Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma.
In this study, we aimed to evaluate the potential anticancer and antiangiogenic effects of FTY720 on hepatocellular carcinoma. In vitro, chemosensitivity was tested on hepatoma cells, nontumorigenic, immortalized hepatocyte cells, as well as human umbilical vein endothelial cells (HUVEC). Moreover, effect of FTY720 on cell cycle and apoptosis was analyzed. In addition, a number of angiogenesis-associated assays were carried out. The in vivo effect of the drug on hepatocellular carcinoma tumor growth on nude mice was studied. Tissues obtained were analyzed in terms of proliferation, apoptosis, tumor microvessel density, and tumor vascular permeability. Compared with the MIHA cells, the hepatoma cell lines as well as HUVECs were found to be highly sensitive to the drugs in the aspect that FTY720 could induce G(1) arrest and apoptosis in the hepatoma cells. Furthermore, FTY720 significantly decreased invasion, migration, and capillary tube formation of HUVECs at very low doses. In vivo study showed that tumor growth was significantly suppressed in the FTY720-treated animals, and staining of the tissue sections showed decreased tumor cell proliferation and increased tumor cell apoptosis in the treatment groups. Interestingly, significant reductions in tumor microvessel density and tumor vascular permeability were also found in the FTY720-treated groups. In conclusion, FTY720 not only shows potent antiangiogenic effects but is also cytotoxic toward hepatoma cells. Results from our preclinical study suggest that FTY720 can be selected as a good candidate for the treatment of hepatocellular carcinoma.
Ho
Joanna W Y
JW
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Queen Mary Hospital, China.
Man
Kwan
K
Sun
Chris K
CK
Lee
Terence K
TK
Poon
Ronnie T P
RT
Fan
Sheung Tat
ST
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D014947:Wounds and Injuries
D018931:Antineoplastic Agents, Hormonal; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine