CHEMOTHERAPEUTICALLY INDUCED DNA-DAMAGE, ATP DEPLETION, AND THE APOPTOTIC BIOCHEMICAL CASCADE

The biochemical death cascade of apoptosis is separate from, although induced by, the anticancer drug-target interaction. The failure of man y of our chemotherapeutic agents reflects an inability of anticancer d rugs to induce apoptosis. Understanding the basic cellular mechanisms that control apoptosis will greatly increase our ability to treat canc er. Identification of the components of the apoptotic biochemical casc ade will present new targets for complementary enhancement of chemothe rapeutically induced cancer cell death. One factor that has been direc tly implicated in apoptosis is adenosine triphosphate (ATP). Neverthel ess, in this regard, ATP is controversial. This commentary takes issue with dogma, and points to the need for additional thought and researc h in this field. ATP-depleting therapy of tumor-bearing mice has been shown to induce a marked therapeutic result with minimal mortality, an d this effect can be further enhanced when combined with chemotherapy. The definitive mechanism of action is still controversial, although s everal mechanisms for ATP depletion have been implicated in the proces s. These include reduction in the mitochondrial transmembrane potentia l, activation of poly (ADP-ribose) polymerase (PARP) and depletion of the coenzyme nicotinamide adenine dinucleotide (NAD(+)). Even though t he definitive experiments have yet to be carried out, the identificati on of ATP depletion as a critical determinant in apoptosis should allo w for the development of new therapeutic strategies in the treatment o f human cancer.