Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.
Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 μmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.
Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
Shaunna L
SL
Beedie
Clinical Pharmacology Program, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Cody J
CJ
Peer
Clinical Pharmacology Program, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Steven
S
Pisle
Clinical Pharmacology Program, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Erin R
ER
Gardner
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
Chris
C
Mahony
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
Shelby
S
Barnett
Pharmaceutical Institute, University of Bonn, Bonn, Germany.
Agnieszka
A
Ambrozak
Pharmaceutical Institute, University of Bonn, Bonn, Germany.
Michael
M
Gütschow
Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Cindy H
CH
Chau
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom. figgw@helix.nih.gov n.vargesson@abdn.ac.uk.
Neil
N
Vargesson
Molecular Pharmacology Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Clinical Pharmacology Program, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. figgw@helix.nih.gov n.vargesson@abdn.ac.uk.
William D
WD
Figg
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
D020533:Angiogenesis Inhibitors; D006845:Hydrocarbons, Fluorinated; D013792:Thalidomide