Vindesine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vindesine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vindesine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the Vinca-binding domain. Binding of just one or two molecules of vindesine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death.
Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity.
One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.