Screening the effects of indoles on the proliferation of yeast via changes in lipid carbon flux

Abstract

Indoles are privileged structures that provide a platform to develop new drugs for the treatment of complex human diseases such as cancer, metabolic syndromes, cardiovascular diseases and neurodegenerative diseases. Many substituted indoles (i.e. 2-aryl indoles) exhibit anti-proliferative effects which has prompted the design modification for new drugs to treat proliferative diseases such as cancer. Compound 209 (2-(1H-indol-2-yl)) is a novel drug modified from 2-phenylindole (2-PI) and is known to inhibit the growth of glioblastoma cell lines and Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast models. Lipids are essential to provide key elements to sustain cell growth and proliferation. In this study, indole, 2-PI and compound 209 were screened in an oleaginous yeast model, Lipomyces starkeyi (L. starkeyi), to ascertain their effect on culture growth in association with the lipid carbon flux. These indole compounds were selected to assess the significance of the 2-phenyl and the hydroxylated 2-phenyl substituents on the activity of indole.
Interestingly, each of the indole compounds exhibited different growth inhibition activity at different points of L. starkeyi growth. Radioassays were performed to ascertain the effect of the indole compounds on lipid synthesis by monitoring the uptake of acetate [1-14C] from the medium and, the carbon flux of lipids extracted from the treated cells. Furthermore, the surviving indole-treated L. starkeyi cells developed super-sized lipid droplets possibly as a cytoprotective mechanism. Hence, there may be a suggestion of the involvement of excess accumulation of reactive oxidative species (ROS) as with L. starkeyi cells treated with compound 209 to divert the metabolic flux towards cell proliferation and against the growth inhibitory effects of the compounds. In conclusion, the combined results indicate that the differences in the structure-activity relationships of the indole compounds may elicit growth inhibition by interacting with different cellular drug targets on L. starkeyi cells resulting in varying growth inhibitory responses.