Selective Antitumor Effect and Lower Toxicity of Mitochondrion-Targeting Derivatization of Triptolide

Triptolide
has a significant antitumor activity, but its toxicity limits its
clinical
application. As the mitochondrion-targeting strategy showed an advantage
in selective antitumor effect based on the higher mitochondrial membrane
potential (MMP) in tumor cells than normal cells, the lipophilic cations
triphenylphosphonium and E-4-(1H-indol-3-yl vinyl)-N-methylpyridinium iodide (F16)
were selected as targeting carriers for structural modification of
triptolide. The derivatives bearing F16 generally retained most antitumor
activities, overcame its inhibition plateau phenomena, and enhanced
its selective antitumor effect in lung cancer. The representative
derivative F9 could accumulate in the mitochondria of
NCI-H1975 cells, inducing apoptosis and a dose-dependent increase
in intracellular reactive oxygen species and reducing MMP. Moreover,
no effects were observed in normal cells BEAS-2B. In vivo studies showed that the developmental, renal, and liver toxicities
of F9 to zebrafish were significantly lower than those
of triptolide. This study provides a promising idea to relieve the
toxicity problem of triptolide.