Melanie Hutchings, MS, RDN: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Lung cancer is the leading cause of cancer deaths in the US. Thus, better therapeutic targets and options with fewer adverse side effects are needed. The Sin3/histone deacetylase complex (HDAC) is implicated in the development and progression of many cancer types including lung cancer. Dietary bioactive agents, known to have fewer adverse effects, have been reported to show potential benefits in many cancer types, in part due to their anti-inflammatory, antioxidant, and anti-cancer properties. Previously, we reported the potential benefits of tocotrienols in lung cancer. The objective of this work is to use metabolomics to investigate the effect of tocotrienols on the Sin3/HDAC complex in lung cancer cells.
Methods: Expression of Sin3A (3A) or Sin3B (3B) was modulated in human lung cancer cells (A549, H1299), using small interfering RNA (siRNA). The cells were subsequently treated with 25 µM of delta-tocotrienol, as determined by a cell viability assay. Differences in the metabolomic profiles upon treatment were analyzed using 1H-NMR-based metabolomics on cell extracts. Multivariate data analysis methods were used to visualize the effect of knockdown and treatment conditions on the metabolomic profile of the cell line. Chenomx NMR Analysis Software and pathway analysis (MetaboAnalyst) are being used to quantify the specific metabolites and corresponding pathways responsible for the changes in the metabolomic profiles.
Results: Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA), show a significant difference between metabolomic profiles, both in the knockdown and tocotrienol-treated A549 cells. Untreated, the metabolomic profiles of 3B was significantly different from the control cells and from 3A, while the latter two have greater similarity. However, both 3A and 3B cells produced significant shifts from the metabolomic profile of the control cells after treatment with DT3.
Conclusions: This investigation provides insight into an upstream mechanism by which DT3 may affect lung cancer cells. Identification of specific metabolites and altered metabolic pathways involved in these differences are under investigation and may provide new and improved targets of therapeutic benefit.
