Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer Mechanisms

Betulin and betulinic
acid have been widely studied for their anticancer
activities. However, their further development is limited due to low
bioavailability, poor aqueous solubility, and limited intracellular
accumulation. In the present study, a triphenylphosphonium cation
moiety was linked to betulin and betulinic acid to specifically target
them to cancer cell mitochondria. Biological characterization established
that uptake of mitochondria-targeted compound 1a in the
mitochondria of cancer cells was increased compared to betulin. The
mitochondria-targeted derivatives of betulin and betulinic acid showed
stronger cytotoxicity than their parent drugs and exhibited more cytotoxic
effects in cancer cells than normal cells. The mechanisms may involve
the mitochondrial apoptotic pathway, probably caused by the induction
of reactive oxygen species production and reducing mitochondrial membrane
potential. More importantly, 1a significantly inhibited
cancer cell proliferation and migration in an in vivo zebrafish xenograft
model. Collectively, these results encourage
further study of 1a analogs as anticancer agents.