Mechanisms of the antitumor action of the new antibiotic NC0604, a member of the bleomycin family.
NC0604, the new antibiotic of the bleomycin family, was isolated from the fermentation broth of Streptomyces verticillus var. pingyangensis n.sp. In this study, we investigated its mechanisms of antitumor action in vitro and in vivo. The results showed that the colony formation inhibition of NC0604 was 2-10 times higher than that of bleomycin to several tumor cell types. In comparison to bleomycin, a better antitumor efficacy of NC0604 was observed in the BALB/c mice loading mouse hepatoma H22 tumors. Flow cytometry assay detected an increase of intracellular reactive oxygen species and arrest at G2/M phase in human hepatoma HepG2 cells after exposure to NC0604. The comet of DNA damage was also observed in the NC0604-treated cells using single cell gel electrophoresis assay. The chromatin condensation appeared in the NC0604-induced apoptotic cells. The activation of apoptotic caspase pathway and increase of apoptosis-modulated protein expression, such as p53, Bax, were also detected by Western blot analysis. Taken together, the anti-tumor actions of NC0604 involve activation of the apoptotic pathway and it is valuable for further drug development.
Shi
Weiwei
W
Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
Chen
Caixia
C
Zhang
Xiumin
X
Xu
Hongzhang
H
Chen
Ruxian
R
He
Qiyang
Q
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C553468:NC 0604; D017382:Reactive Oxygen Species; D001761:Bleomycin