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Article

Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models

  • Authors:
    • Appu Rathinavelu
    • Thanigaivelan Kanagasabai
    • Sivanesan Dhandayuthapani
    • Khalid Alhazzani
  • View Affiliations / Copyright

    Affiliations: Rumbaugh-Goodwin Institute for Cancer Research, College of Pharmacy, Health Professions Division, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
  • Pages: 1711-1724
    |
    Published online on: February 9, 2018
       https://doi.org/10.3892/or.2018.6256
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Abstract

A small molecule that was developed for blocking vascular endothelial growth factor receptor 2 (VEGFR2) has been tested and confirmed for its anti-angiogenic activity. Subsequently, it was modified into a water soluble salt form (JFD-WS) to increase bioavailability and distribution during in vivo pre-clinical testing. The present study was designed to further evaluate the anti-angiogenic and pro-apoptotic effects of JFD-WS in monotherapy as well as in combination with paclitaxel (Taxol) using a mouse xenograft model. The in vitro anti-angiogenic effects of JFD-WS were investigated using cell proliferation, migration, Matrigel tube formation and VEGFR2 phosphorylation assays. The anti-angiogenic effect of JFD-WS was further established using chorioallantoic membrane (CAM) assay followed by in vivo efficacy testing on GI-101A breast adenocarcinoma cells. Pharmacokinetic and toxicity studies were performed using BALB/c mice. Finally, the apoptotic signals were assessed in the control and experimental tumor samples, and the plasma mucin 1 (MUC1) levels were analyzed. In the in vitro tests, JFD-WS effectively inhibited HUVEC proliferation, migration, tube formation and VEGFR2 phosphorylation. Additionally, JFD-WS inhibited the formation of blood vessels in chick chorioallantoic membrane. While inhibiting the xenograft tumor growth in experimental mice, JFD-WS decreased the plasma MUC1 levels. The western blot analysis of apoptotic markers and fragmentation analysis of DNA confirmed the pro-apoptotic effects of JFD-WS. These results indicated that JFD-WS alone or in combination with paclitaxel exerted antitumor and pro-apoptotic effects in the breast cancer xenograft model due to an anti-angiogenic effect. These results strongly support the clinical translation of its use.
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View References

1 

Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29 Suppl 16:15–18. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Ivy SP, Wick JY and Kaufman BM: An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 6:569–579. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Kamba T and McDonald DM: Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 96:1788–1795. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Sridhar J, Akula N, Sivanesan D, Narasimhan M, Rathinavelu A and Pattabiraman N: Identification of novel angiogenesis inhibitors. Bioorg Med Chem Lett. 15:4125–4129. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Dhandayuthapani S and Rathinavelu A: JFD, a novel small molecule for inhibiting vascular endothelial growth factor receptor-mediated angiogenesis. Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5–9; San Diego, CA Philadelphia (PA): AACR; Cancer Res. 74 Suppl 19:Abstract nr1021. 2014;

7 

Auerbach R, Akhtar N, Lewis RL and Shinners BL: Angiogenesis assays: Problems and pitfalls. Cancer Metastasis Rev. 19:167–172. 2000. View Article : Google Scholar : PubMed/NCBI

8 

Mekhail TM and Markman M: Paclitaxel in cancer therapy. Expert Opin Pharmacother. 3:755–766. 2002. View Article : Google Scholar : PubMed/NCBI

9 

Ramaswamy B and Puhalla S: Docetaxel: A tubulin-stabilizing agent approved for the management of several solid tumors. Drugs Today. 42:265–279. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Dorr RT: Pharmacology of the taxanes. Pharmacotherapy. 17:96S–104S. 1997.PubMed/NCBI

11 

Hollstein M, Hergenhahn M, Yang Q, Bartsch H, Wang ZQ and Hainaut P: New approaches to understanding p53 gene tumor mutation spectra. Mutat Res. 431:199–209. 1999. View Article : Google Scholar : PubMed/NCBI

12 

Senapati S, Das S and Batra SK: Mucin-interacting proteins: From function to therapeutics. Trends Biochem Sci. 35:236–245. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Tampellini M, Berruti A, Gerbino A, Buniva T, Torta M, Gorzegno G, Faggiuolo R, Cannone R, Farris A, Destefanis M, et al: Relationship between CA 15-3 serum levels and disease extent in predicting overall survival of breast cancer patients with newly diagnosed metastatic disease. Br J Cancer. 75:698–702. 1997. View Article : Google Scholar : PubMed/NCBI

14 

Morrissey JJ and Raney S: A metastatic breast tumor cell line, GI-101A, is estrogen receptor positive and responsive to estrogen but resistant to tamoxifen. Cell Biol Int. 22:413–419. 1998. View Article : Google Scholar : PubMed/NCBI

