Probing the Anticancer Action of Oridonin with Fluorescent Analogues: Visualizing Subcellular Localization to Mitochondria

Oridonin
(1) is a complex ent-kaurane
diterpenoid exhibiting remarkable antitumor activity. However, the
detailed mechanism or cellular target that underlies this activity
has not yet been identified. Herein, we report an efficient approach
for exploring the anticancer mechanism of oridonin through development
of the potent fluorescent analogues. A series of novel fluorescent
oridonin probes linked with coumarin moieties were designed, synthesized,
and characterized. Fluorescence microscopy and confocal imaging studies
suggested that fluorescent oridonin probe 17d was rapidly
taken up into tumor cells and the mitochondrion was the main site
of its accumulation. Moreover, we confirmed that cytochrome c played
an important role in oridonin induced mitochondrion-mediated apoptosis
and α,β-unsaturated ketone is the active moiety of oridonin,
which is crucial to its uptake, localization, and cytotoxicity. Our
results provide new insights on the molecular mechanism of oridonin
and would be useful for its further development into an antitumor
agent.