Effect of TM208 on QGY-7703 xenograft tumor growth.
A newly synthesized dithiocarbamate derivative, 4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208), has demonstrated anticancer effects with low toxicity in earlier studies; however, the mechanism has yet to be identified. We explored antitumor effects of TM208 and the possible mechanisms by which it inhibited the growth of human hepatocellular carcinoma cell line QGY-7703 xenograft tumors. Cell proliferation was evaluated with the sulforhodamine B assay in vitro. The results suggested that TM208 had slightly antiproliferative activity on QGY-7703 cells. The antitumor effect of TM208 was assessed in nude mice xenografted with QGY-7703 tumors. We found that TM208 significantly inhibited tumor growth but did not cause loss of body weight or leukocytopenia. Western blotting was used to detect the expression of protein kinase C alpha, mitogen-activated protein kinase signal pathways, and cell cycle-related proteins. The results showed that TM208 decreased the expression of protein kinase C alpha, phospho-extracellular signal-regulated kinase-1/2, phospho-p38, cyclin B1, cell division cycle 2 (cdc2), and phospho-cdc2 (Thr161) and increased the expression of phospho-cdc2 (Tyr15). Taken together, our data show that TM208 has little antiproliferative effect on QGY-7703 cells in vitro, whereas it significantly inhibits the growth of QGY-7703 xenograft tumors with low toxicity in vivo. The inhibition of mitogen-activated protein kinase signal pathways and the regulation of the G2/M phase may be responsible for its antitumor effects.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutic Sciences, Peking University Health Science Center, Beijing 100083, PR China.
Ning
N
Zhang
Wei
W
Guo
Li
L
Wang
Wei
W
Huang
Bo
B
Xu
Zemei
Z
Ge
Min
M
Li
Run Tao
RT
Li
Jing Rong
JR
Cui
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016203:CDC2 Protein Kinase / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
C522133:4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D010879:Piperazines; D016203:CDC2 Protein Kinase