13-Hydroxy-15-oxo-zoapatlin, a nor-kaurane diterpene, induces apoptosis in human leukemia cells, affecting thiol-mediated redox regulation

13-Hydroxy-15-oxo-zoapatlin (OZ), a nor-kaurane diterpene, was 1st described as a compd. inhibiting the proliferation of human cancer cell lines. Successively, it was reported that OZ inhibits the G2 DNA damage checkpoint and causes mitotic arrest. To get more insight into the mol. mechanism(s) underlying the antitumor potential of OZ, we evaluated the proapoptotic activity of this mol. OZ was found to induce hypodiploidia and phosphatidylserine externalization, 2 hallmarks of apoptosis; to disrupt mitochondrial membrane potential; and to trigger caspase-3 activation. OZ-induced cell death, mostly dependent upon the presence of the α,β-carbonyl group, is strongly related to alterations in the cellular redox balance. The interaction of OZ with cellular components and proteins contg. reactive thiols was evaluated by mass spectrometry-based approaches. A specific reactivity of this compd. toward glutathione and thioredoxin was obsd.