| Popis: |
(EN) Based on the promising results concerning the anti-cancer properties of redox-silent analogue vitamin E α-tocopheryl succinate (α-TOS), we prepared its mitochondrially targeted derivative MitoVES by attaching the positively charged triphenylphosphonium (TPP+ ) tag to α-TOS molecule. We tested the hypothesis that 'sending' the drug directly to its cellular site of action, mitochondria, should enhance its anti-cancer properties, which would result in more effective anti-cancer agent while making it possible to reduce the effective concentration. We provide evidence that, indeed, MitoVES is a highly effective anti-cancer compound, superior to untargeted α-TOS both in vitro and in vivo. We show that MitoVES exerts its anti-cancer effects by interfering with complex II (CII) activity specifically at the ubiquinone binding site (Qp), where it blocks further electron transfer resulting in increased reactive oxygen species (ROS) production, which then leads to apoptosis induction via the intrinsic mitochondrial pathway, preferentially engaging the pro-apoptotic Bak protein causing mitochondrial membrane permeabilisation. We further show that mitochondrial targeting on the basis of higher mitochondrial membrane potential (ΔΨ) is important for MitoVES pro-apoptotic activity. This feature endows the... |
