Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4-d]pyrimidine nucleoside derivatives-induced cancer cell death.
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.
Liu
Hai-liang
HL
School of Pharmacy, Jiangsu University, Zhenjiang 212013, People's Republic of China.
Xu
Jing-jing
JJ
Dai
Xiao-min
XM
Shi
Jing-bo
JB
Xu
Song
S
Gao
Jing
J
Yao
Qi-zheng
QZ
Liu
Feng
F
D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005562:Formazans / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors
D005562:Formazans; D010069:Oxadiazoles; D011741:Pyrimidine Nucleosides; D013778:Tetrazolium Salts; C079782:MTT formazan