Skip to main content

Advertisement

SpringerLink
Log in

Novel benzoxazines as inhibitors of angiogenesis

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Dysregulation of angiogenesis has been associated with many pathological disorders, including cancer; where angiogenesis has been found to be critical for the maintenance and metastasis of tumours. One of the pathways involved in the regulation of angiogenesis is the phosphatidylinositol3-kinase (PI3K) signalling pathway. The PI3K family consists of enzymes that phosphorylate the 3-OH of the inositol ring of phosphatidyl inositol. There are four isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, that are signalling intermediaries involved in numerous pathways that sustain and maintain the tumours. In this study, we screened eight novel benzoxazine inhibitors of both PI3K isoforms and the related DNA-PK, for their anti-angiogenic effects. Our findings identified the novel benzoxazine (7, 8 (substituted)-2-morpholino-benz (1,3) oxazine: LTUSI122) to be non-toxic at concentrations up to 5 μM, while exhibiting significant inhibition of various aspects of angiogenesis including endothelial proliferation, migration and tube formation. The molecular mechanisms were examined using an angiogenesis array, revealing inhibition of several proliferative and migratory angiogenic factors, including VEGFR, MMP, IL-8, uPAR and MCP; and stimulation of the endogenous inhibitor, endostatin. We hypothesize that these anti-angiogenic effects are mediated by targeting an important signaling intermediary, PI3Kα, and subsequently its action on vascular endothelial growth factor (VEGF, a key growth factor in the process of angiogenesis). If used in combination with more targeted therapies, LTUSI122 could reduce tumour growth and increase the efficacy of these treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DM (2010) Molecular interactions in cancer cell metastasis. Acta Histochem 112(1):3–25

    Article  CAS  PubMed  Google Scholar 

  2. Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33(4):207–14

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Krock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2(12):1117–33

    Article  PubMed Central  PubMed  Google Scholar 

  4. Chen HH, Zhou HJ, Fang X (2003) Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol Res: Off J Ital Pharmacol Soc 48(3):231–6

    Article  CAS  Google Scholar 

  5. Sieczkiewicz GJ, Hussain M, Kohn EC (2002) Angiogenesis and metastasis. Cancer Treat Res 107:353–81

    CAS  PubMed  Google Scholar 

  6. Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28(11):1779–802

    Article  CAS  PubMed  Google Scholar 

  7. Roskoski R Jr (2007) Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 356(2):323–8

    Article  CAS  PubMed  Google Scholar 

  8. Hyunseung L, Kyung J, Yujeong J, Sungwoo H, Soon-Sun H (2013) HS-173, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, has anti-tumor activity through promoting apoptosis and inhibiting angiogenesis. Cancer Lett 328(1):152–9

    Article  Google Scholar 

  9. Graupera M, Guillermet-Guibert J, Foukas LC, Phng L-K, Cain RJ, Salpekar A et al (2008) Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453(7195):662–6

    Article  CAS  PubMed  Google Scholar 

  10. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  CAS  PubMed  Google Scholar 

  11. Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60(4):222–43

    Article  PubMed Central  PubMed  Google Scholar 

  12. Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Fitzgibbon C, Ihmaid S, Al-Rawi J, Meehan-Andrews T, Bradley C (2013) Chemo-sensitisation of HeLa cells to etoposide by a benzoxazine in the absence of DNA-PK inhibition. Investig New Drugs 31(6):1466–75

    Article  CAS  Google Scholar 

  14. Abcam. Human Angiogenesis Antibody Array-Membrane (23 Target) 2014 Available from: http://www.abcam.com/human-angiogenesis-antibody-array-membrane-23-targets-ab169808.html

  15. Abcam. Human Angiogenesis Antibody Array - Membrane (20 Targets) 2014 Available from: http://www.abcam.com/human-angiogenesis-antibody-array-membrane-20-targets-ab134000.html

  16. Folkman J (2007) Angiogenesis: an organising principle for drug discovery? Nat Rev Drug Discov 6:273–286

    Article  CAS  PubMed  Google Scholar 

  17. Samant RS, Shevde LA (2011) Recent advances in anti-angiogenic therapy of cancer. Oncotarget 2(3):122–134

    PubMed Central  PubMed  Google Scholar 

  18. Xue Y, Li N-L, Yang J-Y, Chen Y, Yang L-L, Liu W-C (2011) Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression. Am J Physiol Heart Circ Physiol 300(6):H2169–H76

    Article  CAS  PubMed  Google Scholar 

  19. Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT et al (2005) Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br J Cancer 93(9):1011–8

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Ihmaid SK, Al-Rawi JMA, Bradley CJ, Angove MJ, Robertson MN (2012) Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines. Eur J Med Chem 57:85–101

    Article  CAS  PubMed  Google Scholar 

  21. Dong Z, Cheng Y, Zhao J, Su L, Zhao B, Zhang Y et al (2010) Discovery of a benzoxazine derivative promoting angiogenesis in vitro and in vivo. J Cell Physiol 223(1):202–8

    CAS  PubMed  Google Scholar 

  22. Mannell H, Hammitzsch A, Mettler R, Pohl U, Krotz F (2010) Suppression of DNA-PKcs enhances FGF-2 dependent human endothelial cell proliferation via negative regulation of Akt. Cell Signal 22(1):88–96

    Article  CAS  PubMed  Google Scholar 

  23. Morrison R, Belz T, Ihmaid S, Al-Rawi JA, Angove M (2014) Dual and/or selective DNA-PK, PI3K inhibition and isoform selectivity of some new and known 2-amino-substituted-1,3-benzoxazines and substituted-1,3-naphthoxazines. Med Chem Res 24:1–12

    Google Scholar 

Download references

Conflict of interests

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. School of Pharmacy and Applied Sciences, La Trobe University, Bendigo, VIC, Australia

    Sara Al-Rawi, Chris Bradley & Jasim Al-Rawi

  2. La Trobe Rural Health School, La Trobe University, Bendigo, VIC, Australia

    Terri Meehan-Andrews

Authors
  1. Sara Al-Rawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terri Meehan-Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chris Bradley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasim Al-Rawi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terri Meehan-Andrews.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Rawi, S., Meehan-Andrews, T., Bradley, C. et al. Novel benzoxazines as inhibitors of angiogenesis. Invest New Drugs 33, 45–52 (2015). https://doi.org/10.1007/s10637-014-0172-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-014-0172-8

Keywords

Search

Navigation