15 

Tamilarasan KP, Kolluru GK, Rajaram M, Indhumathy M, Saranya R and Chatterjee S: Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells. BMC Cell Biol. 7:172006. View Article : Google Scholar : PubMed/NCBI

16 

Lamalice L, Le Boeuf F and Huot J: Endothelial cell migration during angiogenesis. Circ Res. 100:782–794. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Budihardjo I, Oliver H, Lutter M, Luo X and Wang X: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 15:269–290. 1999. View Article : Google Scholar : PubMed/NCBI

18 

Jimeno A and Hidalgo M: Pharmacogenomics of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Biochim Biophys Acta. 1766:217–229. 2006.PubMed/NCBI

19 

Kanagasabai T, Alvarez J, Bhalani M, Dhandayuthapani S and Rathinavelu A: The in vivo activity of a novel anti-angiogenic compound, JFD-WS, in human breast adenocarcinoma xenograft implanted athymic nude mice. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18–22; Philadelphia (PA): AACR; Cancer Res. 75 Suppl 15:Abstract nr13802015;

20 

Gotink KJ and Verheul HM: Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action? Angiogenesis. 13:1–14. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Yang F, Brown C, Buettner R, Hedvat M, Starr R, Scuto A, Schroeder A, Jensen M and Jove R: Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther. 9:953–962. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, Fassy F, Reed JC and Kroemer G: The central executioner of apoptosis: Multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med. 186:25–37. 1997. View Article : Google Scholar : PubMed/NCBI

23 

Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssière JL, Petit PX and Kroemer G: Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med. 181:1661–1672. 1995. View Article : Google Scholar : PubMed/NCBI

24 

Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, Haeffner A, Hirsch F, Geuskens M and Kroemer G: Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med. 184:1155–1160. 1996. View Article : Google Scholar : PubMed/NCBI

25 

Kroemer G and Reed JC: Mitochondrial control of cell death. Nat Med. 6:513–519. 2000. View Article : Google Scholar : PubMed/NCBI

26 

Gottlieb TM, Leal JF, Seger R, Taya Y and Oren M: Cross-talk between Akt, p53 and Mdm2: Possible implications for the regulation of apoptosis. Oncogene. 21:1299–1303. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Mukhopadhyay D, Tsiokas L and Sukhatme VP: Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55:6161–6165. 1995.PubMed/NCBI

28 

Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, Fang B, Lee JJ and Roth JA: Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res. 58:2288–2292. 1998.PubMed/NCBI

29 

Fontanini G, Boldrini L, Vignati S, Chinè S, Basolo F, Silvestri V, Lucchi M, Mussi A, Angeletti CA and Bevilacqua G: Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. Eur J Cancer. 34:718–723. 1998. View Article : Google Scholar : PubMed/NCBI

30 

Kumar P, Miller AI and Polverini PJ: p38 MAPK mediates gamma-irradiation-induced endothelial cell apoptosis, and vascular endothelial growth factor protects endothelial cells through the phosphoinositide 3-kinase-Akt-Bcl-2 pathway. J Biol Chem. 279:43352–43360. 2004. View Article : Google Scholar : PubMed/NCBI

31 

Milella M, Estrov Z, Kornblau SM, Carter BZ, Konopleva M, Tari A, Schober WD, Harris D, Leysath CE, Lopez-Berestein G, et al: Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood. 99:3461–3464. 2002. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Rathinavelu A, Kanagasabai T, Dhandayuthapani S and Alhazzani K: Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models. Oncol Rep 39: 1711-1724, 2018.
APA
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., & Alhazzani, K. (2018). Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models. Oncology Reports, 39, 1711-1724. https://doi.org/10.3892/or.2018.6256
MLA
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., Alhazzani, K."Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models". Oncology Reports 39.4 (2018): 1711-1724.
Chicago
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., Alhazzani, K."Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models". Oncology Reports 39, no. 4 (2018): 1711-1724. https://doi.org/10.3892/or.2018.6256
Copy and paste a formatted citation
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Spandidos Publications style
Rathinavelu A, Kanagasabai T, Dhandayuthapani S and Alhazzani K: Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models. Oncol Rep 39: 1711-1724, 2018.
APA
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., & Alhazzani, K. (2018). Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models. Oncology Reports, 39, 1711-1724. https://doi.org/10.3892/or.2018.6256
MLA
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., Alhazzani, K."Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models". Oncology Reports 39.4 (2018): 1711-1724.
Chicago
Rathinavelu, A., Kanagasabai, T., Dhandayuthapani , S., Alhazzani, K."Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models". Oncology Reports 39, no. 4 (2018): 1711-1724. https://doi.org/10.3892/or.2018.6256
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