In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

Our earliest phytochemical separation
of Miliusa
sinensis aided us in the isolation of a class of unique
miliusanes, which were demonstrated as anticancer lead molecules.
In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant
(M. balansae), and synthesized additional
derivatives to elucidate the structure–activity relationship
of miliusanes. When extrapolated to various carcinoma xenograft mouse
models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were
demonstrated with tumor inhibitory efficacy comparable or even superior
to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain
a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered
to a wide spectrum of human cancer cell lines, including those with
specific drug resistance. We further revealed that the antiproliferative
properties of miliusanes in carcinoma cells were highly associated
with the p21-dependent induction of cellular senescence.