Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4‐d]pyrimidine nucleoside derivatives‐induced cancer cell death

Abstract

Eight novel oxdiazolo[3,4-d]pyrimidine nucleoside derivatives (I-VIII) were synthesized to investigate their anti-tumor effects and possible mechanisms. Four human cancer cell lines including Hela, ECA109, HepG2 and A459 cells were used. Compounds VI and VIII showed significant inhibition on cancer cell proliferation by MTT assay and IC50 values were around 30-70 micromol l(-1). Both compounds could release nitric oxide (NO), led to a significant intracellular free Ca2+ overloading and resulted in mitochondrial dysfunction, showing a decrease in mitochondrial membrane potential in HepG2 cells in a dose-dependent manner. Furthermore, compound VIII induced obvious DNA damage on HepG2 cells. These data indicate that compounds VI and VIII are two active antitumor compounds, and both DNA damage and mitochondrial dysfunction are involved in the mechanisms underlying oxadiazolo[3,4-d]pyrimidine nucleoside derivative-induced cancer cell death, which might also be related to the released NO.