Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

Shaunna L. Beedie, Cody J. Peer, Steven Pisle, Erin R. Gardner, Chris Mahony, Shelby Barnett, Agnieszka Ambrozak, Michael Gütschow, Cindy H. Chau, Neil Vargesson, William D Figg

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Abstract

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. Mol Cancer Ther; 14(10); 2228–37. ©2015 AACR.
Original languageEnglish
Pages (from-to)2228-2237
Number of pages10
JournalMolecular Cancer Therapeutics
Volume14
Issue number10
Early online date12 Aug 2015
DOIs
Publication statusPublished - Oct 2015

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Thalidomide
Embryonic Structures
Zebrafish
carboxyamido-triazole
Human Umbilical Vein Endothelial Cells
Microvessels
Heterografts
Blood Vessels
Chickens
Neoplasms
Prostatic Neoplasms
Anti-Inflammatory Agents
Research

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Beedie, S. L., Peer, C. J., Pisle, S., Gardner, E. R., Mahony, C., Barnett, S., ... Figg, W. D. (2015). Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues. Molecular Cancer Therapeutics, 14(10), 2228-2237. https://doi.org/10.1158/1535-7163.MCT-15-0320

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues. / Beedie, Shaunna L.; Peer, Cody J. ; Pisle, Steven ; Gardner, Erin R.; Mahony, Chris; Barnett, Shelby; Ambrozak, Agnieszka; Gütschow, Michael; Chau, Cindy H. ; Vargesson, Neil; Figg, William D.

In: Molecular Cancer Therapeutics, Vol. 14, No. 10, 10.2015, p. 2228-2237.

Research output: Contribution to journalArticle

Beedie, SL, Peer, CJ, Pisle, S, Gardner, ER, Mahony, C, Barnett, S, Ambrozak, A, Gütschow, M, Chau, CH, Vargesson, N & Figg, WD 2015, 'Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues', Molecular Cancer Therapeutics, vol. 14, no. 10, pp. 2228-2237. https://doi.org/10.1158/1535-7163.MCT-15-0320
Beedie, Shaunna L. ; Peer, Cody J. ; Pisle, Steven ; Gardner, Erin R. ; Mahony, Chris ; Barnett, Shelby ; Ambrozak, Agnieszka ; Gütschow, Michael ; Chau, Cindy H. ; Vargesson, Neil ; Figg, William D. / Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 10. pp. 2228-2237.
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AU - Vargesson, Neil

AU - Figg, William D

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N2 - 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. Mol Cancer Ther; 14(10); 2228–37. ©2015 AACR.

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