High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis.
The present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC model, in which hypoxia was generated by hepatic artery ligation (HAL). Compared with HAL alone, PTK787 combined with HAL significantly prolonged the animal survival, reduced the tumor size, induced more tumor tissue necrosis and apoptosis, and down-regulated the expression of von Willebrand factor. The mechanism was explored in vitro using murine HCC and endothelial cell lines, respectively. PTK787 combined with hypoxia decreased the expression of VEGF and VEGF receptors in both cell lines and suppressed the cell viability by induction of cell cycle arrest and promotion of apoptosis. Up-regulation of cleaved form caspase-9 and down-regulation of Bcl-2 and cyclin D1 were detected with the combined treatment. Hypoxia sensitized endothelial cells to the inhibitory effect of PTK787 on forming tubular-like structure. The motility of tumor cells was inhibited by hypoxia and the combined approach, with down-regulation of Rac1, Rho, and phosphorylated Akt expression. However, in the endothelial cells, the combined treatment inhibited the hypoxia-enhanced cell motility, with suppressed Rac1, Rho, and phosphorylated Akt expression. In conclusion, PTK787 combined with hypoxia achieved a better therapeutic efficacy than hypoxia alone through enhancing hypoxia-induced antitumor cell effect and preventing the activation of angiogenic process.
Yang
Zhen Fan
ZF
Center for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Poon
Ronnie T P
RT
Liu
Yuqing
Y
Lau
Chi Keung
CK
Ho
David W
DW
Tam
Ka Ho
KH
Lam
Chi Tat
CT
Fan
Sheung Tat
ST
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011915:Rats, Inbred BUF; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D011505:Protein-Tyrosine Kinases