sorafenib significantly attenuated DHA-induced degradation of Bach1 protein. Consequently, DHA-induced HO-1 gene transcription was reversed by Sorafenib as evidenced by western blot and reporter gene analysis. Sorafenib acted synergistically with DHA to suppress cancer cell viability in various human cancer cell lines and suppressed tumor xenograft growth in mice fed a fish oil enriched diet (high n-3/DHA), as compared to mice fed a corn oil (high n-6) diet. Screening of the NCI-Oncology Drug Set IV identified a group of anticancer compounds, including Sorafenib, which enhanced DHA's cytotoxicity, as well as a set of compounds that attenuated DHA's cytotoxicity.

Conclusions: We demonstrate that sorafenib attenuates DHA-induced HO-1 expression and acts in synergy with DHA to suppress cancer cell viability and tumor growth. Considering the known health benefits of DHA and the clinical effectiveness of Sorafenib, their combination is an attractive therapeutic strategy against cancer.