Lgf-YL-9 induces apoptosis in human epidermoid carcinoma KB cells and multidrug resistant KBv200 cells via reactive oxygen species-independent mitochondrial pathway.
Pyrazolon derivatives were reported to have cytotoxicity to some tumour cells. In the present study, we investigated the effect of Lgf-YL-9 on cytotoxicity and cell apoptosis in human epidermoid carcinoma drug-sensitive parental KB cells and multidrug resistant (MDR) KBv200 cells. Lgf-YL-9 exhibited potent cytotoxicity not only to KB cells but also to KBv200 cells, and the IC(50) were 3.81 and 3.45 microg/mL in KB cells and KBv200 cells, respectively. Importantly, Lgf-YL-9 effectively inhibited tumour growth of KB cell xenografts in nude mice. Lgf-YL-9-induced cell apoptosis was confirmed by chromatin condensation, DNA fragmentation, Annexin-V and propidium iodide (PI) double-staining assay and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, Lgf-YL-9-mediated apoptosis in KB cells and KBv200 cells was accompanied by the loss of mitochondrial membrane potential (DeltaPsi(m)), the release of cytochrome c, and the activation of caspases-3, -7, and -9, but not by intercalating to DNA. Although Lgf-YL-9-induced apoptosis was associated with the decrease of DeltaPsi(m), reactive oxygen species (ROS) reduction was interestingly observed in both cell lines. The data suggest that Lgf-YL-9 has similar cytotoxicity to drug-sensitive parental KB cells and MDR KBv200 cells. Lgf-YL-9-induced apoptosis is involved in a new ROS-independent mitochondrial dysfunction pathway, but not in intercalating to DNA.
Wang
Xiao-Hong
XH
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, PR China.
Jia
Dian-Zeng
DZ
Liang
Yong-Ju
YJ
Yan
Su-Li
SL
Ding
Yan
Y
Chen
Li-Ming
LM
Shi
Zhi
Z
Zeng
Mu-Sheng
MS
Liu
Guang-Fei
GF
Fu
Li-Wu
LW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007624:KB Cells; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D047069:Pyrazolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047069:Pyrazolones; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D004247:DNA