Bael Tree (Aegle marmelos) Protoliminoids Inhibit Mitochondrial Respiration and Suppress Translation Initiation and Elongation Factors

In search of molecular targeted drug leads for cancer, 20,000 natural product-rich extracts of plants and marine organisms were evaluated in a human breast tumor T47D cell-based reporter assay for hypoxia-inducible factor-1 (HIF-1) inhibitory activities. Bioassay-guided isolation and dereplication-based structure elucidation of an active extract from the Bael tree Aegle marmelos afforded two protoliminoids skimmiarepin A (1) and skimmiarepin C (2). In T47D cells, 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC₅₀ values of 0.063µM and 0.068µM, respectively. Compounds 1 and 2 also suppressed hypoxic induction of HIF-1 target genes GLUT-1 and VEGF. Mechanistic studies revealed that 1 and 2 inhibited HIF-1 activation by blocking the hypoxia-induced accumulation of HIF-1α protein. At the range of concentrations that inhibited HIF-1 activation, 1 and 2 suppressed cellular respiration by selectively inhibiting the mitochondrial electron transport chain at complex I (NADH dehydrogenase). Further investigation indicated that mitochondrial respiration inhibitors such as rotenone and skimmiarepin A induced the rapid phosphorylation and inhibition of translation initiation and elongation factors. The inhibition of protein translation may account for the effects exerted by mitochondrial inhibitors on cellular signaling upon short exposure, while the suppression of cellular ATP production may contribute to the inhibitory effects imposed by mitochondrial inhibitors following extended treatment.

Skimmiarepin A

Acknowledgements: This research was supported by NIH Grant CA98787, NOAA/NIUST Grant NA16RU1496, and conducted in a facility constructed with NIH Research Facilities Improvement Grant C06 RR-14503–01.